curcumin and Parkinson-Disease

Parkinson's disease is a common progressive neurodegenerative disease, and presently has no curative agent. Curcumin, as one of the natural polyphenols, has great potential in neurodegenerative diseases and other different pathological settings. The brain-derived neurotrophic factor (BDNF) and phosphatidylinositol 3 kinase (PI3k)/protein kinase B (Akt) signaling pathways are significantly involved nerve regeneration and anti-apoptotic activities. Currently, relevant studies have confirmed that curcumin has an optimistic impact on neuroprotection via regulating BDNF and PI3k/Akt signaling pathways in neurodegenerative disease. Here, we summarized the relationship between BDNF and PI3k/Akt signaling pathway, the main biological functions and neuroprotective effects of curcumin via activating BDNF and PI3k/Akt signaling pathways in Parkinson's disease. This paper illustrates that curcumin, as a neuroprotective agent, can delay the progression of Parkinson's disease by protecting nerve cells.

Topics: Brain-Derived Neurotrophic Factor; Curcumin; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Parkinson's disease (PD) is a slowly progressive multisystem disorder affecting dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is characterized by a decrease of dopamine (DA) in their striatal terminals. Treatment of PD with levodopa or DA receptor agonists replaces the function of depleted DA in the striatum. Prolonged treatment with these agents often has variable therapeutic effects and leads to the development of undesirable dyskinesia. Consequently, a crucial unmet demand in the management of Parkinson's disease is the discovery of new approaches that could slow down, stop, or reverse the process of neurodegeneration. Novel potential treatments involving natural substances with neuroprotective activities are being developed. Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric). It has been demonstrated to have potent anti-inflammatory, antioxidant, free radical scavenging, mitochondrial protecting, and iron-chelating effects, and is considered a promising therapeutic and nutraceutical agent for the treatment of PD. However, molecular and cellular mechanisms that mediate the pharmacological actions of curcumin remain largely unknown. Stimulation of nicotinic receptors and, more precisely, selective α7 nicotinic acetylcholine receptors (α7-nAChR), have been found to play a major modulatory role in the immune system via the "cholinergic anti-inflammatory pathway". Recently, α7-nAChR has been proposed to be a potential therapeutic approach in PD. In this review, the detailed mechanisms of the neuroprotective activities of curcumin as a potential therapeutic agent to help Parkinson's patients are being discussed and elaborated on in detail.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Humans; Neuroprotective Agents; Parkinson Disease

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders worldwide. It is caused by the degeneration of dopaminergic neurons from the substantia nigra pars compacta. This neuronal loss causes the dopamine deficiency that leads to a series of functional changes within the basal ganglia, producing motor control abnormalities. L-DOPA is considered the gold standard for PD treatment, and it may alleviate its clinical manifestations for some time. However, its prolonged administration produces tolerance and several severe side effects, including dyskinesias and gastrointestinal disorders. Thus, there is an urgent need to find effective medications, and current trends have proposed some natural products as emerging options for this purpose. Concerning this, curcumin represents a promising bioactive compound with high therapeutic potential. Diverse studies in cellular and animal models have suggested that curcumin could be employed for the treatment of PD. Therefore, the objective of this narrative mini-review is to present an overview of the possible therapeutic effects of curcumin and the subjacent molecular mechanisms. Moreover, we describe several possible nanocarrier-based approaches to improve the bioavailability of curcumin and enhance its biological activity.

Topics: Animals; Biological Availability; Brain; Curcumin; Drug Liberation; Glutathione Peroxidase; Humans; NADPH Oxidases; Nanoparticles; Neuroprotective Agents; Parkinson Disease; Reactive Oxygen Species; Superoxide Dismutase; Treatment Outcome; Up-Regulation

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Clinical Trials as Topic; Creutzfeldt-Jakob Syndrome; Curcumin; Diabetes Mellitus, Type 2; Humans; Huntington Disease; Hypoglycemic Agents; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Protein Aggregates; tau Proteins

A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid β-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved nutrient-based therapeutic interventions and preventative strategies for this debilitating and currently incurable disorder.

Topics: alpha-Synuclein; Brain; Curcumin; Humans; Parkinson Disease; Prions

Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

Topics: alpha-Synuclein; Animals; Autophagy; Brain Chemistry; Curcuma; Dopamine; Dopaminergic Neurons; Feedback, Physiological; Ferroptosis; Homeostasis; Humans; Iron; Melanins; Mice; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Phytotherapy; Protein Aggregation, Pathological; Reactive Oxygen Species; Substantia Nigra

Curcumin, isolated from the rhizome of Curcuma longa, is one of the most extensively studied phytochemicals. This natural compound has a variety of pharmacological effects including antioxidant, anti-inflammatory, anti-tumor, cardio-protective, hepato-protective and anti-diabetic. Wnt signaling pathway, one of the potential targets of curcumin through upregulation and/or downregulation, plays a significant role in many diseases, even in embryogenesis and development of various organs and systems. In order to exert an anti-tumor activity in the organism, curcumin seems to inhibit the Wnt pathway. The downstream mediators of Wnt signaling pathway such as c-Myc and cyclin D1 are also modified by curcumin. This review demonstrates how curcumin influences the Wnt signaling pathway and is beneficial for the treatment of neurological disorders (Alzheimer's and Parkinson's diseases), cancers (melanoma, lung cancer, breast cancer, colon cancer, endothelial carcinoma, gastric carcinoma and hepatocellular carcinoma) and other diseases, such as diabetes mellitus or bone disorders.

Topics: Alzheimer Disease; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcuma; Curcumin; Humans; Neoplasms; Neuroprotective Agents; Parkinson Disease; Wnt Signaling Pathway

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anxiety; Autistic Disorder; Biological Availability; Curcuma; Curcumin; Dementia; Depression; Drug Delivery Systems; Glioma; Humans; Huntington Disease; Multiple Sclerosis; Muscular Atrophy, Spinal; Neuroprotective Agents; Parkinson Disease; Patents as Topic; Prion Diseases; Stroke

Patients with Parkinson's disease (PD) are looking forward to new therapeutic strategies that may gradually decelerate the rate of neurodegenerative decline, associated with mobility restrictions and related morbidity. Its continuous neurodegenerative process, exacerbated by genetic mutations or environmental toxins, involves a progressive reduction in the dopamine neurotransmission levels, synaptic uptake density, oxidative glucose intake, deficient striatal lactate accumulation and chronic inflammation. Over the last decade, novel bioproducts have received considerable interest due to their unique potential of unifying nutritional, safety and therapeutic natural effects. Some nutraceuticals play a crucial role in the control of the signaling transduction pathways in neurotransmission and inflammation affected in PD, and some natural compounds can beneficially interact with each one of these biological mechanisms to slow down disease progression. Atremorine, a novel plant-derived nutraceutical, probably with a neuroprotective effect in the dopaminergic neurons of the substantia nigra (pars compacta), is a prototype of this new category of bioproducts with potential effects in PD. The major focus of this review will be on the current knowledge and biomedical investigation strategies through a plant-derived neuroprotective approach to improve life quality in PD patients, being of paramount importance for health providers, caregivers and the patients themselves.

Topics: Animals; Curcumin; Dopaminergic Neurons; Ginsenosides; Humans; Levodopa; Neuroprotective Agents; Parkinson Disease; Resveratrol; Vicia faba

Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in Southeast Asia, China and India in food preparation and for medicinal purposes. Meanwhile, the neuroprotective actions of curcumin have been documented for experimental therapy in Parkinson's disease (PD).. In this study, we used a systematic review to comprehensively assess the efficacy of curcumin in experimental PD. Using electronic and manual search for the literatures, we identified studies describing the efficacy of curcumin in animal models of PD.. We identified 13 studies with a total of 298 animals describing the efficacy of curcumin in animal models of PD. The methodological quality of all preclinical trials is ranged from 2 to 5. The majority of the experiment studies demonstrated that curcumin was more significantly neuroprotection effective than control groups for treating PD. Among them, five studies indicated that curcumin had an anti-inflammatory effect in the PD animal models (p < 0.05). Meanwhile, four studies showed the antioxidant capability of curcumin, by which it protected substantia nigra neurons and improved striatal dopamine levels. Furthermore, two studies in this review displayed that curcumin treatment was also effective in reducing neuronal apoptosis and improving functional outcome in animal models of PD. Most of the preclinical studies demonstrated the positive findings while one study reported that curcumin had no beneficial effects against Mn-induced disruption of hippocampal metal and neurotransmitter homeostasis.. The results demonstrated a marked efficacy of curcumin in experimental model of PD, suggesting curcumin probably a candidate neuroprotective drug for human PD patients.

Topics: Animals; Brain; Curcuma; Curcumin; Disease Models, Animal; Humans; Neuroprotective Agents; Parkinson Disease; Phytotherapy; Plant Extracts

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.).

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Cardiomyopathies; Cell Differentiation; Coumaric Acids; Curcumin; Diabetes Complications; Humans; Inflammation; Parkinson Disease; Schwann Cells; Skin Diseases

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly. In recent years increasing evidence supports the pharmaceutical potential of curcumin, a polyphenolic compound in the spice turmeric, against PD. Here we briefly summarize the pharmacological activities of curcumin in vitro and in animal models of PD, including counteracting oxidative stress and inflammation, preventing α-synuclein aggregation and fibrillation, and inhibiting monoamine oxidase B, which endow curcumin with multiple pharmaceutical activities against PD and encourage further studies to investigate its clinical effects.

Topics: Animals; Antiparkinson Agents; Curcumin; Humans; Parkinson Disease

Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD.

Topics: Age Factors; Animals; Antiparkinson Agents; Corpus Striatum; Curcuma; Curcumin; Disease Models, Animal; Dopamine; Humans; Neurons; Neuroprotective Agents; Parkinson Disease

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. Thus antioxidants have been studied for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. Increasing number of studies demonstrated the efficacy of polyphenolic antioxidants from fruits and vegetables to reduce or to block neuronal death occurring in the pathophysiology of these disorders. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these phenolic compounds. We will review some of these mechanisms and particular emphasis will be given to polyphenolic compounds from green tea, the Ginkgo biloba extract EGb 761, blueberries extracts, wine components and curcumin.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blueberry Plants; Clinical Trials as Topic; Cognition; Curcumin; Flavonoids; Ginkgo biloba; Humans; Neurodegenerative Diseases; Parkinson Disease; Phenols; Plant Extracts; Polyphenols; Proteasome Endopeptidase Complex; Resveratrol; Signal Transduction; Stilbenes; Tea; Wine

Preclinical studies suggest that curcumin might be a potential neuroprotective agent in Parkinson's disease (PD). This clinical trial aimed to evaluate the efficacy of adding nanomicelle curcumin on improving the motor and non-motor symptoms of PD patients and their quality of life.. Idiopathic PD patients aged ≥30≥ 30 whose symptoms were under control were included in this pilot, randomized, triple-blind, placebo-controlled, add-on trial. Eligible patients were randomly assigned to either the curcumin (n = 30, 80 mg/day) or placebo (n = 30) groups and were followed for nine months. Primary outcomes were the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Parkinson's Disease Questionnaire (PDQ-39). These variables, along with demographic data, drug history, and possible side effects of curcumin, were gathered at the beginning of the study and every three months. A mixed effects model was used to compare the group-by-time interaction, followed by post hoc analysis.. Although the mean MDS-UPDRS and PDQ-39 scores were not significantly different between the curcumin and placebo groups at any time points, MDS-UPDRS part III (P = 0.04) showed a significant difference in its overall trend between the study groups. However, post hoc analysis failed to spot this difference at study time points. The most common side effects of curcumin were nausea and vomiting (P = 0.25) and gastroesophageal reflux (P = 0.42).. While curcumin is a well-tolerated natural compound, this trial was unsuccessful in showing its efficacy in quality of life and clinical symptoms of PD patients.

Topics: Curcumin; Double-Blind Method; Humans; Parkinson Disease; Pilot Projects; Quality of Life; Treatment Outcome

Parkinson disease (PD) is considered as one of the most worldwide neurodegenerative disorders. The major reasons associated to neurodegeneration process of PD pathogenesis are oxidative stress. Many studies reported that natural antioxidant molecules, especially, curcumin can suppress inflammatory pathways and preserve dopaminergic neurons damage in PD. Further, the poor pharmacokinetics, instability of chemical structure because of fast hydrolytic degradation at physiologic condition and especially, the presence of the blood brain barrier (BBB) has regarded as a considerable restriction factor for transfer of neurotherapeutic molecules to the brain tissue. The present research aims to the fabrication of nanoformulated curcumin loaded human endometrial stem cells derived exosomes (hEnSCs EXOs-Cur) to study on enhancing curcumin penetration to the brain across BBB and to improve anti- Parkinsonism effects of curcumin against neural death and alpha-synuclein aggregation. hEnSCs EXOs-Cur characterization results demonstrated the accurate size and morphology of formulated curcumin loaded exosomes with a proper stability and sustained release profile. In vivo studies including behavioral, Immunohistochemical and molecular evaluations displayed that novel formulation of hEnSCs EXO-Cur is able to cross BBB, enhance motor uncoordinated movements, suppress the aggregation of αS protein and rescue neuronal cell death through elevation of BCL2 expression level as an anti-apoptotic protein and the expression level reduction of BAX and Caspase 3 as apoptotic markers.

Topics: alpha-Synuclein; Animals; Curcumin; Disease Models, Animal; Exosomes; Humans; Mice; Parkinson Disease

Curcumin is identified that it has the potential to treat Parkinson's disease (PD), but its instability limits its further application in clinic. The mono-carbonyl analogs of curcumin (MACs) with diketene structure can effectively improve its stability, but it is highly toxic. In the present study, a less cytotoxic and more stable monoketene MACs skeleton S2 was obtained, and a series of monoketene MACs were synthesized by combining 4-hydroxy-3‑methoxy groups of curcumin. In the 6-OHDA-induced PD's model in-vitro, some compounds exhibited significant neurotherapeutic effect. The quantitative structure-activity relationship (QSAR) model established by the random forest algorithm (RF) for the cell viability rate of above compounds showed that the statistical results are good (R

Topics: Animals; Apoptosis; Curcumin; Mice; Neuroprotective Agents; Parkinson Disease; Proto-Oncogene Proteins c-akt; Reproducibility of Results

Young onset Parkinson disease (YOPD) accounts for about 10% of PD patients, with the onset of symptoms between the ages of 21 and 40. At this age, the probability of pregnancy is high and there is a concern that the disease affects the fetuses. Therefore, in the present study, the effects of rotenone-induced PD on female mice as well as their fetuses and curcumin supplementation on the cerebral tissue of both female mice and their resulted fetuses were studied.. The rotenone was injected subcutaneously to induce PD model of female mice. The different concentrations of curcumin were administrated every day i.p. for 3 weeks and the rotarod test was done on day 1 and 19. Cell viability was measured by MTT test and apoptosis and necrosis of cells were evaluate using flow cytometry technique. After primer design, the expressions of bax, bcl-2, miR-211 and circRNA 0001518 genes were measured using RT-PCR technique.. Curcumin administration were improved cerebral cell viability of both female PD mice and resulted fetuses by preventing cell apoptosis and necrosis. bax, miR-211 and circRNA 0001518 were downregulated and bcl-2 overexpressed in cerebral neurons of PD mice and their fetuses.. PD induction in mice affects their fetal brain, and curcumin can partially reduce the negative effects of PD on fetal brain cells by overexpressing bcl-2 and decreasing bax expression genes.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Curcumin; Female; Mice; MicroRNAs; Necrosis; Neuroprotective Agents; Parkinson Disease; Pregnancy; Proto-Oncogene Proteins c-bcl-2; RNA, Circular; Rotenone

Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key target for developing drugs to treat these conditions. The present study aimed to synthesise and discover compounds that inhibit the MAO enzymes and which may be relevant to the treatment of neurological disorders. A series of nine 2H-1,4-benzothiazin-3(4H)-ones were synthesised and evaluated as potential in vitro inhibitors of human MAO-A and MAO-B. The benzothiazinones bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones that have been shown to be highly potent MAO-B inhibitors. The results show that the benzothiazinones inhibit both MAO isoforms but are more potent MAO-B inhibitors. The most potent inhibitors exhibit IC

Topics: Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Structure-Activity Relationship

The treatment of Parkinson's disease (PD) has been hindered by the complex pathologies and multiple membrane barriers during drug delivery. Although exosomes derived from mesenchymal stem cells (MSCs) have great potential for PD, MSC-derived exosomes alone could not fully meet the therapeutic requirements due to their limitation in therapy and delivery. Here, we develop a self-oriented nanocarrier called PR-EXO/PP@Cur that combines therapeutic MSC-derived exosomes with curcumin. PR-EXO/PP@Cur can be self-oriented across the multiple membrane barriers and directly release drugs into the cytoplasm of target cells after intranasal administration. With enhanced accumulation of drugs in the action site, PR-EXO/PP@Cur achieves three-pronged synergistic treatment to deal with the complex pathologies of PD by reducing α-synuclein aggregates, promoting neuron function recovery, and alleviating the neuroinflammation. After treatment with PR-EXO/PP@Cur, the movement and coordination ability of PD model mice are significantly improved. These results show that PR-EXO/PP@Cur has great prospects in treatment of PD or other neurodegenerative diseases.

Topics: Administration, Intranasal; Animals; Curcumin; Exosomes; Mesenchymal Stem Cells; Mice; Parkinson Disease

Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder. The cerebellum plays a role in PD pathogenesis. Curcumin has numerous medicinal uses, mostly attributed to its potent antioxidant properties. This study investigated the potential protective influence of curcumin on the cerebellum of albino rats with rotenone-induced PD.. Forty adult male albino rats were randomized into four treatment groups: vehicle (group I); rotenone 3 mg/kg/day i.p. injection (group II); rotenone 3 mg/kg/day plus curcumin 30 mg/kg/day i.p. injection (group III); and curcumin 30 mg/kg/day i.p. injection (group IV).. Compared to group I, group II exhibited marked degenerative changes in hematoxylin & eosin-stained sections and a reduction in Nissl granules in the Purkinje cells of the cerebellum. In group III, the neurotoxic effects in the cerebellum were reduced. Furthermore, the degenerated Purkinje and GFAP-positive cells increased considerably in group II and were partially reduced in group III versus group II. Compared to group I, rats in group II showed reduced rotarod motor activity, partially restored in group III. Acetylcholine esterase, glutathione, and superoxide dismutase were significantly reduced, and malondialdehyde was significantly increased in group II compared to group I and was partially increased in group III.. Curcumin attenuated neurotoxic effects and degenerative histological changes and alleviated induced oxidative stress in the cerebellar cortex of a PD rat model. Therefore, curcumin dietary supplementation may have neuroprotective effects against the development of cerebellum-related PD symptoms.

Topics: Animals; Cerebellum; Curcumin; Male; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Rats; Rotenone

Curcumin, a polyphenolic compound extracted from curcuma longa, acts as a nontoxic matter with anti-oxidant and anti-inflammatory effects as well as antiproliferative activities. Here, our research aimed to explore the neuroprotective effects of curcumin both in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) in vivo and 6-OHDA-lesioned PC12 cells in vitro. In vitro, 6-OHDA caused a distinct decrease in cell viability of PC12 cells (150 μM). With the incubation of curcumin (1 μM), 6-OHDA-induced apoptosis was suppressed, increasing the autophagy markers (LC3-II/LC3-I, Beclin-1) and inhibiting phosphor-AKT/AKT, phosphor-mTOR/mTOR. In vivo, curcumin (50 mg/kg) reduced the accumulation of a-synuclein and led to higher parkinsonian disability scores in 6-OHDA-lesioned PD rats, contributing to induction of autophagy through inhibiting AKT/mTOR signal pathway. Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.

Topics: Animals; Autophagy; Curcumin; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats

Rotenone is involved in the degeneration of dopaminergic neurons, and curcumin may prevent or effectively slow the progression of Parkinson's disease (PD). Previous research has shown that the naturally occurring phenolic compound curcumin can reduce inflammation and oxidation, making it a potential therapeutic agent for neurodegenerative diseases. The present study involves investigation of rotenone-induced histological changes in the brain area, hippocampus using Nissl staining after 35 day of subcutaneous injection of rotenone in adult male rats. We sought to determine whether curcumin could protect against rotenone-induced dopaminergic neurotoxicity in a rat model by in vivo electrical recording from Substantia nigra pars compacta (SNc). Curcumin treatment significantly improved electrical activity of neurons in the SNc of rotenone-induced PD model rats. The pattern of histological alterations corresponds with electrophysiological manifestations.

Topics: Animals; Curcumin; Dopaminergic Neurons; Male; Parkinson Disease; Pars Compacta; Rats; Rotenone; Substantia Nigra

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients.

Topics: Biopsy; Curcumin; Humans; Parkinson Disease; Skin

Topics: Animals; Curcumin; Drug Carriers; Levodopa; Nanoparticles; Parkinson Disease; Polyesters; Polyethylene Glycols; Polymers; Rats

The major hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra (SN), which is responsible for the core motor symptoms of PD. Currently, there is no cure for PD, and its prevalence is increasing, prompting the search for novel neuroprotective treatments. Neuroinflammation is a core pathological process in PD, evident by increased inflammatory biomarkers in the SN and cerebrospinal fluid. Interestingly, epidemiological studies have reported a reduced risk of PD in users of non-steroidal anti-inflammatory drugs compared to non-users, suggesting the neuroprotective potential of anti-inflammatory drugs. Therefore, this study aimed to: (1) test the efficacy of novel oral formulations of edaravone (EDR) and curcumin (CUR) (which possess anti-inflammatory and anti-oxidative properties) to alleviate motor and non-motor symptoms, and associated pathology in the intrastriatal lipopolysaccharide (LPS) model of PD; (2) investigate the expression of proteins linked to familial PD and markers of autophagy in the intrastriatal LPS model treated with EDR and CUR. Fifty-two C57BL/6 mice were divided into 4 groups, namely; (1) control + vehicle; (2) LPS + vehicle; (3) LPS + EDR (made in vehicle) and (4) LPS + CUR (made in vehicle). 10 μg of LPS was administered stereotaxically into the right striatum, and EDR and CUR treatments were initiated 2-weeks after the LPS injections. Behavioural tests were carried out at 4- and 8-weeks after LPS injection followed by tissue collection at 8-weeks. Intrastriatal administration of LPS induced motor deficits and anxiety-like behaviours at 4- and 8-weeks, which were accompanied by astroglial activation, increased protein expression of α-synuclein, heat shock cognate protein of 70 kDa (HSC-70) and Rab-10, and reduced levels of tyrosine hydroxylase (TH) protein in the striatum. Additionally, LPS induced astroglial activation in the olfactory bulb, along with changes in the protein expression of HSC-70. The changes associated with EDR and CUR in the striatum and olfactory bulb were not statistically significant compared to the LPS group. Intrastriatal administration of LPS induced pathological changes of PD such as motor deficits, reduced expression of TH protein and increased α-synuclein protein, as well as some alterations in proteins linked to familial PD and autophagy in the olfactory bulb and striatum, without pronounced therapeutic effects of EDR and CUR. Our results may suggest tha

Topics: alpha-Synuclein; Animals; Anti-Inflammatory Agents; Curcumin; Disease Models, Animal; Edaravone; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Parkinson Disease

Parkinson's disease (PD) is a common neurodegenerative disorder, accompanied by motor deficits as well as gastrointestinal dysfunctions. Recent studies have proved that the disturbance of gut microbiota and metabolism contributes to the pathogenesis of PD; however, the mechanisms underlying these effects have yet to be elucidated. Curcumin (CUR) has been reported to provide neuroprotective effects on neurological disorders and modulate the gut flora in intestinal-related diseases. Therefore, it is of significant interest to investigate whether CUR could exert a protective effect on PD and whether the effect of CUR is dependent on the intestinal flora and subsequent changes in metabolites.. In this study, we investigated the neuroprotective effects of CUR on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rRNA sequencing was performed to explore the profile of the gut microbiota among controls, MPTP-treated mice and CUR-treated mice. Then, antibiotic treatment (ABX) and fecal microbiota transplantation (FMT) experiments were conducted to examine the role of intestinal microbes on the protective effects of CUR in PD mice. Furthermore, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics analysis was used to identify the landscape of the CUR-driven serum metabolome. Finally, Pearson's analysis was conducted to investigate correlations between the gut flora-metabolite axis and CUR-driven neuroprotection in PD.. Our results showed that CUR intervention effectively improved motor deficits, glial cell activation, and the aggregation of α-synuclein (α-syn) in MPTP-treated mice. 16S rRNA sequencing showed elevated abundances of. CUR exerts a protective effect on the progression of PD by modulating the gut microbiota-metabolite axis.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Creatine; Curcumin; Disease Models, Animal; Gastrointestinal Microbiome; Levodopa; Metabolome; Methionine; Mice; Mice, Inbred C57BL; Neuroinflammatory Diseases; Neuroprotective Agents; Parkinson Disease; RNA, Ribosomal, 16S; Sarcosine

In the rat model, 6-hydroxydopamine (6-OHDA) known as a selective catecholaminergic neurotoxin used chiefly in modeling Parkinson's disease (PD). Continuous aerobic exercise and curcumin supplementations could play a vital role in neuroprotection. This study aimed to explore the neuroprotective roles of regular aerobic exercise and curcumin during PD. For this, rats were treated as follows for 8 consecutive weeks (5 d in a week): For this, animals were orally treated with curcumin (50 ml/kg) alone or in combination with aerobic exercise. Compared with a control group, induction of PD by 6-OHDA increased the amount of alpha-synuclein protein and malondialdehyde levels and decreased the number of substantia nigra neurons, total antioxidant capacity, and glutathione peroxidase activity in brain tissue. All these changes were abolished by the administration of curcumin with aerobic exercise treatments. Activity behavioral tests also confirmed the above-mentioned results by increasing the rod test time and the number of rotations due to apomorphine injection. Histopathology assays mimic the antioxidant activity and behavioral observations. Combined curcumin with aerobic exercise treatments is potentially an effective strategy for modifying the dopaminergic neuron dysfunction in 6-OHDA-induced rats modeling PD via dual inhibiting oxidative stress indices and regulating behavioral tasks.

Topics: alpha-Synuclein; Animals; Antioxidants; Apomorphine; Curcumin; Disease Models, Animal; Glutathione Peroxidase; Malondialdehyde; Neuroprotective Agents; Neurotoxicity Syndromes; Neurotoxins; Oxidopamine; Parkinson Disease; Rats; Substantia Nigra

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Curcumin; Humans; Multiple Sclerosis; Parkinson Disease

Parkinsonism is a neurodegenerative disorder that affects elderly people worldwide.. Curcumin, adenosine A. Rats injected with rotenone showed severe alterations in adenosine A. Curcumin succeeded in attenuating the severe effects of Parkinson's disease in the rat model and can be considered as a potential dietary supplement. Adenosine A

Topics: Adenosine; Aged; Animals; Curcumin; Disease Models, Animal; Dopamine Agonists; Humans; Inflammation Mediators; Mice; Neuroprotective Agents; Parkinson Disease; Parkinsonian Disorders; Rats; Receptor, Adenosine A2A; Rotenone

Reduced glutathione and excess free iron within dopaminergic, substantia nigra neurons in Parkinson's disease (PD) can drive accumulation of toxic hydroxyl radicals resulting in sustained oxidative stress and cellular damage. Factors such as brain penetrance and bioavailability have limited the advancement of potential antioxidant and iron chelator therapies for PD.. This study aimed to develop novel nanocarrier delivery systems for the antioxidant curcumin and/or iron chelator deferoxamine (DFO) to protect against rotenone-induced changes in cell viability and oxidative stress in SH-SY5Y cells.. Nanocarriers of curcumin and/or DFO were prepared using Pluronic F68 (P68) with or without dequilinium (DQA) by modified thin-film hydration. Cell viability was assessed using an MTT assay and oxidative stress was measured using thiobarbituric acid reactive substances and cellular antioxidant activity assays.. All formulations demonstrated high encapsulation efficiency (65-96%) and nanocarrier size was <200 nm. 3-h pretreatment with P68 or P68+DQA nanocarriers containing various concentrations of curcumin and/or DFO significantly protected against rotenone-reduced cell viability. The addition of DFO to curcumin-loaded P68+DQA nanocarriers resulted in increased protection by at least 10%. All nanoformulations significantly protected against rotenone-induced lipid peroxidation (p < 0.0001). The addition of DQA, which targets mitochondria, resulted in up to 65% increase in cellular antioxidant activity. In nearly all preparations, the combination of 10 μM curcumin and 100 μM DFO had the most antioxidant activity.. This study demonstrates for the first time the formulation and delivery using P68 and P68+DQA curcumin and/or DFO nanocarriers to protect against oxidative stress induced by a rotenone PD model. This strategy to combine antioxidants with iron chelators may provide a novel approach to fully utilise their therapeutic benefit for PD.

Topics: Antioxidants; Cell Line, Tumor; Curcumin; Deferoxamine; Humans; Iron Chelating Agents; Lipid Peroxidation; Nanotechnology; Neurotoxicity Syndromes; Oxidative Stress; Parkinson Disease; Rotenone

Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD

Topics: alpha-Synuclein; Animals; Cell Survival; Cells, Cultured; Curcumin; Drug Liberation; Nanostructures; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Particle Size; PC12 Cells; Protein Aggregates; Rats; Surface Properties

Topics: 1-Methyl-4-phenylpyridinium; Active Transport, Cell Nucleus; alpha-Synuclein; Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line, Tumor; Cell Survival; Curcumin; HeLa Cells; Humans; Lysosomes; Neurodegenerative Diseases; Neurons; Parkinson Disease; PC12 Cells; Rats; RNA Interference; Signal Transduction

Extensive research has shown that assembling of α-synuclein amyloid aggregates on mitochondria is an important mechanistic feature of Parkinson's disease (PD) and other Lewy body disorders. However, the molecular mechanism(s) of its neuronal toxicity remain unclear. Type 1 Hexokinase (HKI), a key enzyme in the control of brain glucose metabolism, plays an important role in protecting against mitochondrially-regulated apoptosis through reducing generation of reactive oxygen species (ROS). The release of mitochondrially-bound HKI causes a significant decrease in enzyme activity and triggers oxidative stress. Here, we have investigated the potency of amyloid fibrillation products arising from α-synuclein and hen egg white lysozyme (HEWL) for the release of HKI and ROS content enhancement in mitochondria isolated from rat brain. Results clearly indicate the capacity of the fibrillation products of α-synuclein, and not HEWL, to trigger release of HKI from the Type A binding site of mitochondria for the enzyme and to induce mitochondrial ROS enhancement in a dose-dependent manner. Moreover, we found that curcumin was very effective in preventing mitochondrial HKI release and ROS enhancement induced by α-synuclein fibrillation products. The pathophysiological significance of mitochondrial HKI activity and localization in pathogenesis of neurodegenerative disorders including PD are discussed. Taken together, these results may offer insight into a possible mechanism by which disease-related peptides and proteins may exert their neuronal toxicity.

Topics: alpha-Synuclein; Amyloid; Animals; Apoptosis; Brain; Chickens; Curcumin; Hexokinase; Humans; Mitochondria; Muramidase; Oxidative Stress; Parkinson Disease; Protective Agents; Rats; Reactive Oxygen Species

Common copathogenic factors, including oxidative stress and neuroinflammation, are found to play a vital role in the development of neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Nowadays, owing to the multifactorial character of the diseases, no effective therapies are available, thus underlying the need for new strategies. Overexpression of the enzyme GSK-3β and downregulation of the Nrf2/ARE pathway are responsible for a decrease in antioxidant defense effects. These pieces of evidence underline the usefulness of dual GSK-3β inhibitors/Nrf2 inducers. In this regard, to design a dual modulator, the structures of a curcumin-based analogue, as GSK-3β inhibitor, and a diethyl fumarate fragment, as Nrf2 inducer, were combined. Among the hybrids,

Topics: Animals; Caenorhabditis elegans; Curcumin; Fumarates; Glycogen Synthase Kinase 3 beta; NF-E2-Related Factor 2; Parkinson Disease

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Corpus Striatum; Curcumin; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Rats; Substantia Nigra

Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.

Topics: Animals; Coumarins; Dose-Response Relationship, Drug; Drug Discovery; Humans; Inflammation; Male; Mannich Bases; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Parkinson Disease; Structure-Activity Relationship; Tumor Cells, Cultured

Rotenone, an environmental toxin, is used to induce neurodegeneration in both the cellular and animal model of Parkinson's disease. Demethoxycurcumin (DMC), derivative of curcumin has been reported to have antioxidant and anti-inflammatory characteristics in

Topics: Animals; Apoptosis; Behavior, Animal; Cognitive Dysfunction; Curcumin; Diarylheptanoids; Disease Models, Animal; Male; Neuroprotective Agents; Parkinson Disease; Random Allocation; Rats, Wistar; Rotenone

Parkinson's disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1β, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.

Topics: alpha-Synuclein; Animals; Apoptosis; Apoptosis Regulatory Proteins; Curcumin; Cytokines; Disease Models, Animal; Glutathione; Lipopolysaccharides; Male; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Rats; Rats, Sprague-Dawley; Substantia Nigra

The relationship between oxidative stress and neurodegenerative diseases has been extensively examined, and antioxidants are considered to be a promising approach for decelerating disease progression. Parkinson's disease (PD) is a common neurodegenerative disorder and affects 1% of the population over 60 years of age. A complex combination of genetic and environmental factors contributes to the pathogenesis of PD. However, since the onset mechanisms of PD have not yet been elucidated in detail, difficulties are associated with developing effective treatments. Curcumin has been reported to have neuroprotective properties in PD models induced by neurotoxins or genetic factors such as

Topics: Animals; Behavior, Animal; Curcumin; Drosophila; Drosophila melanogaster; Male; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Ubiquitin Thiolesterase

We aimed to explore the protective role of curcumin (Cur) in a cell model of Parkinson's disease (PD) and its underlying mechanism.. In this study, genes concerned with PD-related keywords were screened within DiGSeE database. The association network between Cur and selected genes was downloaded from STITCH, with the interactions analyzed by STRING. We built a mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+)-induced SH-SY5Y cell model of PD. Cell morphology was observed under an electron microscope. MTT assay was applied to detect cell proliferation rate. Western blot assay was conducted to determine the level of apoptotic markers, including cleaved caspase 3, Bcl-2-associated X protein (Bax) and B-cell lymphoma-extra-large (Bcl-xl). Tyrosine hydroxylase (TH), dopamine transporter (DAT) protein levels and dopamine (DA) concentration were identified as dopaminergic neuron markers and measured by western blotting or Enzyme-linked immunosorbent assay (ELISA).. Cur rescued the toxicity effects of MPP+ on SH-SY5Y cells, by controlling morphological change, promoting cell proliferation and inhibiting apoptosis. Of all PD-related genes, HSP90 played an important role in Cur-gene network. HSP90 protein level was elevated by MPP+, whereas Cur could reverse this effect. Silencing of HSP90 significantly attenuated the curative effect introduced by Cur, while HSP90 overexpression enhanced the impact of Cur on PD.. Cur can effectively inhibit the toxic effect of MPP+ on SH-SY5Y cells and significantly reduce the adverse effects of MPP+ on dopaminergic neurons via up-regulation of HSP90.

Topics: 1-Methyl-4-phenylpyridinium; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Cell Line, Tumor; Cell Proliferation; Curcumin; Dopamine; Dopamine Plasma Membrane Transport Proteins; Gene Regulatory Networks; HSP90 Heat-Shock Proteins; Humans; Models, Biological; Parkinson Disease; RNA Interference; RNA, Small Interfering

To investigate the effect of curcumin on dopamine neurons in Parkinson's disease (PD) and its mechanism.. SH-SY5Y human neuroblastoma cells were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish the PD cell model. The model cells were treated with curcumin and/or autophagy inhibitor 3-MA. After 48 h of drug treatment, the number of surviving dopamine neurons was detected by tyrosine hydroxylase immunofluorescence method. Western blotting was used to detect protein expression of α-Synuclein (α-Syn), transcription factor EB (TFEB) and autophagy-related proteins lysosome-associated membrane protein 2A (LAMP2A) and microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ); RT-PCR was used to detect mRNA expression of α-Syn.. Compared with MPTP model group, curcumin increased the number of surviving dopamine neurons(. Curcumin exerts protective effect on dopamine neurons in PD, which may be associated with enhancing autophagy and promoting the clearance of α-Syn.

Topics: alpha-Synuclein; Animals; Cell Line; Curcumin; Dopaminergic Neurons; Humans; Mice; Mice, Inbred C57BL; Parkinson Disease

Mitochondrial dysfunction and oxidative stress are the main toxic events leading to dopaminergic neuronal death in Parkinson's disease (PD) and identified as vital objective for therapeutic intercession. This study investigated the neuro-protective effects of the demethoxycurcumin (DMC), a derivative of curcumin against rotenone induced neurotoxicity.. SH-SY5Y neuroblastoma cells are divided into four experimental groups: untreated cells, cells incubated with rotenone (100 nM), cells treated with DMC (50 nM) + rotenone (100 nM) and DMC alone treated. 24 h after treatment with rotenone and 28 h after treatment with DMC, cell viability was assessed using the MTT assay, and levels of ROS and MMP, plus expression of apoptotic protein were analysed.. Rotenone induced cell death in SH-SY5Y cells was significantly reduced by DMC pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of DMC. Rotenone treatment significantly increases the levels of ROS, loss of MMP, release of Cyt-c and expression of pro-apoptotic markers and decreases the expression of anti-apoptotic markers.. Even though the results of the present study indicated that the DMC may serve as a potent therapeutic agent particularly for the treatment of neurodegenerative diseases like PD, further pre-clinical and clinical studies are required.

Topics: Cell Death; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Cytochromes c; Diarylheptanoids; Dopaminergic Neurons; Humans; Insecticides; Membrane Potential, Mitochondrial; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidative Stress; Parkinson Disease; Phytotherapy; Plant Extracts; Reactive Oxygen Species; Rotenone

Numerous findings indicate an involvement of heavy metals in the neuropathology of several neurodegenerative disorders, especially Parkinson's disease (PD). Previous studies have demonstrated that Copper (Cu) exhibits a potent neurotoxic effect on dopaminergic neurons and triggers profound neurobehavioral alterations. Curcumin is a major component of Curcuma longa rhizomes and a powerful medicinal plant that exerts many pharmacological effects. However, the neuroprotective action of curcumin on Cu-induced dopaminergic neurotoxicity is yet to be investigated. The aim of the present study was to evaluate the impact of acute Cu-intoxication (10mg/kg B.W. i.p) for 3days on the dopaminergic system and locomotor performance as well as the possible therapeutic efficacy of curcumin I (30mg/kg B.W.). Intoxicated rats showed a significant loss of Tyrosine Hydroxylase (TH) expression within substantia nigra pars compacta (SNc), ventral tegmental area (VTA) and the striatal outputs. This was correlated with a clear decrease in locomotor performance. Critically, curcumin-I co-treatment reversed these changes and showed a noticeable protective effect; both TH expression and locomotor performance was reinstated in intoxicated rats. These results demonstrate altered dopaminergic innervations following Cu intoxication and a new therapeutic potential of curcumin against Cu-induced dopaminergic neurotransmission failure. Curcumin may therefore prevent heavy metal related Parkinsonism.

Topics: Animals; Brain; Copper; Corpus Striatum; Curcumin; Dopaminergic Neurons; Locomotion; Male; Neuroprotective Agents; Parkinson Disease; Pars Compacta; Rats, Wistar; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The study aimed to investigate the protective effect of curcumin against oxidative stress-induced injury of Parkinson's disease (PD) through the Wnt/β-catenin signaling pathway in rats.. The successfully established PD rat models and normal healthy rats were randomly assigned into the 6-hydroxydopamine (6-OHDA), the curcumin (Cur) and the control groups. Immunohistochemistry was used to detect the positive expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and glial fibrillary acidic protein (GFAP). Deutocerebrum primary cells were extracted and classified into the control, 6-OHDA, Cur (5, 10, 15 µmol/L), Dickkopf-1 (DKK-1) and Cur + DKK-1 groups. MTT assays, adhesion tests and TUNEL staining were used to assess cell viability, adhesion and apoptosis, respectively. Western blotting and qRT-PCR were used to examine the protein and mRNA expressions of Wnt3a and β-catenin and the c-myc and cyclinD1 mRNA expressions.. TH and DAT expressions in the Cur group were elevated and GFAP was reduced compared with the 6-OHDA group. Curcumin enhanced viability, survival and adhesion and attenuated apoptosis of deutocerebrum primary cells by activating the Wnt/β-catenin signaling pathway. Higher Wnt3a and β-catenin mRNA and protein expressions and c-myc and cyclinD1 mRNA expressions, enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) contents, decreased malondialdehyde (MDA) content and elevated mitochondrial membrane potential (∆ψm) were found in the 10 and 15 µmol/L Cur groups compared with the 6-OHDA group. However, opposite tendencies were found in the Cur + DKK-1 group compared to the 10 µmol/L Cur group.. This study suggests that curcumin could protect against oxidative stress-induced injury in PD rats via the Wnt/β-catenin signaling pathway.

Topics: Animals; Apoptosis; Astrocytes; Behavior, Animal; beta Catenin; Cell Adhesion; Cells, Cultured; Curcumin; Cyclin D1; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Glial Fibrillary Acidic Protein; Glutathione Peroxidase; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Oxidative Stress; Oxidopamine; Parkinson Disease; Protective Agents; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tyrosine 3-Monooxygenase; Wnt Signaling Pathway; Wnt3 Protein

Development and progression of neurodegenerative diseases like Parkinson's disease (PD) involve multiple pathways. Thus, effective therapeutic treatments should intervene to address all these pathways simultaneously for greater success. Most of the current pharmacotherapeutic approaches just supplement striatal dopamine. Hence, natural extracts of plants with therapeutic potential have been explored. Curcuminoids belong to one such group of polyphenol which show immense therapeutic effects. Here, we have used intracellular reactive oxygen species (ROS) measurement, and two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of cellular autofluorescent co-enzyme reduced nicotinamide adenine dinucleotide (NADH) to study the inhibitory effects of curcumin and cyclocurcumin in alleviating PD like neurotoxicity of 1-methyl-4-phenylpyridinium (MPP

Topics: 1-Methyl-4-phenylpyridinium; Animals; Cell Differentiation; Cell Survival; Curcumin; Microscopy, Fluorescence; NAD; Nerve Growth Factor; Neuroprotective Agents; Neurotoxicity Syndromes; Parkinson Disease; PC12 Cells; Rats; Reactive Oxygen Species

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Mutations in the PINK1 gene result in an autosomal recessive form of early-onset PD. PINK1 plays a vital role in mitochondrial quality control via the removal of dysfunctional mitochondria. The aim of the present study was to create a cellular model of PD using siRNA-mediated knock down of PINK1 in SH-SY5Y neuroblastoma cells The possible protective effects of curcumin, known for its many beneficial properties including antioxidant and anti-inflammatory effects, was tested on this model in the presence and absence of paraquat, an additional stressor. PINK1 siRNA and control cells were separated into four treatment groups: (i) untreated, (ii) treated with paraquat, (iii) pre-treated with curcumin then treated with paraquat, or (iv) treated with curcumin. Various parameters of cellular and mitochondrial function were then measured. The PINK1 siRNA cells exhibited significantly decreased cell viability, mitochondrial membrane potential (MMP), mitochondrial respiration and ATP production, and increased apoptosis. Paraquat-treated cells exhibited decreased cell viability, increased apoptosis, a more fragmented mitochondrial network and decreased MMP. Curcumin pre-treatment followed by paraquat exposure rescued cell viability and increased MMP and mitochondrial respiration in control cells, and significantly decreased apoptosis and increased MMP and maximal respiration in PINK1 siRNA cells. These results highlight a protective effect of curcumin against mitochondrial dysfunction and apoptosis in PINK1-deficient and paraquat-exposed cells. More studies are warranted to further elucidate the potential neuroprotective properties of curcumin.

Topics: Cell Death; Cell Fusion; Cell Line, Tumor; Cell Respiration; Cell Survival; Curcumin; Electron Transport; Gene Knockdown Techniques; Humans; Membrane Potential, Mitochondrial; Mitochondria; Models, Biological; Oxygen Consumption; Paraquat; Parkinson Disease; Protein Kinases; RNA, Small Interfering

Parkinson's disease is characterized by the presence of insoluble and neurotoxic aggregates (amyloid fibrils) of an intrinsically disordered protein α-synuclein. In this study we have examined the effects of four naturally occurring polyphenols in combination with β-cyclodextrin (β-CD) on the aggregation of α-synuclein in the presence of macromolecular crowding agents. Our results reveal that even at sub-stoichiometric concentrations of the individual components, the polyphenol-β-CD combination(s) not only inhibited the aggregation of the proteins but was also effective in disaggregating preformed fibrils. Curcumin was found to be the most efficient, followed by baicalein with (-)-epigallocatechin gallate and resveratrol coming in next, the latter two exhibiting very similar effects. Our results suggest that the efficiency of curcumin results from a balanced composition of the phenolic OH groups, benzene rings and flexibility. The latter ensures proper positioning of the functional groups to maximize the underlying interactions with both the monomeric form of α-synuclein and its aggregates. The uniqueness of β-CD was reinforced by the observation that none of the other cyclodextrin variants [α-CD and HP-β-CD] used was as effective, in spite of these possessing better water solubility. Moreover, the fact that the combinations remained effective under conditions of macromolecular crowding suggests that these have the potential to be developed into viable drug compositions in the near future. MTT assays on cell viability independently confirmed this hypothesis wherein these combinations (and the polyphenols alone too) appreciably impeded the toxicity of the prefibrillar α-synuclein aggregates on the mouse neuroblastoma cell lines (N2a cells).

Topics: alpha-Synuclein; Amyloid; Amyloidogenic Proteins; Animals; beta-Cyclodextrins; Catechin; Cell Line; Cell Survival; Circular Dichroism; Curcumin; Humans; Mice; Parkinson Disease; Polyphenols; Protein Aggregation, Pathological

Seventy-five compounds, including 21 new compounds (1-21), were isolated from the root bark of Cudrania tricuspidata. The structures of the isolated compounds were elucidated by interpretation of their spectroscopic data. All isolated compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cell death, and nine compounds had activities with EC50 values of 1.9-30.2 μM. The 75 isolated compounds along with 34 previously reported xanthones were tested also for neuroprotective effects against the 1-methyl-4-phenylpyridinium ion (MPP(+)) and oxygen glucose deprivation (OGD)-induced cell death. Three compounds were active against MPP(+)-induced cell death with EC50 values of 0.2-10.3 μM, and 23 compounds were active in the OGD model with EC50 values of 2.9-35.5 μM.

Topics: Animals; Cell Death; Disease Models, Animal; Glucose; Ischemia; Moraceae; Neuroprotective Agents; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Plant Bark; Plant Roots; Republic of Korea; Xanthones

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Lewy bodies that are formed by the aggregated α-synuclein are a major pathological feature of PD. Salvia miltiorrhiza has been used as food and as a traditional medicine for centuries in China, with tanshinone I (TAN I) and tanshinone IIA (TAN IIA) as its major bioactive ingredients. Here, we investigated the effects of TAN I and TAN IIA on α-synuclein aggregation both in vitro and in a transgenic Caenorhabditis elegans PD model (NL5901). We demonstrated that TAN I and TAN IIA inhibited the aggregation of α-synuclein as demonstrated by the prolonged lag time and the reduced thioflavin-T fluorescence intensity; TAN I and TAN IIA also disaggregated preformed mature fibrils in vitro. Moreover, the presence of TAN I or TAN IIA affected the secondary structural transformation of α-synuclein from unstructured coils to β-sheets, and alleviated the membrane disruption caused by aggregated α-synuclein in vitro. Besides, the immuno-dot-blot assay indicated that TAN I and TAN IIA reduce the formation of oligomers and fibrils. We further found that TAN I and TAN IIA extended the life span of NL5901, a strain of transgenic C. elegans that expresses human α-synuclein, possibly by attenuating the aggregation of α-synuclein. Taken together, our results suggested that TAN I and TAN IIA may be explored further as potential candidates for the prevention and treatment of PD.

Topics: Abietanes; alpha-Synuclein; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Curcumin; Escherichia coli; Humans; Molecular Structure; Parkinson Disease; Protein Folding

Neurological diseases such as Alzheimer's and Parkinson's diseases are incurable progressive neurological disorders caused by the degeneration of neuronal cells and characterized by motor and non-motor symptoms. Curcumin, a turmeric product, is an anti-inflammatory agent and an effective reactive oxygen and nitrogen species scavenging molecule. Hydrogen peroxide (H2O2) is the main source of oxidative stress, which is claimed to be the major source of neurological disorders. Hence, in this study we aimed to investigate the effect of curcumin on Ca(2+) signaling, oxidative stress parameters, mitochondrial depolarization levels and caspase-3 and -9 activities that are induced by the H2O2 model of oxidative stress in SH-SY5Y neuronal cells. SH-SY5Y neuronal cells were divided into four groups namely, the control, curcumin, H2O2, and curcumin + H2O2 groups. The dose and duration of curcumin and H2O2 were determined from published data. The cells in the curcumin, H2O2, and curcumin + H2O2 groups were incubated for 24 h with 5 µM curcumin and 100 µM H2O2. Lipid peroxidation and cytosolic free Ca(2+) concentrations were higher in the H2O2 group than in the control group; however, their levels were lower in the curcumin and curcumin + H2O2 groups than in the H2O2 group alone. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values were lower in the H2O2 group although they were higher in the curcumin and curcumin + H2O2 groups than in the H2O2 group. Caspase-3 activity was lower in the curcumin group than in the H2O2 group. In conclusion, curcumin strongly induced modulator effects on oxidative stress, intracellular Ca(2+) levels, and the caspase-3 and -9 values in an experimental oxidative stress model in SH-SY5Y cells.

Topics: Alzheimer Disease; Apoptosis; Calcium; Caspase 3; Cell Polarity; Cell Survival; Curcumin; Humans; Hydrogen Peroxide; Mitochondria; Neurons; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Supranuclear Palsy, Progressive

Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects ≤ 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)-injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and. quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2-related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2-specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.

Topics: Animals; Antioxidants; Chromones; Curcumin; Dopaminergic Neurons; Glutathione; HEK293 Cells; Humans; Male; Malondialdehyde; Morpholines; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Parkinson Disease; Proto-Oncogene Proteins c-akt; Rats, Inbred Lew; Reactive Oxygen Species; RNA, Small Interfering; Rotenone

The purpose of this study is to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) activated by curcumin (CUR) on PC12 cells induced by 1-methyl-4-phenylpyridinium ion (MPP+), a cell model of Parkinson's disease (PD). The supernatant of hUC-MSC and hUC-MSC activated by 5 µmol/L CUR (hUC-MSC-CUR) were collected in accordance with the same concentration. The cell proliferation and differentiation potential to dopaminergic neuronal cells and antioxidation were observed in PC12 cells after being treated with the above two supernatants and 5 µmol/L CUR. The results showed that the hUC-MSC-CUR could more obviously promote the proliferation and the expression of tyrosine hydroxylase (TH) and microtubule associated protein-2 (MAP2) and significantly decreased the expression of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in PC12 cells. Furtherly, cytokines detection gave a clue that the expression of IL-6, IL-10, and NGF was significantly higher in the group treated with the hUC-MSC-CUR compared to those of other two groups. Therefore, the hUC-MSC-CUR may be a potential strategy to promote the proliferation and differentiation of PD cell model, therefore providing new insights into a novel therapeutic approach in PD.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; Caspases; Cell Differentiation; Cell Proliferation; Cell Separation; Curcumin; Cytokines; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Models, Biological; Neurons; Nitric Oxide; Nitric Oxide Synthase Type II; Parkinson Disease; PC12 Cells; Proto-Oncogene Proteins c-bcl-2; Rats; Tyrosine 3-Monooxygenase; Umbilical Cord

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Caspase 3; Caspase Inhibitors; Cinnamates; Curcumin; Depsides; Humans; Huntington Disease; Ligands; Molecular Docking Simulation; Neurodegenerative Diseases; Parkinson Disease; Rosmarinic Acid

To investigate the effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels (mitoKATP) induced by overexpression or mutation of α-synuclein.. Recombinant plasmids α-synuclein-pEGFP-A53T and α-synuclein-pEGFP-WT were transfected into PC12 cells by lipofectamin method, and intervened by application of curcumin (20 μmol/L) and 5-hydroxydecanoate (5-HD). Oligomer formation in the cultured cells was identified by Western blotting and Dot blotting. Cytotoxicity and apoptosis of the PC12 cells were measured by lactate dehydrogenase (LDH) and JC-1 assays. mitoKATP were identified by Western blotting and whole cell patch clamp.. Curcumin has significantly reduced the oligomer formation induced by overexpression or mutation of α-synuclein in the cultured cells. LDH has decreased by 36.3% and 23.5%, and red/green fluorescence ratio of JC-1 was increased respectively by 48.46% and 50.33% after application of curcumin (P<0.05). Protein expression of Kir6.2 has decreased and mitoKATP channel current has significantly increased (P<0.05).. Curcumin can inhibit α-synuclein gene overexpression or mutation induced α-synuclein oligomers formation. It may block apoptosis induced by wild-type overexpression or mutation of α-synuclein. By stabilizing mitochondrial membrane potential. Opening of mitoKATP channel may have been the initiating protective mechanism of apoptosis induced by wild-type overexpression or mutation of α-synuclein. Curcumin may antagonize above cytotoxicity through further opening the mitoKATP channel.

Topics: alpha-Synuclein; Animals; Apoptosis; Cell Line; Curcumin; Humans; KATP Channels; Mitochondria; Mutation; Parkinson Disease; PC12 Cells; Rats

Parkinson's disease (PD) is the second most common neurodegenerative disease, with the prevalence increasing as the population ages. Many mechanisms have been implicated in the pathogenesis of PD including oxidative stress, mitochondrial dysfunction, protein aggregation, and inflammation. Current treatment strategies focus on symptomatic improvement. However, therapies to modify disease progression are lacking. A whole food, plant-based diet contains many compounds that fight oxidative stress and inflammation. Evidence from animal models show that various phytochemicals may alter the mechanisms contributing to PD pathophysiology. Epidemiological studies show a relationship between reduced risk of PD and diet. We hypothesize that phytochemicals in plant-based foods may contribute to neuroprotection in PD and that adopting a plant-based diet may provide symptomatic improvement and alter disease progression in PD.

Topics: Animals; Antioxidants; Curcumin; Diet; Ergothioneine; Fragaria; Humans; Inflammation; Isothiocyanates; Mitochondria; Nervous System; Neurons; Oxidative Stress; Parkinson Disease; Phytochemicals; Plants; Quercetin; Sulfoxides

A time dependent loss of dopaminergic neurons and the formation of intracellular aggregates of alpha synuclein have been reported in PD model flies.. The progeny (PD flies) expressing human alpha synuclein was exposed to 25, 50, and 100 µM of curcumin mixed in the diet for 24 days. The effect of curcumin was studied on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of PD model flies. The activity of PD model flies was monitored by using Drosophila activity monitors (DAMs). For the estimation of oxidative stress, lipid peroxidation and protein carbonyl content were estimated in the flies brains of each treated groups. The cell death in Drosophila brain was analyzed by isolating brains in Ringer's solution placing them in 70% ethanol and stained in acridine orange to calculate the gray scale values.. The exposure of flies to 25, 50, and 100 µM of curcumin showed a dose dependent significant delay in the loss of activity pattern, reduction in the oxidative stress and apoptosis, and increase in the life span of PD model flies.. Curcumin is potent in reducing PD symptoms.

Topics: Animals; Animals, Genetically Modified; Apoptosis; Behavior, Animal; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Drosophila melanogaster; Humans; Longevity; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Survival; Treatment Outcome

The catecholaminergic neurotoxin 6-hydroxydopamine has been widely used to mimic the lesions in dopaminergic neurons to develop Parkinson's disease. The present study was aimed to evaluate the combined treatment with Curcumin and desferrioxamine (DFO) on 6-OHDA-induced neurotoxicity in the striatum of rats. Rat models with 6-OHDA-induced Parkinson's disease were treated with curcumin, DFO, or both and the effect of different treatments on dopamine level was examined. Moreover, the effect of different treatments on the levels of PCC, SOD, and GSH was also assessed to elucidate the underlying mechanisms of the neuroprotective effects of combined treatment of curcumin and DFO.

Topics: Animals; Brain; Curcumin; Deferoxamine; Disease Models, Animal; Dopamine; Drug Interactions; Male; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley

Parkinson's disease (PD) is characterized by the progressive degeneration via apoptosis of nigrostriatal dopaminergic neurons associated with inflammation, resulting in behavioral anomalies. Therefore, an anti-apoptotic and anti-inflammatory regimen may be useful in treatment of PD. CNB-001, a novel pyrazole derivative of curcumin and cyclohexyl bisphenol A has superior biological properties than its parental compounds. The present study utilizes a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate anti-inflammatory and anti-apoptotic mediated neuroprotection of CNB-001. The administration of MPTP (30 mg/kg for four successive days) significantly induced motor impairments as determined by behavioral studies (narrow beam test, catalepsy and akinesia), lowered dopamine levels and up-regulated the expressions of the inflammatory and apoptotic markers (tumor necrosis factor-alpha, interleukin-1β, interleukin-6, inducible nitric oxide synthase, glial fibrillary acidic protein, cyclooxygenase-2 and Bax). Moreover, MPTP treatment attenuated Bcl-2 and nigrostriatal dopamine transporter expression and also increased total nitrite and citrulline levels in comparison to the control group. However, co-treatment with CNB-001 significantly attenuated motor impairments and pathological changes caused by MPTP administration. Collectively, our results demonstrate that CNB-001 is neuroprotective through its anti-inflammatory and anti-apoptotic properties. Thus, CNB-001 has potential to be further developed as a therapeutic candidate for treatment of PD.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Curcumin; Disease Models, Animal; Dopaminergic Neurons; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Motor Activity; Parkinson Disease; Pyrazoles

Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson's disease (PD) pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days) exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH), dopamine transporter, and vesicular monoamine transporter 2 (VMAT2) expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg) not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD.

Topics: Animals; Brain; Curcumin; Dopaminergic Neurons; Glutathione Peroxidase; Humans; Mice; MPTP Poisoning; Neuroprotective Agents; Parkinson Disease; Pyrazoles

Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD. Analysis of different developmental stages in model organisms revealed that they are characterized by different patterns of gene expression which is similar to that of developmental stages of human. Genotropic drugs would be effective only during those life cycle stages for which their target molecules are available. Hence there exists a possibility that targets of genotropic compounds such as curcumin may not be present in all life stages. However, no reports are available in PD models illustrating the efficacy of curcumin in later phases of adult life. This is important because this is the period during which late-onset disorders such as idiopathic PD set in. To understand this paradigm, we tested the protective efficacy of curcumin in different growth stages (early, late health stage, and transition phase) in adult Drosophila flies. Results showed that it can rescue the motor defects during early stages of life but is ineffective at later phases. This observation was substantiated with the finding that curcumin treatment could replenish depleted brain dopamine levels in the PD model only during early stages of life cycle, clearly suggesting its limitation as a therapeutic agent in late-onset neurodegenerative disorders such as PD.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Curcumin; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drosophila melanogaster; Drug Resistance; Humans; Longevity; Movement; Neuroprotective Agents; Paraquat; Parkinson Disease; Time Factors; Treatment Outcome

In human beings, Parkinson's disease (PD) is associated with the oligomerization and amyloid formation of α-synuclein (α-Syn). The polyphenolic Asian food ingredient curcumin has proven to be effective against a wide range of human diseases including cancers and neurological disorders. While curcumin has been shown to significantly reduce cell toxicity of α-Syn aggregates, its mechanism of action remains unexplored. Here, using a series of biophysical techniques, we demonstrate that curcumin reduces toxicity by binding to preformed oligomers and fibrils and altering their hydrophobic surface exposure. Further, our fluorescence and two-dimensional nuclear magnetic resonance (2D-NMR) data indicate that curcumin does not bind to monomeric α-Syn but binds specifically to oligomeric intermediates. The degree of curcumin binding correlates with the extent of α-Syn oligomerization, suggesting that the ordered structure of protein is required for effective curcumin binding. The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn. Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases.

Topics: alpha-Synuclein; Cell Line, Tumor; Curcumin; Humans; Parkinson Disease; Protein Binding

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.

Topics: Adrenal Gland Neoplasms; alpha-Synuclein; Alzheimer Disease; Animals; Antioxidants; Cell Line, Tumor; Curcumin; Cytoprotection; Guaiacol; Parkinson Disease; Pheochromocytoma; Rats; Styrenes

Inflammation and oxidative stress are believed to contribute to neuronal degeneration of the nigrostriatal dopaminergic (DA) pathway in Parkinson's disease. Curcumin, a component of the yellow curry spice, has been reported possessing anti-inflammatory and anti-oxidative effects.. The present study investigated the effects of curcumin on the extent of DA innervation, glial response, and Cu/Zn superoxide dismutase (SOD1) expression in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned mice.. 6-OHDA was unilaterally injected into the right striatum of ICR male mice. Curcumin (200 mg/kg) was administered daily for 7 days starting instantaneously after 6-OHDA injection. Seven days after 6-OHDA insult, mice were euthanized and striatal sections were collected, immunohistochemically stained, and quantitated for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (Iba1), and SOD1 immunoreactivity.. 6-OHDA injection triggered a significant loss of TH-immunoreactive (-IR) axons, induced reaction of GFAP-IR astrocytes and Iba1-IR microglia, and decreased SOD1 expression in the 6-OHDA-lesioned striatum. Curcumin attenuated loss of TH-IR fibers, diminished activation of astrocytes and microglia, and sustained SOD1 level in the lesioned striatum.. These results suggest that curcumin counteracts the neurotoxicity of 6-OHDA through its anti-inflammatory properties (inhibition of glial response) and preservation of SOD1 expression.

Topics: Animals; Anti-Inflammatory Agents; Corpus Striatum; Curcumin; Male; Mice; Mice, Inbred ICR; Neuroglia; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Superoxide Dismutase; Superoxide Dismutase-1; Tyrosine 3-Monooxygenase

Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson's disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain.. In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem.. We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025).. We demonstrated for the first time Lipocurc™'s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

Topics: Animals; Animals, Genetically Modified; Apoptosis; Curcumin; Disease Models, Animal; Dopaminergic Neurons; Exploratory Behavior; Gene Knockout Techniques; Histone Deacetylase Inhibitors; Histone Deacetylases; Nootropic Agents; Parkinson Disease; Psychomotor Disorders; Random Allocation; Rats

Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein positive intracytoplasmic inclusions. The missense mutation, A53T α-synuclein is closely related to hereditary, early-onset PD. Accumulating evidences suggest that pathological accumulation of A53T α-synuclein protein will perturb itself to be efficiently and normally degraded through its usual degradation pathway, macroautophagy-lysosome pathway, therefore toxic effects on the neuron will be exacerbated. Based on the above fact, we demonstrated in this study that A53T α-synuclein overexpression impairs macroautophagy in SH-SY5Y cells and upregulates mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling, the classical suppressive pathway of autophagy. We further found that curcumin, a natural compound derived from the curry spice turmeric and with low toxicity in normal cells, could efficiently reduce the accumulation of A53T α-synuclein through downregulation of the mTOR/p70S6K signaling and recovery of macroautophagy which was suppressed. These findings suggested that the regulation of mTOR/p70S6K signaling may be a participant of the accumulation of A53T α-synuclein protein-linked Parkinsonism. Meanwhile curcumin could be a candidate neuroprotective agent by inducing macroautophagy, and needs to be further investigated by clinical application in patients suffering Parkinson's disease.

Topics: Adenine; alpha-Synuclein; Autophagy; Blotting, Western; Cell Line; Cell Survival; Curcumin; Genetic Vectors; Humans; Immunohistochemistry; Macrophages; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases; Transfection

α-Synuclein aggregation is centrally implicated in Parkinson's disease (PD). It involves multi-step nucleated polymerization process via the formation of dimers, soluble toxic oligomers and insoluble fibrils. In the present study, we synthesized a novel compound viz., Curcumin-glucoside (Curc-gluc), a modified form of curcumin and studied its anti-aggregating potential with α-synuclein. Under aggregating conditions in vitro, Curc-gluc prevents oligomer formation as well as inhibits fibril formation indicating favorable stoichiometry for inhibition. The binding efficacies of Curc-gluc to both α-synuclein monomeric and oligomeric forms were characterized by micro-calorimetry. It was observed that titration of Curc-gluc with α-synuclein monomer yielded very low heat values with low binding while, in case of oligomers, Curc-gluc showed significant binding. Addition of Curc-gluc inhibited aggregation in a dosedependent manner and enhanced α-synuclein solubility, which propose that Curc-gluc solubilizes the oligomeric form by disintegrating preformed fibrils and this is a novel observation. Overall, the data suggest that Curc-gluc binds to α-synuclein oligomeric form and prevents further fibrillization of α-synuclein; this might aid the development of disease modifying agents in preventing or treating PD.

Topics: alpha-Synuclein; Calorimetry; Curcumin; Dose-Response Relationship, Drug; Drug Design; Glucosides; Parkinson Disease; Protein Binding; Protein Multimerization; Solubility

Oxidative/nitrosative stress plays a crucial role in Parkinson's disease (PD) by triggering mitochondrial dysfunction. Nitrosative stress is mediated by reactive species such as peroxynitrite (PN) which could damage biomolecules thereby impinging on the cellular machinery. We observed that PN (0-1000 μM) inhibited brain mitochondrial complex I (CI) activity in a dose-dependent manner with concomitant tyrosine nitration of proteins. We also observed that exposure to PN at low concentrations (62.5-125 μM) significantly decreased the mitochondrial membrane potential and affected the mitochondrial integrity at higher doses (500-750 μM) as indicated by the mitochondrial swelling experiment. Therefore, it could be surmised that compounds that prevent such mitochondrial damage might have therapeutic value in neurological conditions such as PD. We previously showed that curcumin could detoxify PN and protect against CI inhibition and protein nitration. However, the therapeutic potential of curcumin is constrained by limited bioavailability. To address this issue and obtain improved antioxidants, three bioconjugates of curcumin (Di-demethylenated piperoyl, di-valinoyl and di-glutamoyl esters) were generated and tested against PN-mediated nitrosative stress and mitochondrial damage. We found that among the bioconjugates, the glutamoyl diester of curcumin showed improved protection against PN-dependent CI inhibition and protein nitration compared to other conjugates. Di-glutamoyl curcumin protected dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated neuronal death. These effects were improved compared to curcumin alone suggesting that di-glutamoyl curcumin could be a better neuroprotective agent in neurodegenerative diseases such as PD.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Brain; Curcumin; Diet; Electron Transport Complex I; Esters; Flavonoids; Glutamates; Mice; Mitochondria; Mitochondrial Proteins; Mitochondrial Swelling; Parkinson Disease; Peroxynitrous Acid; Phenols; Polyphenols; Protective Agents; Tyrosine

Nitrosative stress has recently been demonstrated as a causal in a select sporadic variant of Parkinson's (PD) and Alzheimer's (AD) diseases. Specifically, elevated levels of NO disrupt the redox activity of protein-disulfide isomerase, a key endoplasmic reticulum-resident chaperone by S-nitroso modification of its redox-active cysteines. This leads to accumulation of misfolded AD- and PD-specific protein debris. We have recently demonstrated in vitro that polyphenolic phytochemicals, curcumin and masoprocol, can rescue S-nitroso-PDI formation by scavenging NOx. In this study, using dopaminergic SHSY-5Y cells, we have monitored the aggregation of green-fluorescent protein (GFP)-tagged synphilin-1 (a known constituent of PD Lewy neurites) as a function of rotenone-induced nitrosative stress. Importantly, we demonstrate a marked decrease in synphilin-1 aggregation when the cell line is previously incubated with 3,5-bis(2-flurobenzylidene) piperidin-4-one (EF-24), a curcumin analogue, prior to rotenone insult. Furthermore, our data also reveal that rotenone attenuates PDI expression in the same cell line, a phenomenon that can be mitigated through EF-24 intervention. Together, these results suggest that EF-24 can exert neuroprotective effects by ameliorating nitrosative stress-linked damage to PDI and the associated onset of PD and AD. Essentially, EF-24 can serve as a scaffold for the design and development of PD and AD specific prophylactics.

Topics: Benzylidene Compounds; Carrier Proteins; Cell Line, Tumor; Curcumin; Flavonoids; Free Radical Scavengers; Green Fluorescent Proteins; Humans; Lewy Bodies; Nerve Tissue Proteins; Nitric Oxide; Parkinson Disease; Phenols; Piperidones; Polyphenols; Reactive Oxygen Species; Stress, Physiological

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Evidence from human and animal studies has suggested that oxidative damage critically contributes to neuronal loss in PD. Here we test whether curcumin, a potent antioxidant compound, derived from the curry spice turmeric, can protect against mutant A53T α-synuclein-induced cell death. We used PC12 cells that inducibly express A53T α-synuclein. We found that curcumin protected against A53T α-synuclein-induced cell death in a dose-dependent manner. We further found that curcumin can reduce mutant α- synuclein-induced intracellular reactive oxygen species (ROS) levels, mitochondrial depolarization, cytochrome c release, and caspase-9 and caspase-3 activation. This study demonstrate that curcumin protected against A53T mutant α-synuclein-induced cell death via inhibition of oxidative stress and the mitochondrial cell death pathway, suggesting that curcumin may be a candidate neuroprotective agent for A53T α-synuclein-linked Parkinsonism, and possibly for other genetic or sporadic forms of PD.

Topics: alpha-Synuclein; Animals; Antioxidants; Caspase 3; Caspase 9; Cell Death; Curcuma; Curcumin; Cytochromes c; Humans; Mitochondria; Mutation; Neuroprotective Agents; Parkinson Disease; PC12 Cells; Rats; Reactive Oxygen Species

Multiple pathways including oxidative stress and mitochondrial damage are implicated in neurodegeneration during Parkinson's disease (PD). The current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Therefore, there is a demand for novel compound(s)/products that could target multiple pathways and protect the dying midbrain dopaminergic neurons, with potential utility as adjunctive therapy along with conventional drugs. Turmeric is a spice used in traditional Indian cuisine and medicine with antioxidant, anti-inflammatory and potential neuroprotective properties. To explore the neuroprotective property of turmeric in PD, mice were subjected to dietary supplementation with aqueous suspensions of turmeric for 3 months, mimicking its chronic consumption and challenged in vivo with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Brain samples from untreated and treated groups were characterised based on mitochondrial complex I (CI) activity, protein nitration and tyrosine hydroxylase immunoreactivity. Chronic turmeric supplementation induced the enzyme activity of γ-glutamyl cysteine ligase, which in turn increased glutathione levels and protected against peroxynitrite-mediated inhibition of brain CI. These mice were also protected against MPTP-mediated protein nitration, CI inhibition and degeneration of substantia nigra neurons in the brain. We conclude that chronic dietary consumption of turmeric protects the brain against neurotoxic insults, with potential application in neurodegeneration. Further characterisation of the active constituents of turmeric that potentially promote neuroprotection could improve the utility of dietary turmeric in brain function and disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Curcuma; Diet; Dietary Supplements; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Parkinson Disease; Substantia Nigra

Turmeric (curry powder), an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound known as curcumin or diferuloylmethane. Curcumin is a widely studied phytochemical with a variety of biological activities. In addition to its anti-inflammatory and antimicrobial/antiviral properties, curcumin is considered as a cancer chemopreventive agent as well as a modulator of gene expression and a potent antioxidant. Since oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD), curcumin has been proposed to have potential therapeutic value for the treatment of neurodegenerative diseases such as PD. Following age, a family history of PD is the most commonly reported risk factor, suggesting a genetic component of the disease in a subgroup of patients. The LRRK2 gene has emerged as the gene most commonly associated with both familial and sporadic PD. Here, we report that exposure of rat mesencephalic cells to curcumin induces the expression of LRRK2 mRNA and protein in a time-dependent manner. The expression of other PD-related genes, such alpha-synuclein and parkin, was not affected by exposure to curcumin, and PTEN-induced putative kinase 1 (PINK1) was not expressed in rat mesencephalic cells. As LRRK2 overexpression is strongly associated with the pathological inclusions found in several neurodegenerative disorders, further studies are needed to evaluate the effects of curcumin as a therapeutic agent for neurodegenerative diseases.

Topics: alpha-Synuclein; Animals; Cell Line; Curcumin; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mesencephalon; Parkinson Disease; Protein Kinases; Protein Serine-Threonine Kinases; Rats; RNA, Messenger; Time Factors; Ubiquitin-Protein Ligases

Advances in understanding the neurodegenerative pathologies are creating new opportunities for the development of neuroprotective therapies, such as antioxidant food factors, lifestyle modification and drugs. However, the biomarker by which the effect of the agent on neurodegeneration is determined is limited. We here address hexanoyl dopamine (HED), one of novel dopamine adducts derived from brain polyunsaturated acid, referring to its in vitro formation, potent toxicity to SH-SY5Y cells, and application to assess the neuroprotective effect of antioxidative food factors. Dopamine is a neurotransmitter, and its deficiency is a characterized feature in Parkinson's disease (PD); thus, HED provides a new insight into the understanding of dopamine biology and pathophysiology of PD and a novel biomarker for the assessment of neuroprotective therapies. We have established an analytical system for the detection of HED and its toxicity to the neuroblstoma cell line, SH-SY5Y cells. Here, we discuss the characteristics of the system and its applications to investigate the neuroprotective effect of several antioxidants that originate from food.

Topics: Antioxidants; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Curcumin; Dioxoles; Dopamine; Humans; Lignans; Neuroblastoma; Parkinson Disease; Tandem Mass Spectrometry; Tocopherols; Tocotrienols; Xanthophylls

Oxidative stress is implicated in mitochondrial dysfunction associated with neurodegeneration in Parkinson's disease (PD). Depletion of the cellular antioxidant glutathione (GSH) resulting in oxidative stress is considered as an early event in neurodegeneration. We previously showed that curcumin, a dietary polyphenol from turmeric induced GSH synthesis in experimental models and protected against oxidative stress. Here we tested the effect of three bioconjugates of curcumin (involving diesters of demethylenated piperic acid, valine and glutamic acid) against GSH depletion mediated oxidative stress in dopaminergic neuronal cells and found that the glutamic acid derivative displayed improved neuroprotection compared to curcumin.

Topics: Antioxidants; Biological Availability; Cell Line; Curcumin; Dopamine; Glutathione; Glutathione Transferase; Humans; Hydrogen Peroxide; Indicators and Reagents; Lipid Peroxidation; Models, Molecular; Neurons; Neuroprotective Agents; Oxidants; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species

Overexpression and abnormal accumulation of aggregated alpha-synuclein (alphaS) have been linked to Parkinson's disease (PD) and other synucleinopathies. alphaS can misfold and adopt a variety of morphologies but recent studies implicate oligomeric forms as the most cytotoxic species. Both genetic mutations and chronic exposure to neurotoxins increase alphaS aggregation and intracellular reactive oxygen species (ROS), leading to mitochondrial dysfunction and oxidative damage in PD cell models.. Here we show that curcumin can alleviate alphaS-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary.. Since curcumin is a natural food pigment that can cross the blood brain barrier and has widespread medicinal uses, it has potential therapeutic value for treating PD and other neurodegenerative disorders.

Topics: alpha-Synuclein; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Models, Biological; Neurons; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Substantia Nigra

Advances in understanding the neurodegenerative pathologies are creating new opportunities for the development of neuroprotective therapies, such as antioxidant food factors, lifestyle modification, and drugs. However, the biomarker by which to determine the effect of the agent on neurodegeneration is limited. We here address hexanoyl dopamine (HED), one of novel dopamine adducts derived from brain polyunsaturated acid, referring to its in vitro formation, potent toxicity to SH-SY5Y cells, and application to assess the neuroprotective effect of antioxidative food factors. Dopamine is a neurotransmitter and its deficiency is a characterized feature in Parkinson's disease (PD), thereby HED represents a new addition to understanding of dopamine biology and pathophysiology of PD and a novel biomarker for the assessment of neuroprotective therapies. We have established an analytical system using for the detection of HED and its toxicity to the neuroblstoma cell line, SH-SY5Y cells. Here, we discuss the characteristics of the system and its applications to investigate the neuroprotective effect of several antioxidants that originate from food.

Topics: Antioxidants; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Curcumin; Dioxoles; Dopamine; Food; Humans; Lignans; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Tandem Mass Spectrometry; Tocopherols; Tocotrienols; Xanthophylls

Oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients. An important biochemical feature of presymptomatic PD is a significant depletion of the thiol antioxidant glutathione (GSH) in these neurons resulting in oxidative stress, mitochondrial dysfunction, and ultimately cell death. We have earlier demonstrated that curcumin, a natural polyphenol obtained from turmeric, protects against peroxynitrite-mediated mitochondrial dysfunction both in vitro and in vivo. Here we report that treatment of dopaminergic neuronal cells and mice with curcumin restores depletion of GSH levels, protects against protein oxidation, and preserves mitochondrial complex I activity which normally is impaired due to GSH loss. Using systems biology and dynamic modeling we have explained the mechanism of curcumin action in a model of mitochondrial dysfunction linked to GSH metabolism that corroborates the major findings of our experimental work. These data suggest that curcumin has potential therapeutic value for neurodegenerative diseases involving GSH depletion-mediated oxidative stress.

Topics: Animals; Antineoplastic Agents; Brain; Buthionine Sulfoximine; Cells, Cultured; Computer Simulation; Curcumin; Dopamine; Glutathione; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mitochondria; Models, Theoretical; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Rats; Systems Biology

We investigated the effects of the polyphenolic compound curcumin and its metabolite tetrahydrocurcumin (ThC), in the model of Parkinson's disease induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this model depletion of dopamine(DA) and DOPAC (3,4-dihydroxy phenyl acetic acid)) occurs with increased monoamine oxidase (MAO-B) activity. We used HPLC with electrochemical detection to measure DA and DOPAC respectively while MAO-B was assayed by spectroflourimetry using the conversion of the fluorogenic substrate, kyuramine. Systemic administration of curcumin (80 mg/kg i. p.) and tetrahydrocurcumin (60 mg/kg i. p.) significantly reversed the MPTP-induced depletion of DA and DOPAC. The MAO-B activity was also significantly inhibited by these compounds. The results showed that curcumin and tetrahydrocurcumin reversed the MPTP induced depletion of DA and DOPAC which may in part be due to inhibition of MAO-B activity. In conclusion, both curcumin and its metabolite ThC exert neuroprotection against MPTP induced neurotoxicity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Curcumin; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Flavonoids; Male; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nerve Degeneration; Neurons; Parkinson Disease; Phenols; Polyphenols

Selective damage of mitochondrial complex I within the dopaminergic neurons of the substantia nigra is the central event during Parkinson disease. Peroxynitrite is one of the important free radicals probably mediating complex I damage. Peroxynitrite inhibits brain complex I mainly by 3-nitrotyrosine and nitrosothiol formation, but how these modifications alter the structure-function relation of complex I is unclear. Curcumin pretreatment protects brain mitochondria against peroxynitrite in vitro by direct detoxification and prevention of 3-nitrotyrosine formation and in vivo by elevation of total cellular glutathione levels. These results suggest a potential therapeutic role for curcumin against nitrosative stress in neurological disorders.

Topics: Curcumin; Electron Transport Complex I; Enzyme Inhibitors; Humans; Mitochondria; Neuroprotective Agents; Parkinson Disease

The aim of present study is to explore the cytoprotection of curcumin against 1-methyl-4-phenylpridinium ions (MPP(+))-induced apoptosis and the molecular mechanisms underlying in PC12 cells. Our findings indicated that MPP(+) significantly reduced the cell viability and induced apoptosis of PC12 cells. Curcumin protected PC12 cells against MPP(+)-induced cytotoxicity and apoptosis not only by inducing overexpression of Bcl-2, but also reducing the loss of mitochondrial membrane potential (MMP), an increase in intracellular reactive oxygen species (ROS) and overexpression of inducible nitric oxide synthase (iNOS). The selective iNOS inhibitor AG partly blocked MPP(+)-induced apoptosis of PC12 cells. The results of present study suggested that the cytoprotective effects of curcumin might be mediated, at least in part, by the Bcl-2-mitochondria-ROS-iNOS pathway. Because of its non-toxic property, curcumin could be further developed to treat the neurodegenerative diseases which are associated with oxidative stress, such as Parkinson's disease (PD).

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; Curcumin; Enzyme Inhibitors; Herbicides; Mitochondria; Nitric Oxide Synthase Type II; Parkinson Disease; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species

Although the cause of dopaminergic cell death in Parkinson's disease (PD) remains unknown, oxidative stress has been strongly implicated. Because of their ability to combat oxidative stress, diet derived phenolic compounds continue to be considered as potential agents for long-term use in PD. This study was aimed at investigating whether the natural phenolic compounds curcumin, naringenin, quercetin, fisetin can be neuroprotective in the 6-OHDA model of PD. Unilateral infusion of 6-OHDA into the medial forebrain bundle produced a significant loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) as well as a decreased of dopamine (DA) content in the striata in the vehicle-treated animals. Rats pretreated with curcumin or naringenin showed a clear protection of the number of TH-positive cells in the SN and DA levels in the striata. However, neither pretreatment with quercetin nor fisetin had any effects on TH-positive cells or DA levels. The ability of curcumin and naringenin to exhibit neuroprotection in the 6-OHDA model of PD may be related to their antioxidant capabilities and their capability to penetrate into the brain.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antioxidants; Curcumin; Disease Models, Animal; Dopamine; Flavanones; Flavonoids; Flavonols; Homovanillic Acid; Male; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Phenols; Quercetin; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase