curcumin and Parkinsonian-Disorders

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

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

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction. Recent studies have shown that curcumin (CUR) has neuroprotective effects in PD experimental models. However, its efficacy is limited due to low water solubility, bioavailability, and access to the central nervous system. In this study, we compared the effects of new curcumin-loaded nanoemulsions (NC) and free CUR in an experimental model of PD. Adult Swiss mice received NC or CUR (25 and 50 mg/kg) or vehicle orally for 30 days. Starting on the eighth day, they were administered rotenone (1 mg/kg) intraperitoneally until the 30th day. At the end of the treatment, motor assessment was evaluated by open field, pole test, and beam walking tests. Oxidative stress markers and mitochondrial complex I activity were measured in the brain tissue. Both NC and CUR treatment significantly improved motor impairment, reduced lipoperoxidation, modified antioxidant defenses, and prevented inhibition of complex I. However, NC was more effective in preventing motor impairment and inhibition of complex I when compared to CUR in the free form. In conclusion, our results suggest that NC effectively enhances the neuroprotective potential of CUR and is a promising nanomedical application for PD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Emulsions; Male; Mice; Nanoparticles; Neuroprotective Agents; Parkinsonian Disorders; Rotenone

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumin-treated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphine-induced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.

Topics: Animals; Antioxidants; Cell Line; Curcumin; Dantrolene; Mice; Neurons; Neuroprotection; Neuroprotective Agents; Oxindoles; Parkinsonian Disorders

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

Topics: Animals; Antiparkinson Agents; Ascorbic Acid; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Behavior, Animal; Brain; Cell Line, Tumor; Curcumin; Disease Models, Animal; Dopaminergic Neurons; Female; Humans; Mice, Inbred C57BL; Mitophagy; Naphthyridines; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Signal Transduction; TOR Serine-Threonine Kinases

Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.

Topics: Anacardic Acids; Animals; Antiparkinson Agents; Curcumin; Cytoskeletal Proteins; Drug Evaluation, Preclinical; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Fos-Related Antigen-2; Gene Expression Regulation; Histone Acetyltransferases; Histone Code; Levodopa; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Oxidopamine; Parkinsonian Disorders; Proto-Oncogene Proteins c-fos; Specific Pathogen-Free Organisms; Substantia Nigra; Terpenes

Our previous study has demonstrated that curcumin (CM), a natural ingredient isolated from Zingiberaceae, exerts the effect of inhibiting hippocampal injury in 6-hydroxydopamine (6-OHDA)-induced parkinsonian rat. However, the potential effect of CM on 6-OHDA-injured substantia nigra (SN) needs to be investigated. This study aimed to further evaluate the therapeutic effectiveness of CM against damaged SN in rats. Methodologically, Parkinson's disease (PD) rat was prepared by using a surgical approach of injecting 6-hydroxydopamine (6-OHDA) into the SN. Morris water maze, open-field assays, and rotarod test were used to assess the neurobehavioral manifestations. Neurotransmitter contents in the SN were determined by using the biochemical tests. Western blotting was employed to evaluate the target protein expressions. The representative data showed that CM protected against 6-OHDA-induced neural impairments in the SN, as evidenced by improved memory abilities, elevated intercalatum levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduced concentration of malonaldehyde (MDA). In addition, dopamine (DA) and acetylcholine (ACh) levels were increased in the SN. Moreover, intercalatum heat shock protein 70 (HSP70) was lowered, while basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and receptor tyrosine kinase A (TrkA) expressions were up-regulated, respectively. Taken together, the findings indicate that curcum in exerts neuroprotection in the SN via ameliorating neurofunctions of PD rats.

Topics: Adrenergic Agents; Animals; Behavior, Animal; Blotting, Western; Curcumin; Disease Models, Animal; Male; Neuroprotective Agents; Neurotransmitter Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Substantia Nigra

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Topics: Alkaloids; alpha-Synuclein; Animals; Antiparkinson Agents; Benzodioxoles; Blood-Brain Barrier; Capillary Permeability; Curcumin; Drug Delivery Systems; Drug Therapy, Combination; Liposomes; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Neuroprotective Agents; Parkinsonian Disorders; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Protein Aggregation, Pathological; Random Allocation; Rats; Rotenone; Surface-Active Agents

Clinically, Parkinson's disease (PD)-related neuronal lesions commonly occur. The purpose of this study is to investigate potential therapeutic effect of curcumin against hippocampal damage of 6-hydroxydopamine (6-OHDA)-PD rat model. These results showed that curcumin significantly increased the body weight of 6-OHDA-impaired rats (P<0.01), and reversed the anhedonia in rats induced by 6-OHDA impairment (P<0.01). Meanwhile, behavioral manifestations of curcumin-treated PD rats were effectively ameliorated as shown in open field test (P<0.01). In addition, curcumin increased the contents of monoaminergic neurotransmitters (P<0.01), such as dopamine (DA) and norepinephrine (NE), in hippocampal homogenate through high performance liquid chromatography (HPLC) assay. Curcumin effectively alleviated the 6-OHDA-induced hippocampal damage as observed in hematoxylin-eosin (H&E) staining. Furthermore, curcumin obviously up-regulated hippocampal brain derived neurotrophic factor (BDNF), TrkB, phosphatidylinositide 3-kinases (PI3K) protein expressions, respectively as shown in Western blot analysis. These findings demonstrated that curcumin mediated the neuroprotection against 6-OHDA-induced hippocampus neurons in rats, which the underlying mechanism is involved in activating BDNF/TrkB-dependent pathway for promoting neural regeneration of hippocampal tissue.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Curcumin; Cytoprotection; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Hippocampus; Male; Nerve Regeneration; Neuroprotective Agents; Norepinephrine; Oxidopamine; Parkinsonian Disorders; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction

Oxidative stress and mitochondrial dysfunction are underpinned for initiating a cascade of toxic events leading to dopaminergic neuronal death in Parkinson's disease (PD) and identified as vital target for therapeutic intervention. Curcumin, a potent antioxidant has been reported to display diverse neuroprotective properties against various neurodegenerative diseases including PD. In this present study, we investigated the protective effect of CNB-001, a pyrazole derivative of curcumin on rotenone-induced toxicity and its possible mechanisms in neuroblastoma SK-N-SH cells. Rotenone insult significantly reduced cell viability (MTT assay) and resulted in 78 % apoptosis (dual staining) by altering Bcl-2, Bax, caspase-3, and cytochrome C expression. Moreover, rotenone enhanced ROS production and disrupts mitochondrial membrane potential. These resultant phenotypes were distinctly alleviated by CNB-001. Pretreatment with CNB-001(2 μM) 2 h before rotenone exposure (100 nM) increased cell viability, decreased ROS formation, maintained normal physiological mitochondrial membrane potential, and reduced apoptosis. Furthermore, CNB-001 inhibited downstream apoptotic cascade by increasing the expression of vital antiapoptotic protein Bcl-2 and decreased the expression of Bax, caspase-3, and cytochrome C. Collectively, the results suggest that CNB-001 protects neuronal cell against toxicity through antioxidant and antiapoptotic properties through its action on mitochondria. Therefore, it may be concluded that CNB-001 can be further developed as a promising drug for treatment of PD.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Curcumin; Humans; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinsonian Disorders; Pyrazoles; Rotenone

This study investigated the effects of curcumin on nigrostriatal dopaminergic (DA) neurons and glial response in 6-hydroxydopamine (6-OHDA) hemiparkinsonian mice. Following unilateral intrastriatal 6-OHDA injection, mice were daily injected with curcumin for seven days, beginning on the day of lesion. Seven days after 6-OHDA lesioning, sections from the striatum and the substantia nigra pars compacta (SNpc) were collected and immunohistochemically stained for DA neurons and reactive glia. Curcumin decreased 6-OHDA-induced loss of nigral tyrosine hydroxylase-immunoreactive (TH-IR) neurons and striatal TH-IR fibers. The neuroprotection was coincided with a significant attenuation of microglial and astroglial reaction in the SNpc and the striatum. These results suggest that the neuroprotective effects of curcumin in 6-OHDA-lesioned mice may be mediated through its anti-inflammatory properties or direct protection on nigral DA neurons, thereby reducing neuronal injury-induced glial activation.

Topics: Animals; Corpus Striatum; Curcumin; Disease Models, Animal; Dopaminergic Neurons; Male; Mice; Mice, Inbred ICR; Neural Pathways; Neuroglia; Parkinsonian Disorders; Substantia Nigra; Treatment Outcome

Parkinson's disease (PD) is a progressive neurological disorder which is emanated by dopaminergic death cell and depletion. Curcumin as a nontoxic matter has antioxidant, anti-inflammatory, and antiproliferative activities, and it involves antioxidant property same to vitamins C and E. In this study, we investigated the neuroprotective properties of the natural polyphenolic antioxidant compound, curcumin, against homocysteine (Hcy) neurotoxicity. Curcumin (50 mg/kg) was injected intraperitoneally (i.p.) once daily for a period of 10 days beginning 5 days prior to Hcy (2 μmol/μl) intracerebroventricular (i.c.v.) injection in rats. The studies included immunohistological and locomotor activity tests. These results suggest that homocysteine intracerebroventricular administration (2 μmol/μl i.c.v.) may induce changes in rat brain, and subsequently, polyphenol treatment curcumin 50 mg/kg (i.p.) was capable in improving locomotor function in insulted animal by protecting the nervous system against homocysteine toxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Brain; Curcumin; Disease Models, Animal; Drug Interactions; Homocysteine; Male; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Wistar

The present study investigated the neuroprotective effect of curcuminoids, the active polyphenols of Curcuma longa (L.) rhizomes against inflammation-mediated dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Male C57BL/6 mice were pre-treated with curcuminoids (150 mg/kg/day) for 1 week, followed by four intra-peritoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals with further administration of curcuminoids or deprenyl (3 mg/kg/day) for 2 weeks. Our results show that oral administration of curcuminoids significantly prevented MPTP-mediated depletion of dopamine and tyrosine hydroxylase (TH) immunoreactivity. In-addition, pre-treatment with curcuminoids reversed glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) protein expression, as well as, reduced pro-inflammatory cytokine and total nitrite generation in the striatum of MPTP-intoxicated mice. Significant improvement in motor performance and gross behavioural activity, as determined by rota-rod and open field tests were also observed. Taken together, our findings suggest that curcuminoids exert a neuroprotective effect against MPTP-induced dopaminergic neurodegeneration through its anti-inflammatory action and thus holds immense potential as a therapeutic candidate for the prevention and management of PD.

Topics: Animals; Curcuma; Curcumin; Dopaminergic Neurons; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Parkinsonian Disorders; Plant Extracts

Curcumin, the active principle of turmeric used in Indian curry is known for its antitumor, antioxidant, antiarthritic, anti-ischemic and anti-inflammatory properties and might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimer's disease patients. A Parkinsonian model in rats was developed by giving 6-hydroxydopamine (10 μg/2 μl in 0.1% ascorbic acid-saline) in the right striatum. After 3 weeks of lesioning, the behavior activities (rotarod, narrow beam test, grip test and contra-lateral rotations) were increased in a lesioned group as compared to a sham group and these activities were protected significantly with the pretreatment of curcumin. A significant protection on lipid peroxidation, glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, tyrosine hydroxylase and D(2) receptor binding was observed in the striatum of lesioned group animals pretreated with 80 mg/kg body weight of curcumin for 21 days as compared to lesion group animals. No significant alterations on behavior and biochemical parameters were observed in sham group animals and the animals of sham group pretreated with curcumin. This study indicates that curcumin, which is an important ingredient of diet in India and also used in various systems of indigenous medicine, is helpful in preventing Parkinsonism and has therapeutic potential in combating this devastating neurologic disorder.

Topics: Animals; Antioxidants; Behavior, Animal; Corpus Striatum; Curcumin; Disease Models, Animal; Immunohistochemistry; Lipid Peroxidation; Male; Neuroprotective Agents; Oxidative Stress; Parkinsonian Disorders; Rats; Rats, Wistar; Time Factors; Treatment Outcome

Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on shortterm memory using a Drosophila model of Parkinson disease.. Transgenic strains of Drosophila melanogaster.. Using the GAL4-UAS system, human alpha-synuclein was expressed throughout the nervous system of adult flies. Alpha-synuclein expressing flies (alpha S flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry. MEASURMENTS AND RESULTS: When sleep deprived at an intermediate stage of the pathology, alpha S flies showed persistent short-term memory deficits that lasted > or = 3 days. Cognitive deficits were not observed in younger alpha S flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived alpha S flies. Blocking D1-like receptors during sleep deprivation prevented persistent shortterm memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits.. These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics.

Topics: Age Factors; alpha-Synuclein; Animals; Animals, Genetically Modified; Avoidance Learning; Choice Behavior; Curcumin; Drosophila melanogaster; Drosophila Proteins; Enzyme Inhibitors; Gene Expression Profiling; Humans; Inhibition, Psychological; Light; Maze Learning; Memory, Short-Term; Motivation; Neurotoxins; Oxidopamine; Parkinsonian Disorders; Receptors, Dopamine; Receptors, Dopamine D2; RNA, Messenger; Sleep Deprivation