curcumin and Nerve-Degeneration

For thousands of years, humankind has used plants for therapeutics. Nowadays, there is a renewed public interest in naturally occurring treatments with minimal toxicity and diets related to health. Alterations in hippocampal neurogenesis have been recognized as an integral part of brain ischemia. Neuronal stem/progenitor cells in the hippocampus are positively and negatively regulated by intrinsic and extrinsic agents. One positive regulator of neurogenesis in the hippocampus is curcumin in the diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis and neuroprotection studies in brain ischemia and focuses on the role of curcumin in the diet. Data suggest that dietary intake of curcumin enhances neurogenesis. Recent studies performed in ischemic models have suggested that curcumin also has neuroprotective features. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent ageing-associated changes in cellular proteins that lead to protein insolubility and aggregation after ischemia such as β-amyloid peptide and tau protein. Here, we also review the evidence from ischemic models that curcumin improves cognition and health span by overexpression of life supporting genes and preventing or delaying the onset of neurodegenerative changes. Available data provide evidence that curcumin induces neurogenesis and neuroprotection and may provide a novel therapeutic agent for both regenerative medicine and for the treatment of neurodegenerative diseases such as postischemic brain neurodegeneration with Alzheimer phenotype.

Topics: Alzheimer Disease; Animals; Brain; Brain Ischemia; Curcumin; Humans; Nerve Degeneration; Neurogenesis; Neuroprotective Agents; Phenotype

Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Benzyl Alcohols; Biological Products; Biphenyl Compounds; Catechin; Catechols; Curcumin; Encephalitis; Fatty Alcohols; Ginsenosides; Glucosides; Microglia; Molecular Structure; Nerve Degeneration; Neuroprotective Agents; Phenyl Ethers; Plant Extracts; Resveratrol; Stilbenes

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Animals; Anxiety; Apoptosis; Body Weight; Cell Survival; Cognitive Dysfunction; Curcumin; Cytokines; Disease Models, Animal; Hippocampus; Inflammation; Inflammation Mediators; Male; Nerve Degeneration; Neuroprotective Agents; Neurotoxicity Syndromes; Organ Size; Oxidative Stress; Rats, Wistar

Diffuse axonal injury (DAI) accounts for more than 50% of all traumatic brain injury. In response to the mechanical damage associated with DAI, the abnormal proteins produced in the neurons and axons, namely, β-APP and p-tau, induce endoplasmic reticulum (ER) stress. Curcumin, a major component extracted from the rhizome of Curcuma longa, has shown potent anti-inflammatory, antioxidant, anti-infection, and antitumor activity in previous studies. Moreover, curcumin is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2) and promotes its nuclear translocation. In this study, we evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and β-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2.

Topics: Animals; Apoptosis; Axons; Brain; Curcumin; Diffuse Axonal Injury; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum Stress; Male; Nerve Degeneration; Neuroprotective Agents; NF-E2-Related Factor 2; Phosphorylation; Random Allocation; Rats, Sprague-Dawley

Protection of neurons from degeneration is an important preventive strategy for dementia. Much of the dementia pathology implicates oxidative stress pathways. Turmeric (Curcuma longa L.) contains curcuminoids which has anti-oxidative and neuro-protective effects. These effects are considered to be similar to those of citicoline which has been regularly used as one of standard medications for dementia.. This study aimed at investigating the effects of turmeric rhizome extract on the hippocampus of trimethyltin (TMT)-treated Sprague-Dawley rats.. The rats were divided randomly into six groups, i.e., a normal control group (N); Sn group, which was given TMT chloride; Sn-Cit group, which was treated with citicoline and TMT chloride; and three Sn-TE groups, which were treated with three different dosages of turmeric rhizome extract and TMT chloride. Morris water maze test was carried out to examine the spatial memory. The estimated total number of CA1 and CA2-CA3 pyramidal cells was calculated using a stereological method.. The administration of turmeric extract at a dose of 200 mg/kg bw has been shown to prevent the deficits in the spatial memory performance and partially inhibit the reduction of the number of CA2-CA3 regions pyramidal neurons.. TMT-induced neurotoxic damage seemed to be mediated by the generation of reactive oxygen species and reactive nitrogen species. Turmeric extract might act as anti inflammatory as well as anti-oxidant agent.. The effects of turmeric extract at a dose of 200 mg/kg bw seem to be comparable to those of citicoline.

Topics: Animals; Behavior, Animal; Curcuma; Cytidine Diphosphate Choline; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Neuroprotective Agents; Nootropic Agents; Phytotherapy; Plant Extracts; Plants, Medicinal; Pyramidal Cells; Rats, Sprague-Dawley; Reactive Nitrogen Species; Reactive Oxygen Species; Rhizome; Spatial Memory; Time Factors; Trimethyltin Compounds

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Astrocytes; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Curcumin; Humans; Inflammation; Memory Disorders; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Nerve Degeneration; Neuroimmunomodulation; Neuroprotective Agents; Nootropic Agents

Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with surface wheat germ agglutinin (WGA) to downregulate the phosphorylation of kinases in Alzheimer's disease (AD) therapy. Cardiolipin (CL)-conjugated LIP carrying CRM (CRM-CL/LIP) and also carrying NGF (NGF-CL/LIP) were used with AD models of SK-N-MC cells and Wistar rats after an insult with β-amyloid peptide (Aβ). We found that CRM-CL/LIP inhibited the expression of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase (p-JNK), and p-tau protein at serine 202 and prevented neurodegeneration of SK-N-MC cells. In addition, NGF-CL/LIP could enhance the quantities of p-neurotrophic tyrosine kinase receptor type 1 and p-extracellular signal-regulated kinase 5 for neuronal rescue. Moreover, WGA-grafted CRM-CL/LIP and WGA-grafted NGF-CL/LIP significantly improved the permeation of CRM and NGF across the blood-brain barrier, reduced Aβ plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD rats. Based on the marker expressions and in vivo evidence, current LIP carriers can be promising drug delivery systems to protect nervous tissue against Aβ-induced apoptosis in the brain during the clinical management of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cardiolipins; Cell Survival; Curcumin; Drug Delivery Systems; Fluorescence; Hippocampus; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Kinetics; Liposomes; Male; Nerve Degeneration; Neurons; Particle Size; Phosphorylation; Rats, Wistar; Static Electricity; tau Proteins; Wheat Germ Agglutinins

Bisphenol A (BPA) is an environmental xenoestrogenic endocrine disruptor, utilized for production of consumer products, and exerts adverse effects on the developing nervous system. Recently, we found that BPA impairs the finely tuned dynamic processes of neurogenesis (generation of new neurons) in the hippocampus of the developing rat brain. Curcumin is a natural polyphenolic compound, which provides neuroprotection against various environmental neurotoxicants and in the cellular and animal models of neurodegenerative disorders. Here, we have assessed the neuroprotective efficacy of curcumin against BPA-mediated reduced neurogenesis and the underlying cellular and molecular mechanism(s). Both in vitro and in vivo studies showed that curcumin protects against BPA-induced hippocampal neurotoxicity. Curcumin protects against BPA-mediated reduced neural stem cells (NSC) proliferation and neuronal differentiation and enhanced neurodegeneration. Curcumin also enhances the expression/levels of neurogenic and the Wnt pathway genes/proteins, which were reduced due to BPA exposure in the hippocampus. Curcumin-mediated neuroprotection against BPA-induced neurotoxicity involved activation of the Wnt/β-catenin signaling pathway, which was confirmed by the use of Wnt specific activators (LiCl and GSK-3β siRNA) and inhibitor (Dkk-1). BPA-mediated increased β-catenin phosphorylation, decreased GSK-3β levels, and β-catenin nuclear translocation were significantly reversed by curcumin, leading to enhanced neurogenesis. Curcumin-induced protective effects on neurogenesis were blocked by Dkk-1 in NSC culture treated with BPA. Curcumin-mediated enhanced neurogenesis was correlated well with improved learning and memory in BPA-treated rats. Overall, our results conclude that curcumin provides neuroprotection against BPA-mediated impaired neurogenesis via activation of the Wnt/β-catenin signaling pathway.

Topics: Animals; Apoptosis; Benzhydryl Compounds; beta Catenin; Cell Differentiation; Cell Nucleus; Cell Proliferation; Curcumin; Female; Gene Knockdown Techniques; Glycogen Synthase Kinase 3 beta; Hippocampus; Memory; Models, Biological; Nerve Degeneration; Neural Stem Cells; Neurogenesis; Neuroprotection; Phenols; Rats, Wistar; Wnt Signaling Pathway

Axon degeneration is a hallmark of several central nervous system (CNS) disorders, including multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Previous neuroprotective approaches have mainly focused on reversal or prevention of neuronal cell body degeneration or death. However, experimental evidence suggests that mechanisms of axon degeneration may differ from cell death mechanisms, and that therapeutic agents that protect cell bodies may not protect axons. Moreover, axon degeneration underlies neurologic disability and may, in some cases, represent an important initial step that leads to neuronal death. Here, we develop a novel quantitative microfluidic-based methodology to assess mechanisms of axon degeneration caused by local neuroinflammation. We find that LPS-stimulated microglia release soluble factors that, when applied locally to axons, result in axon degeneration. This local axon degeneration is mediated by microglial MyD88/p38 MAPK signaling and concomitant production of nitric oxide (NO). Intra-axonal mechanisms of degeneration involve JNK phosphorylation. Curcumin, a compound with both anti-oxidant and JNK inhibitory properties, specifically protects axons, but not neuronal cell bodies, from NO-mediated degeneration. Overall, our platform provides mechanistic insights into local axon degeneration, identifies curcumin as a novel axon protectant in the setting of neuroinflammation, and allows for ready screening of axon protective drugs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Axons; Cells, Cultured; Coculture Techniques; Curcumin; Embryo, Mammalian; Enzyme Inhibitors; Gene Expression Regulation; Hippocampus; Hydrazines; Lipopolysaccharides; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroglia; Neurons; Nitric Oxide Donors; Nitrites; Rats; Rats, Sprague-Dawley; Time Factors

The Alzheimer's disease (AD) brain is characterized by β-amyloid deposition, hyperphosphorylation of microtubule-associated proteins, formation of senile plaques and neurofibrillary tangles, and degeneration of specific neuronal populations. Collapsin response mediator protein 2 (CRMP-2) hyperphosphorylation has been implicated in AD-associated neural process regression and neurofibrillary tangle formation. Curcumin is a promising AD drug with incompletely defined therapeutic mechanisms. One possibility is that curcumin prevents β-amyloid-induced CRMP-2 hyperphosphorylation, thereby protecting against axonal regression and (or) promoting axonal regrowth. We examined spatial learning in the Morris water maze, hippocampal expression levels of CRMP-2 and phosphorylated CRMP-2 (p-CRMP-2) by Western blot, and NF-200 (an axon-specific marker) by immunohistochemistry in Sprague-Dawley rats subjected to a single intrahippocampal injection of Aβ1-40 alone or Aβ1-40 followed by curcumin (i.p. daily for 7 days). Compared to controls, spatial learning was significantly impaired in these Aβ1-40-injected AD model rats (P<0.05). In addition, hippocampal expression levels of CRMP-2 and NF-200 were reduced while p-CRMP-2 expression was significantly enhanced (P<0.05 for all). Overexpression of p-CRMP-2 was correlated with NF-200 underexpression (r(2)=-0.67308, P<0.05), suggesting that Aβ1-40 damaged hippocampal axons. Spatial learning deficits were reversed, CRMP-2 and NF-200 expression levels increased, and p-CRMP-2 expression reduced in curcumin-treated rats (all P<0.05). We propose that curcumin improves spatial learning by inhibiting CRMP-2 hyperphosphorylation, thus protecting against β-amyloid-induced hippocampal damage or promoting regeneration.

Topics: Amyloid beta-Peptides; Animals; Axons; Blotting, Western; Curcumin; Hippocampus; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Maze Learning; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Phosphorylation; Rats; Rats, Sprague-Dawley

In order to determine the efficacy of curcumin in ameliorating symptoms of neurodegeneration in the mouse model of Niemann-Pick C1, a variety of formulations and dosages of curcumin, one comparable to one previously reported as efficacious, were provided orally to Npc1(-/-)mice. Plasma levels of curcumin, survival, tests of motor performance, and memory (in some cases) were performed. We found variable, but mild, increases in survival (1.5% to 18%). The greatest increased survival occurred with the highest dose (which was unformulated) while the control for the lipidated formulation (containing phosphatidylcholine and stearic acid) had an equivalent impact and other formulations, while not significantly increased, are also not statistically different in effect from the highest dose. We conclude that curcumin is not a highly efficacious treatment for neurodegeneration in Npc1(-/-) mice. Phosphatidylcholine and stearic acid should be studied further.

Topics: Aging; Animals; Avoidance Learning; Carrier Proteins; Chromatography, High Pressure Liquid; Curcumin; Diet; Intracellular Signaling Peptides and Proteins; Lipids; Mass Spectrometry; Membrane Glycoproteins; Memory; Mice; Mice, Inbred BALB C; Mice, Knockout; Motor Activity; Nerve Degeneration; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Pharmaceutical Vehicles; Phosphatidylcholines; Polymerase Chain Reaction; Postural Balance; Stearic Acids; Survival

One of the main concerns regarding organophosphate pesticides (OP) is their possible toxic effects. Doses that do not produce acute toxicity are capable of altering the structure and biochemistry of different tissues and organs by production of reactive oxygen species (ROS). Curcumin (CUR) is the main substance in Curcuma longa (Zingiberacea) rhizome that has strong antioxidant activity. However, the neuroprotective properties of curcumin against oxidative stress induced by prolonged exposure to parathion (PAR) is not clear.. The present work evaluated the protective effect of curcumin against the oxidative damage induced in the rat hippocampus by the OP PAR.. Forty female Wistar rats were distributed in four groups as follows: exposed to PAR by inhalation (PAR group); pre-treated with CUR and then exposed to PAR by inhalation, (CUR + PAR group); exposed to environmental air and treated with CUR in the food (CUR group); and exposed to environmental air (the control group). At the end of the handling process, the concentration of erythrocyte cholinesterase was monitored, as indicator of PAR intoxication and lipoperoxidation, immunohistochemistry for astrocytes, and activated microglia and apoptosis was determined in the hippocampus.. In the present study, we show that the administration of CUR (200 mg/kg body weight) significantly diminished the oxidative damage in the hippocampus of rats exposed to the OP PAR.. These data suggest that CUR may be an alternative to prevent neurodegenerative damage after pesticide exposure.

Topics: Animals; Antioxidants; Curcuma; Curcumin; Female; Hippocampus; Insecticides; Nerve Degeneration; Oxidative Stress; Parathion; Plant Extracts; Rats; Rats, Wistar; Reactive Oxygen Species

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

Oxidative stress (OS) plays a pivotal role in the pathogenesis of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a neurotoxin used to induce oxidative cell death of dopaminergic neurons in experimental models of PD. Curcumin I, or diferuloylmethane is a pure compound isolated from Curcuma longa Linn. that has been reported to have neuroprotective properties. The precise mechanism, however, remains unclear. This study aims to elucidate the mechanisms by which curcumin I exerts its effects, using 6-OHDA-induced neurotoxicity in the human dopaminergic cell line SH-SY5Y. In our experiments, pretreatment with curcumin I improved cell viability, and significantly reduced reactive oxygen species (ROS). Further investigations revealed a reduction of p53 phosphorylation and decrease of the Bax/Bcl-2 ratio, as measured by mRNA expression and protein level. Taken together, these findings indicate that curcumin I protects dopaminergic neurons from 6-OHDA-induced toxicity via the reduction of ROS production, and subsequent attenuation of p53 phosphorylation and reduction of the Bax/Bcl-2 ratio.

Topics: Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Survival; Curcumin; Dopamine; Humans; Nerve Degeneration; Neurons; Neuroprotective Agents; Neurotoxins; Oxidopamine; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Tumor Suppressor Protein p53

Reduced cognitive function is associated with Alzheimer's and Parkinson's diseases as well as brain trauma and ischemia. However, there are few compounds that enhance memory and are also orally active. We recently synthesized a pyrazole derivative of curcumin called CNB-001 that enhances the activity of Ca(2+)/calmodulin dependent protein kinase II (CaMKII). Since CaMKII plays a central role in long-term potentiation (LTP) and memory, it was asked if CNB-001 can facilitate the induction of LTP in rat hippocampal slices and enhance memory in a rat object recognition test. It is shown that CNB-001 enhances both LTP and memory.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognition Disorders; Curcumin; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Nerve Degeneration; Neurodegenerative Diseases; Neuroprotective Agents; Neuropsychological Tests; Nootropic Agents; Organ Culture Techniques; Pyrazoles; Rats; Rats, Wistar; Recognition, Psychology; Treatment Outcome

Recent studies have shown that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in dopaminergic neuronal degeneration, and direct blockade of JNK by specific inhibitors may prevent or effectively slow the progression of Parkinson disease (PD). Previous studies have revealed that the natural phenolic compound curcumin can reduce inflammation and oxidation, which makes it a potential therapeutic agent for neurodegenerative diseases. In this study, we investigated whether curcumin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) or 1-methyl-4-phenylpyridnium ion- (MPP(+)) induced dopaminergic neurotoxicity in C57BL/6N mice or SH-SY5Y cells by inhibiting JNK pathways both in vivo and in vitro. Curcumin treatment significantly improved behavioral deficits, and enhanced the survival of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) in the MPTP-induced PD model mice. Most importantly, curcumin treatment significantly inhibited MPTP/MPP(+)-induced phosphorylation of JNK1/2 and c-Jun, and cleaved caspase-3. Our study suggests that the neuroprotective effect of curcumin is not related simply to its antiinflammatory and antioxidant properties, but involves other mechanisms, particularly by targeting the JNK pathways.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Astrocytes; Behavior, Animal; Caspase 3; Cell Death; Cell Line; Curcumin; Dopamine; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Proto-Oncogene Proteins c-jun; Substantia Nigra

The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-beta accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cholinergic Agents; Curcumin; Disease Models, Animal; Hindlimb; Humans; Lipid Peroxidation; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria; Motor Neurons; Movement Disorders; Nerve Degeneration; Potassium Cyanide; Reflex; Spinal Cord; Tremor

Recent evidence indicates that curcumin (CUR), the principal curcuminoid of turmeric, exhibits antioxidant potential and protects the brain against various oxidative stressors. The aim of the present study was to examine the modulating impacts of CUR against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with CUR (80 mg/kg) for three weeks. After two weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks and then sacrificed for biochemical and histopathological assays. ICV-STZ rats showed significant cognitive deficits, which were significantly improved by CUR supplementation. CUR supplementation significantly augmented increased 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC) and oxidized glutathione (GSSG); decreased levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) in the hippocampus and cerebral cortex; and increased choline acetyltransferase (ChAT) activity in the hippocampus of ICV-STZ rats. The study suggests that CUR is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimer's type (SDAT).

Topics: Alzheimer Disease; Animals; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Cognition; Curcumin; Disease Models, Animal; Hippocampus; Injections, Intraventricular; Male; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Streptozocin; Time Factors

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

Curcumin is a major active component isolated from Curcuma longa. Previously, we have reported its significant antidepressant effect. However, the mechanisms underlying the antidepressant effects are still obscure. In the present study, we explored the effect of curcumin against glutamate excitotoxicity, mainly focusing on the neuroprotective effects of curcumin on the expression of Brain-Derived Neurotrophic Factor (BDNF), which is deeply involved in the etiology and treatment of depression. Exposure of rat cortical neurons to 10 microM glutamate for 24 h caused a significant decrease in BDNF level, accompanied with reduced cell viability and enhanced cell apoptosis. Pretreatment of neurons with curcumin reversed the BDNF expression and cell viability in a dose- and time-dependent manner. However, K252a, a Trk receptor inhibitor which is known to inhibit the activity of BDNF, could block the survival-promoting effect of curcumin. In addition, the up-regulation of BDNF levels by curcumin was also suppressed by K252a. Taken together, these results suggest that the neuroprotective effect of curcumin might be mediated via BDNF/TrkB signaling pathway.

Topics: Animals; Animals, Newborn; Antidepressive Agents; Apoptosis; Brain-Derived Neurotrophic Factor; Carbazoles; Cell Survival; Cells, Cultured; Cerebral Cortex; Curcumin; Depressive Disorder; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Glutamic Acid; Indole Alkaloids; Nerve Degeneration; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptor, trkB; Up-Regulation