Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes

The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin’s efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50–100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.     

Melatonin reduces traumatic brain injur y-induced oxidative stress in the cerebral cortex and blood of rats

Free radicals induced by traumatic brain injury have deleterious effects on the function and antioxidant vitamin levels of several organ systems including the brain. Melatonin possesses antioxidant effect on the brain by maintaining antioxidant enzyme and vitamin levels. We investigated the effects of melatonin on antioxidant ability in the cerebral cortex and blood of traumatic brain injury rats. Results showed that the cerebral cortex β-carotene, vitamin C, vitamin E, reduced glutathione, and erythrocyte reduced glutathione levels, and plasma vitamin C level were decreased by traumatic brain injury whereas they were increased following melatonin treatment. In conclusion, melatonin seems to have protective effects on traumatic brain injury-induced cerebral cortex and blood toxicity by inhibiting free radical formation and supporting antioxidant vitamin redox system.     

Melatonin in Alzheimer's disease and other neurodegenerative disorders

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.     

Effects of melatonin on mitochondria after cerebral isehemic reperfusion

Melatonin has been regarded as a free radical scavenger and antioxidant. In both in vitro and in vivo experiments. Melatonin was found to protect cells, tissues and organs against oxidative damage induced by a variety of free radical generating agents and processes, e.g., ischemic reperfusion. The mechanisms underlying these interactions have not been defined. The goal of the present study was to observe the effects of melatonin on rnitochondria after cerebral ischemic reperfusion and the mechanisms of neuroprotection of melatonin by gerbil ischemic model. Male Mongolian gerbils were subjected to 10 min of forebrain ischemia by occlusion of both common carotid arteries under anesthesia. Melatonin(0.8 mg/kg) was administrated intraperitoneum 30 min befbre arteries occlusion. We measured the respiratory function of mitochondria, the activities of ATPase, the free mitochondrial calcium contents and the GSH level of mitochondria. The results show that oxidative phosphorylation function of mitochondria was damaged after cerebral ischemic reperfusion. And mitochondrial calcium was overloaded after cerebral ischemic reperfusion. And the level of GSH in mitochondria decreased after cerebral ischemic reperfision. It is concluded that melatonin have neuroprotection effects after cerebral ischemic repertusion and this effects probably related to the protection mitochondria.     

Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer's disease after chronic exposure to aluminum

It is well established that aluminum (Al) is a neurotoxic agent that induces the production of free radicals in brain. Accumulation of free radicals may cause degenerative events of aging such as Alzheimer's disease. On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, AβPP female transgenic (Tg2576) (Tg) and wild‐type mice (5 months of age) were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Simultaneously, animals received oral Mel (10 mg/kg) dissolved in tap water until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild‐type mice: control, Al only, Mel only, and Al+Mel. At the end of the period of treatment, hippocampus was removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Moreover, the gene expression of Cu‐ZnSOD, GR, and CAT was evaluated by real‐time RT‐PCR. Aluminum concentration in hippocampus was also determined. The biochemical changes observed in this tissue suggest that Al acts as a pro‐oxidant agent. Melatonin exerts an antioxidant action by increasing the mRNA levels of the antioxidant enzymes SOD, CAT, and GR evaluated in presence of Al and Mel, with independence of the animal model. © 2009 Wiley‐Liss, Inc.     

An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer's disease

Summary. This review summarizes recent advancements in our understanding of the potential role of the amyloid β protein in Alzheimer's disease. It also discusses the significance of amyloid β in initiating the generation of partially reduced oxygen species and points out their role in damaging essential macromolecules in the CNS which leads to neuronal dysfunction and loss. Recently acquired experimental data links these destructive oxidative processes with some neurodegenerative aspects of Alzheimer's disease. The experimental findings related to the free radical scavenging and antioxidative properties of melatonin are tabulated and its efficacy and the likely mechanisms involved in its ability to reduce neuronal damage mediated by oxygen-based reac-tive species in experimental models of Alzheimer's disease are summarized. Besides the direct scavenging properties and indirect antioxidant actions of melatonin, its ability to protect neurons probably also stems from its antiamyloidogenic properties. Melatonin is also unique because of the ease with which it passes through the blood-brain barrier. Received June 28, 1999, accepted August 12, 1999     

Oxygen free radicals as inducers of heat shock protein synthesis in cultured human neuroblastoma cells: Relevance to neurodegenerative disease

Summary We studied heat shock protein (HSP) synthesis by cultured human neuroblastoma cells in response to either hyperthermia or high levels of superoxide anion (oxygen free radical). Both treatment modalities resulted in induced synthesis of the same major HSP species with an additive effect on the latter and on cell growth inhibition upon combined treatments. Exposure to superoxide anion in the presence of the free radical scavening enzymes, superoxide dismutase and catalase improved cell survival and prevented HSP induction. These findings suggest a common mechanism by which various forms of injury, such as hyperthermia, cause HSP induction, that is, via oxidative stress or increased production of oxygen free radicals. Increased expression of some HSPs has been detected in association with the pathological lesions that characterize some neurodegenerative diseases such as the neurofibrillary tangles of Alzheimer's disease. This, in turn, suggests that chronic oxidative stress may play a role in the pathogenesis of these disorders.     

Melatonin prevents brain oxidative stress induced by obstructive jaundice in rats

The aim of the study was to analyze the impact of melatonin on brain oxidative stress in experimental biliary obstruction. Cholestasis was done by a double ligature and section of the extrahepatic biliary duct. Melatonin was injected intraperitoneally (500 microg/kg/day). Malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) contents were determined in the brain tissue. Biliary obstruction raised MDA and reduced GSH contents in the cortex, cerebellum, and hypothalamus areas. Moreover, the scavenger enzyme activity significantly dropped in all areas of the brain. Melatonin drastically reduced MDA concentration and enhanced GSH concentration, as well as all antioxidant enzyme activity in all brain areas obtained from the bile duct-ligated animals. In conclusion, the treatment with melatonin decreased lipid peroxidation and recovered the antioxidant status in the brain from cholestatic animals.     

Oxidative toxicity in models of neurodegeneration: responses to melatonin

In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from beta-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury.     

Protective role of melatonin on PCB (Aroclor 1254) induced oxidative stress and changes in acetylcholine esterase and membrane bound ATPases in cerebellum, cerebral cortex and hippocampus of adult rat brain

Polychlorinated biphenyls (PCBs) are one of the environmental toxicants and neurotoxic compounds which induce the production of free radicals leading to oxidative stress. Membrane proteins that control ion gradients across organellar and plasma membranes appear to be particularly susceptible to oxidation induced changes. Melatonin plays an important role in neurodegenerative diseases as an antioxidant and neuroprotector. The aim of this study was to determine the protective role of melatonin on PCB (Aroclor 1254) induced changes in activities of membrane bound ATPases and acetylcholine esterase in selected brain regions of adult rats. Group I: rats intraperitoneally (i.p.) administered corn oil (vehicle) for 30 days. Group II: rats injected i.p. with Aroclor 1,254 (PCB) at 2mg/kg bw/day for 30 days. Groups III and IV: rats intraperitoneally received melatonin (5 or 10mg/kg bw/day) simultaneously with Aroclor 1,254 for 30 days. Groups V and VI: rats intraperitoneally received melatonin (5 or 10mg/kg bw/day) alone for 30 days. After 30 days, rats were sacrificed and the brain regions were dissected to cerebral cortex (Cc), cerebellum (C) and hippocampus (H). Lipid peroxidation (LPO), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH) and the activities of Na(+)K(+) ATPase, Ca(2+) ATPase, Mg(2+) ATPase and acetyl cholinesterase were determined. Reduced glutathione (GSH) level was also determined. Melatonin levels in serum was measured by enzyme labeled immunosorbent assay (ELISA). Activities of all the enzymes and GSH level were decreased while an increase in H(2)O(2), OH and LPO were observed in brain regions of PCB treated animals. Melatonin levels in serum was decreased in PCB exposed animals. Exogenous melatonin supplementation retrieved all the parameters, significantly. These results suggest that PCB alters membrane bound ATPases and cholinergic function by inducing oxidative stress in brain regions, which can be protected by melatonin.     

Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials

Melatonin has been proposed as a treatment for Alzheimer's disease based on the demonstration of antioxidant and "anti-amyloid" effects in vitro and in vivo. Chronic melatonin therapy in old, amyloid plaque-bearing transgenic mice was studied. Tg2576 mice started melatonin treatment at 14 months of age. After 4 months of treatment, there were no differences between untreated and melatonin-treated mice in cortical levels of soluble, formic acid extracted, or histologically detectable beta amyloid (Abeta), nor in brain levels of lipid peroxidation product (total 8,12-isoprostane F(2alpha)-VI), despite marked elevations in plasma melatonin. We conclude that melatonin fails to produce anti-amyloid or antioxidant effects when initiated after the age of amyloid plaque deposition. These findings diminish the possibility that melatonin will be useful for the treatment of established Alzheimer's disease.     

Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative disorders: tools for diagnosis and therapy?

Oxidative stress has been implicated as a common pathogenetic mechanism in neurodegenerative disorders. Central nervous system is particularly exposed to free radical injury, given its high metal content, which can catalyze the formation of oxygen free radicals, and the relatively low content of antioxidant defenses. Indeed, several studies show markers of oxidative damage - lipid peroxidation, protein oxidation, DNA oxidation and glycoxidation markers - in brain areas affected by neurodegenerative disorders. Oxidative stress damage is intimately linked to glutamate neurotoxicity - known as "excitotoxicity". An excessive concentration of extracellular glutamate over-activates ionotropic glutamate receptors, resulting in intracellular calcium overload and a cascade of events leading to neural cell death. In this study we reviewed pathogenetic mechanisms that link oxidative stress and excitotoxicity in three neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) and described peripheral markers of these mechanisms, that may be analyzed in patients as possible diagnostic and therapeutic tools.     

Quercetin and Omega 3 Ameliorate Oxidative Stress Induced by Aluminium Chloride in the Brain

Exposure to high levels of aluminum (Al) leads to neurodegeneration, which may be mediated through over-generation of free radicals. So, in the present study, we investigated the ability of both quercetin and omega 3 to ameliorate adverse effects of Al on brain antioxidants by monitoring the main brain antioxidant enzymes on molecular and cellular levels. The obtained results indicated that Al induced oxidative stress through induction of free radical production and inhibition of activity and expression of the antioxidant enzymes catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx); and at the same time induced superoxide dismutase (SOD) activity and gene expression. Both quercetin (QE) and omega 3 have the ability to overcome Al-induced oxidative stress, manifested by the significant reduction in free radical concentration and induction of the activity and gene expression of the brain antioxidant enzymes.     

Antioxidant capacity in postmortem brain tissues of Parkinson's and Alzheimer's diseases

Oxidative stress has been associated with damage and progressive cell death that occurs in neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). The aim of this study was to investigate the antioxidant capacity in postmortem motor cortex (MC), nucleus caudatus (NC), gyrus temporalis (GT) and substantia nigra (SN) from controls (C) and patients with PD and AD. The initial samples consisted of 68 subjects of PD, AD and C. Brains were matched for age, sex and postmortem time. Brain tissue was homogenized in a phosphate buffer pH 7.3 and separated with two-step centrifugation at 15,000rpm for 30 min and 15,000 rpm for 10 min at 4 degrees C. Antioxidant capacity in the supernatants was measured using the oxygen radical absorbance assay (ORAC). The results showed that in the SN of parkinsonian's brain the balance between production of free radicals and the neutralization by a complex antioxidant system is disturbed. No changes in the antioxidant capacity of postmortem MC and NC of parkinsonian's brain in comparison with C were found. In the SN of parkinsonian's brain, antioxidant capacity seems to be lower in comparison with C (p < 0.05). Antioxidant capacity against peroxyl radical showed that MC of AD patients was lower than in the MC of C (p < 0.005). In NC of AD patients the antioxidant capacity against hydroxyl radical was increased in comparison with C (p < 0.04). No changes in the antioxidant capacity were found in brain tissues of AD in comparison with C, when CuSO4 was used as a free radical generator.     

D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats

Large amounts of d-2-hydroxyglutaric acid (DGA) accumulate in d-2-hydroxyglutaric aciduria (D-2-OHGA), an inherited neurometabolic disorder characterized by severe neurological dysfunction and cerebral atrophy. Despite the significant brain abnormalities, the neurotoxic mechanisms of brain injury in this disease are virtually unknown. In this work, the in vitro effect of DGA on various parameters of oxidative stress was investigated; namely chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and the activities of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase in cerebral cortex from 30-day-old-rats. DGA significantly increased chemiluminescence and TBA-RS and decreased TAR values in the cortical supernatants. In contrast, TRAP and the antioxidant enzyme activities were not altered by the metabolite. Furthermore, the DGA-induced increase of TBA-RS was fully prevented by the free radical scavengers ascorbic acid plus Trolox (water-soluble alpha-tocopherol) and attenuated by the inhibitor of nitric oxide synthase Nomega-nitro-L-arginine methyl ester (L-NAME), suggesting the role of superoxide, hydroxyl and nitric oxide radicals in this action. The data indicate a stimulation of lipid peroxidation through the production of free radicals and a reduction of the brain capacity to efficiently modulate the damage associated with the enhanced generation of free radicals by DGA. In the case that these findings also occur in human D-2-OHGA, it is feasible that oxidative stress may be involved in the pathophysiology of the brain injury observed in patients with this disease.     

The effects of melatonin on the antioxidant systems in experimental spinal injury

Melatonin has been recently shown by various in-vivo and in-vitro studies to exert potent neutralising effects on hydroxyl radicals, stimulate glutathione peroxidase (GSH-Px) activity, and protect catalase (CAT) from the destructive activity of hydroxyl radicals in neural tissue. We aimed to investigate the possible effects of pharmacological dose of melatonin on some of the antioxidant defence systems in an in-vivo study of experimental spinal injury. Seven groups of adult male Sprague Dawley rats were used in the following scheme: Group I: Naive (n = 6), Group II: Lesion (n = 8), Group III: Melatonin (n = 5), Group IV: Melatonin + Lesion (n = 8), Group V: Placebo + Lesion (n = 5), Group VI: Sham operation (n = 5), and Group VII: Placebo (n = 5). Experimental spinal injury was induced at level T7-T8 by 5 sec compression of the total cord with an aneurysm clip on anaesthetised and laminectomized animals. The total 10 mg/kg dose of melatonin (Sigma) dissolved in alcohol-water was administered i.p. four times in 2.5 mg/kg doses, at 20 min pre-, at the time of and at 1 h and 2h post-compression. At 24 +/- 2h post-injury, the rats were euthanized and the lesioned segments of cord were dissected and homogenised with special care taken to distribute equal amount of injured tissue in each sample for analysis of reduced glutathione (GSH), oxidised glutathione (GSSG), superoxide dismutase (SOD), and CAT activity. Compression injury decreased GSH/GSSG ratio significantly (p < .0001). Melatonin, by itself, significantly decreased GSSG content (p < .05) and increased CAT activity (p < .05) in the na?ve rats. Melatonin treatment decreased GSSG activity, thus elevating GSH/GSSG ratio, and also increased SOD and CAT activity without reaching statistical significance in the lesioned animals. In conclusion, pharmacological dose of systemically applied melatonin seemed to support some features of the antioxidant defence systems in our hands.     

Comparison of the beneficial effect of melatonin on recovery after cut and crush sciatic nerve injury: a combined study using functional, electrophysiological, biochemical, and electron microscopic analyses

Purpose

Following tissue injury, melatonin is known to reduce detrimental effects of free radicals by stimulating antioxidant enzymes and also to inhibit posttraumatic polymorphonuclear infiltration. Beneficial effects after peripheral nerve injury have been suggested, but not studied in detail. Therefore, we aimed to elucidate the effects of melatonin on the recovery of the lesioned rat sciatic nerve by means of combined analysis.

Methods

A total number of 90 rats were randomly distributed into six groups: control (group 1), sham-operated (group 2), sciatic nerve cut (group 3), sciatic nerve cut + melatonin treatment (group 4), sciatic nerve crush (group 5), and sciatic nerve crush + melatonin treatment (group 6). Melatonin was administered intraperitoneally at a dose of 50 mg/kg/day for 6 weeks. Recovery of function was analyzed by assessment of the sciatic functional index based on walking track analysis, somatosensory evoked potentials, biochemical quantification of malondialdehyde, antioxidant enzymes levels, and ultrastructural analysis.

Results

Our data showed the beneficial effect of melatonin on sciatic nerve recovery. Rats treated with melatonin demonstrated better structural preservation of the myelin sheaths compared to the nontreated group. The biochemical analysis confirmed the beneficial effects of melatonin displaying lower lipid peroxidation and higher superoxide dismutase, catalase, and glutathione peroxidase activities in sciatic nerve samples in comparison to nontreated groups.

Conclusions

The beneficial effects of melatonin administration on the recovery of the cut and crush injured sciatic nerve may be attributed to its antioxidant properties. Based on these investigations, we think that our data would be helpful for clinicians who deal with peripheral nerve injuries.     

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.     

Curcumin Attenuates Aluminum-Induced Oxidative Stress and Mitochondrial Dysfunction in Rat Brain

Aluminum is neurotoxic both in animals and human beings primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondrial dysfunction is one such mechanism that has been implicated in the pathogenesis of neurodegenerative diseases like Alzheimer's disease. Aluminum toxicity is very closely related to Alzheimer's disease. We evaluated the potentials of curcumin, a known cytoprotectant, against neurotoxic consequences of aluminum that acts through a wide range of mechanisms. Curcumin has been reported to be an antioxidant, and it is this property that is widely held to be responsible for its protective effects in tissue. Aluminum was administered by oral gavage at a dose level of 100 mg/kg body wt/day for a period of 8 weeks. Curcumin was administered in conjunction with aluminum at a dose of 50 mg/kg of body wt i.p. for a period of 8 weeks on alternate days. The effects of different treatments were studied on oxidative phosphorylation and reduced glutathione of different regions of rat brain. The study indicates reduced activity of NADH dehydrogenase (complex I), succinic dehydrogenase (complex II), and cytochrome oxidize (Complex IV) in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. Curcumin supplementation to aluminum-treated rats was able to normalize significantly the activities of all the three mitochondrial complexes as well as reduced glutathione content in all the three regions of brain which were altered following aluminum treatment. We conclude that curcumin, by attenuating oxidative stress, as evident by hypoxia in histological observations and mitochondrial dysfunction holds a promise as an agent that can potentially reduce aluminum-induced adverse effects in brain.