Rajeswara Babu Mythri

Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: therapeutic implications for Parkinson's disease explained via in silico studies.

Oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinsons 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.

INTEGRATING GLUTATHIONE METABOLISM AND MITOCHONDRIAL DYSFUNCTION WITH IMPLICATIONS FOR PARKINSON'S DISEASE : A DYNAMIC MODEL

UNLABELLED Oxidative/nitrosative stress and mitochondrial dysfunction have been implicated in the degeneration of dopaminergic neurons in the substantia nigra during Parkinsons disease (PD). During early stages of PD, there is a significant depletion of the thiol antioxidant glutathione (GSH), which may lead to oxidative stress, mitochondrial dysfunction, and ultimately neuronal cell death. Mitochondrial complex I (CI) is believed to be the central player to the mitochondrial dysfunction occurring in PD. We have generated a dynamic, mechanistic model for mitochondrial dysfunction associated with PD progression that is activated by rotenone, GSH depletion, increased nitric oxide and peroxynitrite. The potential insults independently inhibit CI and other complexes of the electron transport chain, drop the proton motive force, and reduce ATP production, ultimately affecting the overall mitochondrial performance. We show that mitochondrial dysfunction significantly affects glutathione synthesis thereby increasing the oxidative damage and further exacerbating the toxicities of these mitochondrial agents resulting in neurodegeneration. Rat dopaminergic neuronal cell culture and in vitro experiments using mouse brain mitochondria were employed to validate important features of the model. MAJOR CONCLUSIONS Using a combination of experimental and in silico modeling approaches, we have demonstrated the interdependence of mitochondrial function with GSH metabolism in relation to neurodegeneration in PD.

Bioconjugates of curcumin display improved protection against glutathione depletion mediated oxidative stress in a dopaminergic neuronal cell line: Implications for Parkinson’s disease

Oxidative stress is implicated in mitochondrial dysfunction associated with neurodegeneration in Parkinsons 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.

Mitochondrial alterations and oxidative stress in an acute transient mouse model of muscle degeneration: Implications for muscular dystrophy and related muscle pathologies

Background: Human muscular dystrophies and inflammatory myopathies share common pathological events. Results: The cardiotoxin (CTX) model displayed acute and transient muscle degeneration and all the cellular events usually implicated in human muscle pathology. Conclusion: Mitochondrial alterations and oxidative stress significantly contribute to muscle pathogenesis. Significance: The CTX model is valuable in understanding the mechanistic and therapeutic paradigms of muscle pathology. Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption, and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism, and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data were supported by enzyme assays, Western blot, and histochemistry. The CTX model also displayed markers of oxidative stress and a lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies, and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy samples (n = 6) (versus controls; n = 6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases.

Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimers presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimers presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.

Chronic dietary supplementation with turmeric protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-mediated neurotoxicity in vivo: implications for Parkinson's disease

Multiple pathways including oxidative stress and mitochondrial damage are implicated in neurodegeneration during Parkinsons 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.

Nutraceuticals and Other Natural Products in Parkinson’s Disease Therapy: Focus on Clinical Applications

Parkinson’s disease (PD) is a neurodegenerative disease involving the degeneration of nigral dopaminergic neurons and consequent depletion of striatal dopamine (DA). The current PD drugs replenish brain DA, leading only to symptomatic relief. However, most drugs elicit adverse motor complications and fail to prevent disease progression. There have been continued efforts to find alternative approaches to improve clinical outcome among PD patients. The differential susceptibility of ethnic populations to PD, probably due to distinct dietary patterns, prompted researchers to examine food supplements, nutraceuticals, and natural products in PD pharmacotherapy. Clinical studies have associated vitamins, omega fatty acids, coenzyme Q-10, and so on with the risk for PD. Retrospective studies on healthy subjects and PD patients consuming tea, a healthy diet, and so on have provided clues about their importance in the susceptibility to PD. This chapter investigates the clinical relevance of dietary practices in neuroprotection and the use of dietary supplements/natural products as therapeutic agents.

Therapeutic Potential of Polyphenols in Parkinson’s Disease

Increased human life expectancy has resulted in larger geriatric population throughout the world. Consequently, there is increased prevalence of age-associated neurodegenerative diseases including Parkinson’s disease (PD) with serious impact on healthcare. This has intensified the scientific research on the pathology and therapy of the central nervous system (CNS). Although modern approach in biomedical research has made major breakthroughs in understanding the pathological basis of PD, the knowledge about therapy is limited. Consequently, PD does not have a permanent cure. During recent years, there have been several options for PD therapy including both pharmacological and neurosurgical approaches. These strategies are primarily aimed at improving the motor symptoms without any major side effects ultimately improving the quality of the life of the patient. Drugs such as L-dihydroxyphenyl alanine (levodopa or LDOPA) replenish the lost dopamine in the brain in early PD and provide symptomatic relief. Apart from L-dopa therapy, other drugs including dopamine receptor agonists, MAO-B inhibitors and anti-cholinergic drugs have been utilized in the pharmacotherapy of PD (Almeida & Hyson, 2008). But, each class of drugs is limited by potential side effects and motor complications with chronic treatment. Further, most PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Moreover, most of these drugs are not completely effective against degeneration of the remaining dopaminergic neurons (Almeida & Hyson, 2008). Due to these serious lacunae, there is a tremendous momentum to develop newer treatments involving disease modifying, restorative, possibly curative drugs with lesser side effects. Most importantly, these drugs should protect the dying neurons thus preventing further neuronal loss. In this direction there have been novel strategies of PD pharmacotherapy applicable either as independent therapies or as a supplement with the existing therapies. These have been tested in experimental models and although many of these molecules show promise, their toxicology, bioavailability and clinical efficacy in human subjects needs to be examined thoroughly before application to PD.

Evaluation of oxidative / nitrosative stress markers in non-SN regions of post-mortem Parkinson?s Disease Brain: Neuroprotection by natural antioxidant

September 5-7, 2012 Volume 3 Issue 6 56 J Neurol Neurophysiol ISSN: 2155-9562 JNN, an open access journal Background: Central neurologic injury resulting from different etiological factors (stroke, traumatic brain injury, cerebral palsy) is the main cause of long-term disability. Spontaneous motor recovery would occur at the acute stage predominantly in the initial weeks to the first three months, but continue at a slower pace throughout the years. The activation of ipsilateral motor structures, including primary motor and premotor cortex has been reported to be beneficial to the performance in the chronic stage of central neurologic injury. It could be a novel approach to the medical problem to enhance the unaffected hemisphere control. Our research on brachial plexus roots avulsion demonstrated that ipsilateral motor cortex was capable of controlling both the affected and healthy hand following the peripheral cross-neurotization. Based on the discovery, peripheral cross-neurotization was performed to treat the hemiplegic hands after central neurologic injury for the first time.Central Nervous System-2012 September 5-7, 2012 Volume 3 Issue 6 55 J Neurol Neurophysiol ISSN: 2155-9562 JNN, an open access journal H glioblastoma multiforme is the most frequent and aggressive type of brain tumors. The purpose of this study was to design cisplatin-loaded nanogels conjugated with monoclonal antibodies to membrane protein connexin 43 (Cx43) or to brain-specific anion transporter type 1 (BSAT1) for treatment of glioma 101/8 and glioma C6 in vivo.September 5-7, 2012 Volume 3 Issue 6 58 J Neurol Neurophysiol ISSN: 2155-9562 JNN, an open access journal A disease (AD) is a neurodegenerative disorder caused by progressive loss of synapses and neurons, characterized by memory dysfunction and global cognitive impairment. The pathological hallmarks for AD are extracellular senile plaques of amyloid-β-peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) of hyper-phosphorylated tau protein. Tau inclusions are not found only in Alzheimer’s disease but in many others neurodegenerative diseases. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here we report an elegant mechanism of Tau degradation involving the co-chaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades toxic Tau. Thus we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.