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Neurodegenerative Disorders and Oxidative Stress

Govind Singh, V. K. Khanna, M. Parle and A.B. Pant

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Studies using experimental models and human brain have demonstrated the possible role of oxidative stress in neuronal degenerative disorders like, epilepsy, stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis by causing damage in cell membrane, lipid peroxidation, protein oxidation and carbohydrate damage and DNA damage which ultimately leads to either necrotic or apoptotic cell death. However, lots of gaps are remain to understand the etiology and pathogenesis of these diseases. These neurodegenerative disorders are posing an increased pressure on medical and social strengths round the globe.

Neurodegenerative disorders: status of pathogenesis mechanism: A number of neurodegenerative disorders e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, tardive dyskinesia, frontal temporal dementia’s (FTD’s) and prion disease have complex etiopathology and multiple biochemical factors in the brain areas are involved. The precise role of the different neurotransmitters and their preponderance is yet not fully understood. There are some similarities in the neurochemical changes in the brain and overlaps in the pathogenic mechanisms that underlie these neurodegenerative processes. Elucidation of the intracellular pathological pathways reveled the formation of the free radicals, which have deleterious effects on the cellular targets in neurodegenerative disorders. This may be important not only for understanding the pathophysiologic basis of neuronal death in these disorders, but also for devising the rational pharmacologic strategies to slow or prevent neuronal degeneration.

CNS susceptibility to oxidative stress: Tissues of the central nervous system may be more vulnerable to oxidative stress because of their constant high rate of oxygen consumption and high mitochondrial density. Free radicals are the byproducts of energy metabolism, and the energy metabolism in brain is high. It is one of the most metabolically active organs of the body with an oxygen consumption of 35 ml/min/kg. It is estimated that approximately 2% of the oxygen used is converted to oxygen radicals. Brain contains relatively high levels of unsaturated fatty acids that are particularly good substrates for peroxidation reactions. Endogenous defense mechanisms are poor in brain. Most H2O2 in the brain is removed by glutathione peroxidase, which result in oxidation of reduced glutathione. Catalase removes H2O2, but is found at very low level in brain. The high iron content in brain coupled with high degree of unsaturation of brain lipids leads to extremely rapid peroxidation in brain.

Alzheimer’s disease and oxidative stress: Alzheimer’s disease (AD) is characterized by degeneration of neurons, especially pyramidal neurons in the hippocampus, entrohinal cortex and neocortical areas and cholinergic neurons in the median forebrain. The two neuropathologic hallmarks of AD are amyloid plaques and neurofibrillary tangles. The amyloid plaque is the deposition of the b-amyloid (Ab). In vitro experiments suggest that oxidative stress may contribute to Ab toxicity. Also it is reported that amyloid itself may generate free radicals that can damage neurons. Polymerization of tau, the major component of intracellular neurofibrillary tangles has also been associated with oxidative stress. Certain antioxidants, like trans resveratrol, melatonin and alpha lipoic acid, have been found to be effective in rat models of AD. Also the Indian herbal drugs like Centella asiatica and Celastrus paniculatus, which possess antioxidant property, have been found to improve memory in normal rats and rat models of AD.

Parkinson’s disease and oxidative stress: Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons

Govind Singh*, V. K. Khanna, M. Parle* and A.B. Pant

Industrial Toxicology Research Centre, Lucknow. India ([email protected])

*Department of Pharmaceutical Sciences, Guru Jambheshwar University, Hisar- India