Neurodegeneration in Hypoxia: Implications in Aging

Abstract

Hypoxia and ischemia resulting in reduced oxygen delivery to brain tissues is reported to cause neurodegeneration in both in vitro and in vivo models. Similar decrease in partial pressure of oxygen occurs on ascent to high altitude, a situation referred to as hypobaric hypoxia that limits oxygen availability to the brain. Our studies on human subjects reveal decrease in vigilance and response time along with decreased cerebral oxygenation which is both altitude and duration dependent. Alterations in evoked potentials and change in hedonic matrix were also observed following exposure to high altitude environment. Investigations in animal models exposed to simulated altitude showed occurrence of oxidative stress, neurodegeneration and memory impairment. This hypoxic response of neurons is multi-factorial and involves complex signaling pathways thereby limiting the therapeutic efficacy of several antioxidants in ameliorating hypobaric hypoxia-induced memory impairment. Animals exposed to hypobaric hypoxia show depletion in the antioxidant status along with increased free radical generation. Neuromorphological studies revealed neurodegeneration and dendritic atrophy in the hippocampus. Altered neurotransmitter synthesis, release and metabolism have also been observed along with occurrence of calcium overload in hypoxic neuronal cells. These changes in the hypoxic brain find an analogy with the aging related changes that include decreased conduction rate, generation of free radicals, protein oxidation and cellular apoptosis. Administration of N-acetyl cysteine to animals exposed to hypobaric hypoxia showed considerable improvement in memory functions along with decrease in free radical generation. Acetyl-L-Carnitine administration during hypobaric hypoxia also improved the cognitive capabilities in animal models. Our investigations revealed a multifactorial action of Acetyl-L-Carnitine that included

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Hypoxia-Induced Degenerative Protein Modifications Associated with Aging and Age-Associated Disorders

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