Exposure to hypobaric
hypoxia, a condition involving decreased availability of
oxygen is known to be associated with oxidative stress, neurodegeneration and memory impairment. The multifactorial response of the brain and the complex signaling pathways involved therewith limits the therapeutic efficacy of several
antioxidants in ameliorating hypobaric
hypoxia-induced memory impairment. The present study was therefore aimed at investigating the potential of
acetyl-l-carnitine (
ALCAR), a known
antioxidant that has been reported to augment
neurotrophin-mediated survival mechanisms, in ameliorating
hypoxia-induced neurodegeneration and memory impairment. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key
transcription factor involved in the cellular defense mechanism against oxidative stress related to
brain injury and
neurological disorders. The study was designed to understand the mechanisms involving Nrf2 stabilization following exposure to hypobaric
hypoxia. The results displayed reference memory impairment in Sprague-Dawley rats exposed to hypobaric
hypoxia (7620 m) for 14 consecutive days which however improved on administration of
ALCAR during hypoxic exposure. The study also revealed Nrf2 regulated augmented
antioxidant response on administration of
ALCAR which was through a novel
tyrosine kinase A (
TrkA) receptor-mediated mechanism. A decrease in
free radical generation, lipid peroxidation and
protein oxidation was also observed along with a concomitant increase in
thioredoxin and
reduced glutathione levels on administration of
ALCAR during exposure to hypobaric
hypoxia. The present study therefore reveals the therapeutic potential of
ALCAR under conditions of hypobaric
hypoxia and elucidates a novel mechanism of action of the
drug.