• Richa Choudhary, Udayabanu Malairaman, and Anju Katyal.
• Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
• Neuroscience. 2017 Sep 17; 359: 308-324.

Abstract12/15 Lipoxygenase has recently been described as potent propagator of oxidative stress and is closely associated with cognitive decline in neurodegenerative diseases. The mechanism/s behind 12/15 LOX involvement in cognitive deficits remain obscure. The current study has been designed to investigate the underlying role of 12/15LOX and effect of 12/15 LOX inhibition on hypobaric hypoxia-induced memory impairment and cholinergic deficits. Male Balb/c mice subjected to simulated hypobaric hypoxia/reoxygenation condition for 3days showed marked working memory impairment concomitant with hippocampal neuronal damage and malondialdehyde production which were significantly attenuated by baicalein, a specific inhibitor of 12/15LOX. Hypobaric hypoxia-exposed mice had consistently increased expression of 12/15LOX and elevated 12(S) HETE levels in the hippocampus as well as plasma which were significantly mitigated following baicalein treatment. 12/15LOX inhibition also reduced hypobaric hypoxia-mediated upregulation of hippocampal HIF-1α protein expression along with reduction in expression of inflammatory genes. The inhibition of 12/15 LOX resulted in a significant decrease in NO levels in the hippocampal homogenate associated with downregulated iNOS, nNOS transcription but not eNOS speculating that 12/15 LOX is critically involved in HIF-1α, mediated by nitric oxide-induced neurotoxicity. We also observed a similar effect of 12/15 LOX inhibition on hippocampal COX2 expression. 12/15LOX inhibition could effectively modulate central cholinergic indices during hypobaric hypoxia by restoring mAChR-1, α7NAChR expression and AChE, ChAT activity in the hippocampus comparable to normal mice. We report here the mechanistic involvement of 12/15LOX in orchestrating hypoxia-associated neuronal damage and HIF-1α-dependent neuroinflammation resulting in cognitive decline.Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

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