Naringenin improves depressive- and anxiety-like behaviors in mice exposed to repeated hypoxic stress through modulation of oxido-inflammatory mediators and NF-kB/BDNF expressions

Abstract

Oxidative and inflammatory signaling pathways have been identified as important targets for mitigating hypoxic stress-induced neurological complications. Thus, the effects of naringenin, a potent antioxidant, anti-inflammatory and neuroprotective bioflavonoid on hypoxic stress-induced depressive-like and anxiety-related behaviors in mice, and the underlying molecular mechanisms were evaluated in this study. Forty-two male Swiss mice were distributed into 5 groups (n\u2009=\u20097). Mice in group I (non-stress control) and group 2 (stress-control) both had vehicle (5% DMSO), while groups 3-5 received naringenin (10, 25 and 50\u2009mg/kg), intraperitonally. Thirty minutes later, mice in groups 2-5 were subjected to 15\u2009min hypoxic stress, daily for 14 days. Locomotor activity, anxiety and depression were evaluated on day 15. The mice brains were processed for malondialdehyde, glutathione, superoxide-dismutase, catalase, tumor necrosis factor-alpha (TNF-α) and interleukin-1β assays. The serum corticosterone concentration and expressions of the brain immunopositive cells of iNOS, NF-kB and BDNF as well as histomorphological changes of the amygdala were also determined. Naringenin (25-50\u2009mg/kg) ameliorated the hypolocomotion, depressive- and anxiety-like behaviors in hypoxic mice. The increased brain contents of malondialdehyde, TNF-α, interleukin-1β, and decreased antioxidant (GSH and SOD) status were attenuated by Naringenin. Naringenin (10\u2009mg/kg) increases BDNF expression but did not significantly (p\u2009<\u20090.05) alter corticosterone and catalase contents. The increased expressions of iNOS and NF-kB as well as loss of amygdala neuronal cells were reduced by naringenin (10\u2009mg/kg). Overall, these findings suggest that naringenin improves depressive- and anxiety-like behaviors in mice exposed to hypoxic stress by modulating oxido-inflammatory insults and NF-kB/BDNF expressions.