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. Thirty-five male Swiss mice were distributed into 5 groups (n = 7). 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 mg/kg), intraperitonally. Thirty minutes later, mice in groups 2–5 were subjected to 15 min 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 (SOD), catalase, tumor necrosis factor-alpha (TNF-α) and interleukin-1β assays. The serum corticosterone concentration and expressions of the brain immunopositive cells of inducible nitric oxide synthase (iNOS), nuclear factor kappa-B (NF-kB) and brain derived neurotrophic factor (BDNF) as well as histomorphological changes of the amygdala were also determined. Naringenin (25−50 mg/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 (glutathione and SOD) status were attenuated by naringenin. Naringenin (10 mg/kg) increases BDNF expression but did not significantly (p < 0.05) 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 mg/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.