Clonidine attenuates chronic hypoxic stress-induced behavioral abnormalities in male Swiss mice through suppression of oxidative stress and pro-inflammatory cytokines.

Abstract

Hypoxia is a potent stressor arising from insufficient oxygen delivery to the brain that can trigger neuronal damage and neurological complications. Oxidative stress (OS) and neuroinflammation have been implicated in hypoxia-induced neuropathologies. Clonidine, an alpha-2 adrenoceptor agonist, has been reported to exhibit neuroprotective effects in various animal models by reducing oxidative stress-mediated neurodegeneration. This study further explored its neuroprotective effects in mice subjected to chronic hypoxic stress (CHS). Male Swiss mice (20-25 g) were randomly distributed into five groups (n = 8). Group 1 (non-stress control) and group 2 (stress control) received distilled water (10 mL/kg), and groups 3-5 had clonidine (25, 50 and 100 µg/kg), orally for 14 days. Thirty minutes after each daily treatment, mice in groups 2-5 underwent a scheduled CHS protocol in a 300-mL sealed vessel for 20 min, daily for 14 days. Neurobehavioral changes and plasma corticosterone were determined. The malondialdehyde, nitrites, acetylcholinesterase (AChE), myeloperoxidase (MPO), antioxidant profile (SOD, GSH, catalase, GST), pro-inflammatory cytokines (IL-6 and TNF-α), and histomorphological changes were evaluated in the hippocampus, prefrontal cortex, and amygdala. Clonidine attenuated neurobehavioral deficits and reduced plasma corticosterone in mice exposed to CHS. Clonidine treatment reduced malondialdehyde, nitrites, pro-inflammatory cytokines, AChE, and MPO contents ; enhanced antioxidant defense molecules; and preserved the neuronal cell integrity in the discrete brain regions of mice subjected to CHS. These findings suggest that clonidine mitigated CHS-induced behavioral impairments by reducing OS and pro-inflammatory cytokines, and may be repurposed as a promising therapeutic candidate for chronic stress-related disorders.