Heat stroke-induced structural and functional impairments of cognition-relevant brain areas in mice is associated with alpha-7 nicotinic acetylcholine receptors downregulation.

OBJECTIVE

Classic heat stroke (CHS) results from prolonged exposure to high environmental temperatures without physical exertion. However, the involvement of α7 nicotinic acetylcholine receptors (α7nAChR) in CHS-associated neurobehavioral abnormalities remains unclear.

METHODS

Immediately after CHS onset, mice received intraperitoneal lonafarnib (LNF-40; 40 mg/kg) or vehicle twice daily for 14 days. Animals were assigned to four groups: non-CHS + Veh, non-CHS + LNF-40, CHS + Veh, and CHS + LNF-40. After the final dose, neurobehavioral performance was evaluated using novel object recognition, forced swim, rotarod, and Morris water maze tests. Dendritic morphology of prefrontal cortical neurons was assessed by Golgi staining, whereas hippocampal neurogenesis was evaluated by doublecortin (DCX) immunofluorescence. Finally, α7nAChR levels and pro-inflammatory cytokines in the prefrontal cortex and hippocampus were quantified by ELISA.

RESULTS

Compared with non-CHS controls, CHS + Veh mice exhibited impaired recognition and spatial memory, increased depressive-like behavior, and reduced motor coordination. Relative to CHS + Veh, CHS + LNF-40 mice showed attenuated neurobehavioral deficits. Structurally, Golgi analyses indicated that LNF-40 reduced CHS-associated dendritic/spine pathology in prefrontal cortical neurons, and DCX immunofluorescence showed higher hippocampal neurogenesis in LNF-40-treated CHS mice. Biochemically, LNF-40 was associated with higher α7 nAChR levels and lower pro-inflammatory cytokines in both the prefrontal cortex and hippocampus. LNF-40 did not significantly alter these measures in non-CHS mice.

CONCLUSION

CHS is associated with structural and functional impairments in cognition-relevant brain regions, accompanied by reduced α7nAChR expression. Lonafarnib mitigated CHS-related neurobehavioral abnormalities in parallel with restoration of α7nAChR expression in mice.