Neuroprotective effects of therapeutic hypercapnia on spatial memory and sensorimotor impairment via anti-apoptotic mechanisms after focal cerebral ischemia/reperfusion

Abstract

A number of studies have demonstrated that therapeutic hypercapnia ameliorates neurological deficits and attenuates the histological damage of cerebral ischemia-reperfusion injury. However, the effects of therapeutic hypercapnia on impaired spatial memory have not been reported. Here we aimed to investigate the effects and mechanisms of therapeutic hypercapnia on spatial memory in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Adult male rats were randomly assigned into three experimental groups: sham (sham operation), IR (MCAO/R), and hypercapnia [arterial blood CO2 tension (PaCO2) 80-100 mmHg+IR] groups. Sensorimotor deficits and spatial memory testing were evaluated by an 18-point scoring system and an 8-arm radial maze task, respectively. The hippocampal histological damage and the percentage of apoptotic neurons were evaluated by hematoxylin and eosin (HE) staining as well as flow cytometry. Western blotting was used to investigate the changes of the apoptosis-related Bcl-2 and Bax proteins. The results indicated that hypercapnia treatment significantly improved the abilities of impaired sensorimotor and spatial memory after MCAO/R. Moreover, hypercapnia treatment significantly increased the percentage of surviving neurons and decreased the percentage of apoptotic neurons in the hippocampus after MCAO/R damage. The expressions of anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax were significantly increased and decreased in the hypercapnia treated rats, respectively. These findings suggest that therapeutic hypercapnia can attenuate neuronal apoptosis and improve impaired spatial memory and sensorimotor after MCAO/R, which may be attributable to its anti-apoptotic effects through modulation of apoptosis-related protein.

Keywords: Apoptosis; Focal cerebral ischemia; Spatial memory; Therapeutic hypercapnia.