Enriched environment alleviates neurological deficits via downregulation of Cx43 after experimental stroke

While it has been demonstrated that enriched environment (EE) can protect against cerebral ischemia/reperfusion (I/R) injury, the underlying mechanism remains largely unknown. Connexin 43 (Cx43) is a key component of gap junctions, which may mediate cell-to-cell communication in neural cells. This study aimed to investigate the neuroprotective effects of EE against cerebral I/R injury in rats by modulating Cx43. A rat model of cerebral I/R injury was established by middle cerebral artery occlusion (MCAO)/reperfusion. Rats were randomly divided into the sham, MCAO, MCAO + EE, MCAO + Gap19, and MCAO + EE + Gap19 groups. The modified neurological severity score test and Morris water maze assay were used to assess neurological deficits. The infarct volume was measured using triphenyltetrazolium chloride (TTC) staining. Neuronal survival was detected by immunofluorescence. The indices of oxidative stress were determined using ELISA, and the reactive oxygen species levels were determined using a dihydroethidium probe. Cx43 and inflammation-related protein expression levels were also measured using western blotting and immunohistochemistry. EE and Gap19 treatment significantly improved neurological deficits, reduced infarct volumes, attenuated neuronal injury, and suppressed inflammatory cytokine expression and oxidative stress. Furthermore, EE and Gap19 treatment notably downregulated the expression of Cx43 and the inflammation-related pathway TLR4/MyD88/NF-κB in the ischemic penumbra. Gap19, a Cx43 inhibitor, markedly enhanced the neuroprotective effects of EE in rats with cerebral I/R injury. EE treatment protects against cerebral I/R injury in rats via Cx43 downregulation. Our findings may shed light on the mechanism underlying the protective efficacy of EE.