Therapeutic effects of combination environmental enrichment with necrostatin-1 on cognition following vascular cognitive impairment in mice

Cognitive dysfunction resulting from the reduction of cerebral blood flow has been defined as “vascular cognitive impairment” (VCI) which has become the second cause of dementia only after Alzheimer’s disease (AD) and arouses great concerns. There is accumulating evidence that environmental enrichment (EE) can induce functional and anatomical alterations and then bring about overt improvement in memory and learning tasks in many injury paradigms, including ischemic brain injury. Moreover, necrostatin-1 (Nec-1), the special inhibitor of necroptosis, improved functional outcomes following ischemic brain injury and AD. The question of whether and what effect EE and EE + Nec-1 could bring about on cognitive performance and microenvironment and histopathological consequences in the mice suffering from VCI is still unclear. In this study, we investigated this question using the bilateral common carotid artery stenosis (BCAS) mouse model. A week after surgical operation for BCAS, mice were reared for 3 weeks either in standard housing condition or in an EE consisting of special cage filling with various stimulatory items. The results found that the mice in the BCAS + EE and BCAS + EE + Nec-1 groups showed significantly shorter latencies and distances to reach the platform in behavioral tests versus untreated mice at 4 weeks after BCAS surgery. However, three injured groups showed significant deficits compared with the sham group ( P  < 0.05). In addition, there were no differences between the EE-reared mice and EE + Nec-1-treated mice except in the level of expression of inflammation cytokines. Our results indicated that noninvasive environmental stimulation is beneficial in ameliorating cognitive deficits and inflammation response in mice following VCI and that Nec-1 enhanced the inhibitory effect of EE on inflammation response.