Neudesin attenuates ischemic brain injury by regulating Nos2 expression in microglia

Ischemic stroke causes neurological deficits and severe disabilities such as paresis, ataxia, and cognitive impairment. Therefore, the development of treatments for cerebral infarction and search for new therapeutic targets are of paramount importance. The secretory factor neudesin is known to suppress inflammation. Inflammation contributes to the progression of stroke. Therefore, we investigated role of neudesin in cerebral ischemia using neudesin knockout (KO) mice. These animals exhibited significantly large infarct volumes, suggesting that neudesin suppresses stroke progression. Furthermore, in microglia-depleted mice generated by the administration of a colony-stimulating factor 1 receptor inhibitor, the infarct expansion in neudesin KO mice was attenuated, suggesting that neudesin suppresses stroke progression through microglia. Interestingly, activated microglia in neudesin KO mice did not show an overall increase in inflammatory markers except for a marked upregulation of nitric oxide synthase 2 (Nos2; also known as inducible nitric oxide synthase (iNOS)). Treatment with an iNOS inhibitor mitigated the increase in infarct size caused by neudesin deficiency. These findings suggest that neudesin suppresses ischemic brain damage by regulating Nos2 expression in microglia.