Adrenomedullin Deficiency and Aging Exacerbate Ischemic White Matter Injury after Prolonged Cerebral Hypoperfusion in Mice

Abstract

Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM+/−group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM+/−group(P<0.05). Oxidative stress was detected in oligodendrocytes, with a larger increase in the AM+/−group(P<0.05). Aged mice showed the same tendency, but white matter damage was worse, especially in the aged AM+/−group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM+/−group. Adrenomedullin may be an important target in the control of ischemic white matter injury.