Adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion in mice.

Yumiko Mitome-Mishima,Hajime Arai,Hidenori Oishi,Nobutaka Hattori,Ryota Tanaka,Tatsuo Shimosawa,Takao Urabe,Nobukazu Miyamoto

doi:10.1155/2014/861632

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.

Highlights

Adrenomedullin (AM) is a hypotensive peptide discovered in human pheochromocytoma [1]
Age-related accumulation of oxidative stress is involved in blood pressure regulation and insulin resistance in aged AM+/− mice, and AM is an endogenous substance counteracting oxidative stress-induced insulin resistance associated with aging
Prolonged cerebral hypoperfusion-induced white matter (WM) lesions contribute to the development of cognitive impairments that are common and difficult to cure in the elderly population

Summary

Introduction

Adrenomedullin (AM) is a hypotensive peptide discovered in human pheochromocytoma [1]. AM has a variety of effects on the vasculature that include vasodilation, regulation of permeability, inhibition of endothelial cell apoptosis and oxidative stress, regulation of smooth muscle cell proliferation, and promotion of angiogenesis [1, 4]. Some studies have demonstrated that oxidative stress in vascular endothelial and smooth muscle cells can increase production of AM, which acts as an endogenous antioxidant to protect organs [8,9,10]. A recent study demonstrated that circulating AM is a highly potent and effective modality for restoring perfusion, promoting arteriogenesis and angiogenesis in the chronically ischemic brain, inhibiting oxidative damage in cerebral microvessels, preserving ischemic white matter (WM) integrity, and attenuating working memory deficits in a mouse model of subcortical vascular dementia [14]. We compared white matter injury formation in aged WT and AM+/− mice to evaluate the effect of high blood sugar and aging on prolonged cerebral hypoperfusion

Experimental Procedures

Results and Discussion

Conclusion