The effect of captopril on the expression of MMP-9 and the prognosis of neurological function in herpes simplex encephalitis mice

Abstract

Background and purpose: Early increased matrix metalloproteinase-9 (MMP-9) expression is involved in the evolution of herpes simplex encephalitis (HSE) by facilitating the development of cerebrovascular complications. However, the molecular mechanism underlying the detrimental effects of MMP-9 in HSE has not been elucidated. Recent research finds angiotensin II plays an important role in regulation of MMP-9 activity. The aim of this work was to identify the influence of angiotensin-converting enzyme inhibitor (ACEI) captopril on MMP-9 activation after herpes simplex virus 1 (HSV-1) infection.Methods: Animal models of HSE were established by intracerebral inoculation of HSV-1 into mice. Brain tissue ROS levels were measured by staining with dihydroethidium. MMP-9 protein expression was detected by immunofluorescence and brain water content was measured with dry-wet weight method. Neurological function score was quantified 5 d after HSV-1 infection. Microglial cells were treated with various concentrations of captopril. MMP-9 gelatinolytic activity in the supematant of the cell cultures was assessed by zymography. RT-PCR was used to detect the mRNA expressions of p47phox and MMP-9.Results: Immunofluorescence showed that expression of MMP-9 in brain tissue was mainly presented in OX-42 positive microglia. Quantification of gelatinolytic activity by densitometry showed that expression of MMP-9 in microglia was significantly increased after HSV-1 infection and inhibited by captopril treatment. NADPH oxidase subunit p47phox and MMP-9 mRNA expression were significantly increased 6 h after HSV-1 infection, and were seen reduced after captopril treatment in dose dependence. Captopril also downregulated ROS and MMP-9 protein expression following encephalitis in vivo, and attenuated brain edema, and improved neurological function.Discussion: This compelling evidence suggests that MMP-9 is a key pathogenic factor within HSE. ACEI captopril could reduce the expression of MMP-9 mediated by ROS, then relieve cerebral edema and improve neurological function, which may lay a foundation for further basic research and clinical application.