title: The effect of captopril on the expression of MMP-9 and the prognosis of neurological function in herpes simplex encephalitis mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zeng
authors.affiliation: a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.
authors.forename: Jing-Xia
authors.initials: JX
authors.lastname: Guan
authors.affiliation: a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.
authors.forename: Zu-Neng
authors.initials: ZN
authors.lastname: Lu
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001929:Brain Edema / Q000209:etiology; D039481:CD11b Antigen / Q000378:metabolism; D002216:Captopril / Q000627:therapeutic use*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020803:Encephalitis, Herpes Simplex / Q000150:complications*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000821:virology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D039481:CD11b Antigen; D024141:Collagen Type IV; D017382:Reactive Oxygen Species; D002216:Captopril; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020780:Matrix Metalloproteinase 9
keywords: Angiotensin II; Blood–brain barrier; Herpes simplex encephalitis; Matrix metalloproteinase-9; ROS