title: Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.
abstract: OBJECTIVE
  Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine.
  
  
  METHODS
  We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions.
  
  
  RESULTS
  Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine.
  
  
  CONCLUSIONS
  These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
authors.forename: Zheng-Zhen
authors.initials: ZZ
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China. Electronic address: xiulans@njmu.edu.cn.
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Sun
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology*; D002550:Cerebral Veins / Q000294:innervation*; D024141:Collagen Type IV / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005947:Glucose / Q000172:deficiency; D051528:Guanylate Kinases / Q000378:metabolism; D002534:Hypoxia, Brain / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008559:Memantine / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture
chemical_list: D024141:Collagen Type IV; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D051528:Guanylate Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D005947:Glucose; D008559:Memantine
keywords: Cerebral ischemia; Memantine; Neurovascular unit