Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage

Sci Rep. 2015 May 8:5:9504. doi: 10.1038/srep09504.

Abstract

This study highlights the possible pathological role of MMP-12 in the context of ischemic stroke. Male rats were subjected to a two-hour middle cerebral artery occlusion (MCAO) procedure. MMP-12 shRNA expressing plasmid formulation was administered to these rats twenty-four hours after reperfusion. The results showed a predominant upregulation of MMP-12 (approximately 47, 58, 143, and 265 folds on days 1, 3, 5, 7 post-ischemia, respectively) in MCAO subjected rats. MMP-12 expression was localized to neurons, oligodendrocytes and microglia, but not astrocytes. Transcriptional inactivation of MMP-12 significantly reduced the infarct size. The percent infarct size was reduced from 62.87±4.13 to 34.67±5.39 after MMP-12 knockdown compared to untreated MCAO subjected rats. Expression of myelin basic protein was increased, and activity of MMP-9 was reduced in ischemic rat brains after MMP-12 knockdown. Furthermore, a significant reduction in the extent of apoptosis was noticed after MMP-12 knockdown. TNFα expression in the ipsilateral regions of MCAO-subjected rats was reduced after MMP-12 knockdown in addition to the reduced protein expression of apoptotic molecules that are downstream to TNFα signaling. Specific knockdown of MMP-12 after focal cerebral ischemia offers neuroprotection that could be mediated via reduced MMP-9 activation and myelin degradation as well as inhibition of apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Brain Injuries / enzymology*
  • Brain Injuries / genetics*
  • Brain Ischemia / enzymology*
  • Brain Ischemia / genetics*
  • Cell Line, Tumor
  • Gene Knockdown Techniques
  • Gene Silencing* / drug effects
  • Male
  • Matrix Metalloproteinase 12 / genetics*
  • Matrix Metalloproteinase 12 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Myelin Basic Protein / metabolism
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / pathology
  • Plasmids / metabolism
  • RNA, Small Interfering / metabolism
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Reperfusion
  • Substrate Specificity / drug effects
  • Transcription, Genetic* / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects

Substances

  • Myelin Basic Protein
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 12