title: Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage.
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.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Chelluboina
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Warhekar
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Dillard
authors.affiliation: 1] Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA [2] Comprehensive Stroke Center, Illinois Neurological Institue, Peoria, IL, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Klopfenstein
authors.affiliation: Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Pinson
authors.affiliation: 1] Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA [2] Comprehensive Stroke Center, Illinois Neurological Institue, Peoria, IL, USA.
authors.forename: David Z
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: Krishna Kumar
authors.initials: KK
authors.lastname: Veeravalli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000201:enzymology* / Q000235:genetics*; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015424:Reperfusion; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004676:Myelin Basic Protein; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12