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

Authors

Bharath Chelluboina, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
Aditi Warhekar, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
Matt Dillard, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
Jeffrey D. Klopfenstein, 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.
David M. Pinson, Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
David Z. Wang, 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.Follow
Krishna Kumar Veeravalli, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.

Document Type

Article

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.

Medical Subject Headings

Animals; Apoptosis (drug effects); Brain Injuries (enzymology, genetics); Brain Ischemia (enzymology, genetics); Cell Line, Tumor; Gene Knockdown Techniques; Gene Silencing (drug effects); Male; Matrix Metalloproteinase 12 (genetics, metabolism); Matrix Metalloproteinase 9 (metabolism); Myelin Basic Protein (metabolism); Neurons (drug effects, enzymology, 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)

Publication Date

5-8-2015

Publication Title

Scientific reports

E-ISSN

2045-2322

Volume

5

First Page

9504

PubMed ID

25955565

Digital Object Identifier (DOI)

10.1038/srep09504

Recommended Citation

Chelluboina, Bharath; Warhekar, Aditi; Dillard, Matt; Klopfenstein, Jeffrey D.; Pinson, David M.; Wang, David Z.; and Veeravalli, Krishna Kumar, "Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage" (2015). Neurology. 1811.
https://scholar.barrowneuro.org/neurology/1811