MMP-12 knockdown prevents secondary brain damage after ischemic stroke in mice

Vijay Arruri; Anil K Chokkalla; Soomin Jeong; Bharath Chelluboina; Suresh L Mehta; Krishna Kumar Veeravalli; Raghu Vemuganti

doi:10.1016/j.neuint.2022.105432

MMP-12 knockdown prevents secondary brain damage after ischemic stroke in mice

Neurochem Int. 2022 Dec:161:105432. doi: 10.1016/j.neuint.2022.105432. Epub 2022 Oct 14.

Authors

Vijay Arruri¹, Anil K Chokkalla¹, Soomin Jeong², Bharath Chelluboina¹, Suresh L Mehta¹, Krishna Kumar Veeravalli³, Raghu Vemuganti⁴

Affiliations

¹ Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI, USA.
² Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.
³ Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA; Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA; Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL, USA; Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA. Electronic address: krishnav@uic.edu.
⁴ Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Veterans Administration Hospital, Madison, WI, USA. Electronic address: vemuganti@neurosurgery.wisc.edu.

Abstract

We previously reported that increased expression of matrix metalloproteinase-12 (MMP-12) mediates blood-brain barrier disruption via tight junction protein degradation after focal cerebral ischemia in rats. Currently, we evaluated whether MMP-12 knockdown protects the post-stroke mouse brain and promotes better functional recovery. Adult male mice were injected with negative siRNA or MMP-12 siRNA (intravenous) at 5 min of reperfusion following 1 h transient middle cerebral artery occlusion. MMP-12 knockdown significantly reduced the post-ischemic infarct volume and improved motor and cognitive functional recovery. Mechanistically, MMP-12 knockdown ameliorated degradation of tight junction proteins zonula occludens-1, claudin-5, and occludin after focal ischemia. MMP-12 knockdown also decreased the expression of inflammatory mediators, including monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6, and the expression of apoptosis marker cleaved caspase-3 after ischemia. Overall, the present study indicates that MMP-12 promotes secondary brain damage after stroke and hence is a promising stroke therapeutic target.

Keywords: Inflammation; Ischemia-reperfusion; Matrix metalloproteinases; Neuroprotection; Tight junction proteins.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / metabolism
Brain Injuries* / metabolism
Brain Ischemia* / metabolism
Infarction, Middle Cerebral Artery / metabolism
Ischemic Stroke*
Male
Matrix Metalloproteinase 12 / genetics
Matrix Metalloproteinase 12 / metabolism
Mice
Occludin / metabolism
RNA, Small Interfering
Stroke* / metabolism

Substances

Matrix Metalloproteinase 12
Occludin
RNA, Small Interfering

Abstract

Publication types

MeSH terms

Substances

Grants and funding