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American Heart Association

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Final ID: DP56

Efficacy of Matrix Metalloproteinase-12 Gene Silencing on Post-Stroke Neurological Recovery in Aged Mice and Hypertensive Rats

Abstract Body: Introduction: We discovered a marked upregulation of MMP-12 levels in the brain following an ischemic stroke and demonstrated that reducing MMP-12 levels in otherwise healthy rodents decreases brain damage and facilitates functional recovery. This study aimed to assess the effectiveness of MMP-12 gene silencing in improving sensorimotor function recovery in aged mice and hypertensive rats. Methods: Both male and female C57BL/6 mice (≥16 months old) and male spontaneously hypertensive rats (SHRs) (2-3 months old) were subjected to 35-min and 1-h transient right middle cerebral artery occlusion (MCAO), respectively. Appropriate cohorts of animals (25 mice/group; 18 rats/group) received either control shRNA or MMP-12 shRNA plasmids (1 mg/kg) formulated as nanoparticles that were administered intravenously via tail vein 2 h after reperfusion. In mice, stroke symptoms were evaluated using the neurological deficit score at 2-4 hours and 1 day after reperfusion, while the modified neurological severity score was used in rats. Sensorimotor functions were assessed using the sticky tape test, pole test, and rotarod test at baseline (before MCAO) and at regular intervals post-MCAO (days 3, 5, and 7 in mice, and days 1, 3, 5, 7, and 14 in rats). Results: MMP-12 expression in the ischemic brain was significantly increased by 35-min MCAO in aged mice and 1-h MCAO in SHRs, as was previously observed in healthy young mice and rats that were subjected to 1-h and 2-h MCAO, respectively. In comparison to the control shRNA treatment, MMP-12 shRNA treatment facilitated a greater mean recovery of somatosensory function in aged mice (sticky tape latency was significant on day 3 and day 5; sticky tape interaction was significant on day 5) and in SHRs (sticky tape ratio was significant on day 14). Furthermore, MMP-12 shRNA treatment resulted in a greater mean recovery of motor function across all tested time points in aged mice (pole descent score was significant on day 7; rotarod latency was significant on day 7) and in SHRs (rotarod latency was significant on day 5 and day 14). Conclusions: Reducing MMP-12 expression in the ischemic brain facilitates the recovery of both somatosensory and motor function in aged mice and hypertensive rats after transient focal cerebral ischemia. Our findings further reinforce the potential benefits of MMP-12 gene silencing as a therapeutic approach for improving recovery outcomes in stroke patients.
  • Challa, Siva Reddy  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Klopfenstein, Jeff  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Veeravalli, Krishna Kumar  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Baker, Isidra  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Fornal, Casimir A.  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Sama, Vinay  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Veeravalli, Sahil  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Frakes, Rachel  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Unnam, Pavani  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Wang, Billy  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Pinson, David  ( University of Illinois College of Medicine Peoria , Peoria , Illinois , United States )
  • Author Disclosures:
    Siva Reddy Challa: DO NOT have relevant financial relationships | Jeff Klopfenstein: No Answer | Krishna Kumar Veeravalli: DO NOT have relevant financial relationships | Isidra Baker: DO NOT have relevant financial relationships | Casimir A. Fornal: No Answer | Vinay Sama: DO NOT have relevant financial relationships | Sahil Veeravalli: DO NOT have relevant financial relationships | Rachel Frakes: DO NOT have relevant financial relationships | Pavani Unnam: DO NOT have relevant financial relationships | Billy Wang: DO NOT have relevant financial relationships | David Pinson: DO NOT have relevant financial relationships
Meeting Info:
Session Info:

Translational Basic Science Moderated Digital Posters II

Thursday, 02/06/2025 , 03:00PM - 03:30PM

Moderated Digital Poster Abstract Session

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