Protective Effects of NIM811 in Transient Focal Cerebral Ischemia Suggest Involvement of the Mitochondrial Permeability Transition

2007 ◽  
Vol 24 (5) ◽  
pp. 895-908 ◽  
Author(s):  
Amit S. Korde ◽  
L. Creed Pettigrew ◽  
Susan D. Craddock ◽  
Chava B. Pocernich ◽  
Peter C. Waldmeier ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mitochondrial Permeability Transition ◽  
Focal Cerebral Ischemia ◽  
Permeability Transition ◽  
Protective Effects ◽  
Mitochondrial Permeability ◽  
Transient Focal Cerebral Ischemia

Abstract 2584: Inhibition of Mitochondrial Permeability Transition with NIM811 Improves Functional Recovery after Focal Cerebral Ischemia

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Luther C Pettigrew
Keyword(s):  
Cerebral Ischemia ◽  
Functional Recovery ◽  
Mitochondrial Permeability Transition ◽  
Functional Performance ◽  
Neuronal Degeneration ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Ischemic Reperfusion

Introduction: Mitochondrial dysfunction plays a seminal role in acute ischemic neuronal degeneration, the signature injury in stroke. A selective inhibitor of mitochondrial permeability transition (mPT) may prevent collapse of the mitochondrial membrane potential, thereby inhibiting the intrinsic pathway to neuronal death. Hypothesis: A novel mPT inhibitor, NIM811, will reduce infarct volume and improve functional recovery after focal cerebral ischemia. Methods: NIM811 was obtained as a gift from Novartis Pharma Ltd. (Basel, Switzerland). Focal cerebral ischemia was induced by unilateral carotid and middle cerebral artery occlusion for 2 hrs in male spontaneously hypertensive rats (SHRs). During post-ischemic reperfusion, animals received NIM811 (50 mg/kg at 1- and 24-hrs of post-ischemic reperfusion) or drug-free vehicle. Infarct volume was measured at 24 hrs or 7 days. Functional performance was assessed with 2 measures, fall latency time (FLT) in a Rotarod device and Removal Delay (RD) in a tape removal task, over 28 days. Results: When given after 1 hr of post-ischemic reperfusion, 50 mg/kg NIM811 reduced 24-hr infarct volume (63.6 ± 18.7 [SD] v. 89.3 ± 12.5 mm 3 in controls; n = 8 - 10/group; p ≤ 0.01; unpaired t -test). Serial dosing of NIM811 lowered 7-day infarct volume compared to controls (51.9 ± 7.4 v. 61.9 ± 10.3 mm 3 ; n = 13 - 16/group; p ≤ 0.01; unpaired t -test). In the Rotarod task, NIM811-treated animals had prolonged FLT over controls at all examination times up to 28 days (n = 7 per group; p ≤ 0.0001; ANOVA/Scheffe’s test). NIM811-treated SHRs also had shorter RD for discarding tape applied to the paretic forelimb, compared to controls (n = 7 per group; p ≤ 0.002; ANOVA/Scheffe’s test). Conclusions: Inhibition of mPT with NIM811 significantly reduced infarct volume, when given within a clinically relevant post-ischemic interval. Serial dosing of NIM811 achieved neuroprotective resilience at 7 days. Reductions in infarct volume by NIM811 were complemented by improved functional performance up to 28 days after ischemia. These promising results highlight the potential of NIM811 for neuroprotective treatment of stroke in man.

Neuronal protective effects of focal ischemic pre- and/or postconditioning on the model of transient focal cerebral ischemia in rats

2009 ◽  
Vol 16 (5) ◽  
pp. 693-697 ◽  
Author(s):  
M. Ozgur Taskapilioglu ◽  
Tulin Alkan ◽  
Bulent Goren ◽  
Kudret Tureyen ◽  
Soner Sahin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Protective Effects ◽  
Transient Focal Cerebral Ischemia

NIM811 prevents induction of mitochondrial permeability transition in cerebral ischemia

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S5-S5 ◽  
Author(s):  
Amit S Korde ◽  
Peter Waldmeier ◽  
L Creed Pettigrew ◽  
Susan D Craddock ◽  
William F Maragos
Keyword(s):  
Cerebral Ischemia ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability
Sign in / Sign up

Export Citation Format

Share Document