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

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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.