Randomized Controlled Preclinical Trial of a Benzodiazepine–Dihydropyridine Hybrid Molecule in Rodent Stroke
Abstract
Background The 3‐ethoxycarbonyl‐2‐methyl‐4‐(2‐nitrophenyl)‐4,11‐dihydro‐1H‐pyrido[2,3‐b][1,5]benzodiazepine (JM‐20) molecule is a novel multifunctional molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide a robust preclinical evidence base for potential clinical development in stroke, we performed a 2‐center preclinical trial with sufficiently large group sizes to detect relevant effects, minimizing biases in experimental design as much as possible (randomization, blinding, predefined in‐ and exclusion criteria) and increasing external and construct validities. Methods Experimental focal cerebral ischemia was induced by different surgeons in 2 different laboratories on 2 continents, including 2 species (480 mice and 55 rats), different suppliers, mature adult and middle‐aged male animals (age range, 2–16 months) as well as comorbid animals (streptozotocin‐induced diabetes). Results Although JM‐20 improved functional outcomes after middle cerebral artery occlusion in young adult mice at day 7 and appeared to reduce mortality (not statistically significant), it had no effect on mature adult or comorbid mice. Effect sizes, where statistically significant, were modest, and much lower than those reported in the previous studies. Meta‐analysis of all individual mouse data did not reveal statistically significant different functional outcomes or mortalities…
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