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Randomized Controlled Preclinical Trial of a Benzodiazepine-Dihydropyridine Hybrid Molecule in Rodent Stroke
Jeney Ramírez-Sánchez1, André Rex2, Sarah K McCann3
1Experimental Neuropharmacology Laboratory Center for Pharmaceutical Research and Development La Habana Cuba.
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 between vehicle- and JM-20-treated animals, although neuroscores and survival were slightly better in JM-20-treated animals. In the less-severe model of permanent cortical focal cerebral ischemia in rats, JM-20 significantly reduced brain infarction.
Conclusions:
We were able to confirm the neuroprotective potential of JM-20. However, effect sizes were substantially lower than previously described in small monocentric trials. Further study is needed to determine whether JM-20 could be effective in less-severe cases of focal cerebral ischemia or when used in combination with thrombolysis.
Registration:
URL: Unique identifier: DOI: 10.17590/asr.0000181.
