Abstract
JM-20 is a novel multifunctional benzodiazepine 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 have performed a two-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 by performing experimental focal cerebral ischemia by different surgeons in two different laboratories on two continents, including two species (480 mice and 55 rats), different suppliers, young, young adult, and mature adult animals (range 2 -16 months) as well as comorbid animals (diabetes). While 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 in mature adult or comorbid (STZ-induced diabetes) 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. We conclude that we were able to confirm the neuroprotective potential of JM-20. However, effect sizes were substantially lower as 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.
Competing Interest Statement
JRS, LAFF, MWG and YNF and are co-inventors on patent EP2487174A2 TRICYCLIC AND TETRACYCLIC SYSTEM WITH ACTIVITY ON THE CENTRAL NERVOUS AND VASCULAR SYSTEMS and WO2017190713 BENZODIAZEPINE PRODUCT WITH ACTIVITY ON THE CENTRAL NERVOUS AND VASCULAR SYSTEMS, related to JM-20 for the treatment of diseases of the central nervous and vascular systems.
Footnotes
Abbreviations
- ART
- adhesive removal test
- CONSORT
- CONsolidated Standards Of Reporting Trials
- CoT
- Corner test
- CyT
- cylinder test
- FBGL
- Fasting blood glucose levels
- ITT
- intention to treat
- NS
- neuroscore
- pFCI
- permanent focal cerebral ischemia
- SOPs
- Standard Operating Procedures
- STZ
- Streptozotocin
- tMCAO
- transient middle cerebral artery occlusion