Delayed Administration Of A Repurposed Drug With Sigma 1 Receptor Activity Improves Stroke Outcomes In Male Rats

Sigma-1 receptor ligands including agonists and antagonists have been shown to improve outcomes from experimental stroke when administered at delayed time points. However, clinical trials for one such agonist, cutamesine, failed to demonstrate benefit. In the present study, we sought to identify approved drugs that could be repurposed for Sigma-1 activity and the delayed treatment of stroke. High-throughput screening was used to identify Sigma-1 receptor selective binding and stimulation of brain-derived neurotrophic factor (BDNF) release for several potential ligands that are already approved for other indications. Two lead compounds, promethazine (an antihistamine) and oxeladin (a cough suppressant), were advance to in vivo studies. Both compounds displayed favorable oral absorption into the brain and high dose tolerance in rats. Neither compound significantly altered thrombosis in an in vitro blood coagulation assay. Daily oral administration of oxeladin (3 doses) or vehicle was started 48 hours after 90-minute transient middle cerebral artery occlusion in adult male Sprague-Dawley rats (n=12/group) and continued for 10 days in a treatment-blind manner. Rats receiving the two highest doses showed significant (P<0.05, 2-way ANOVA and Dunnett’s test) improvements in Bederson scores (0.4±0.1 vs 1.5±0.2), an 11 point Neurological assessment (1.2±0.1 vs 3.9±0.2) , and the elevated body swing test (60% vs 90% bias) 1, 4, and 10 days after dosing compared to vehicle controls. A subset of rats was administered BrdU (50 mg/kg ip) every other day. However, there were no significant differences among groups in BrdU incorporation observed in the subventricular zone at 14 days after stroke. Additional studies are being performed to assess the mechanisms of neuroprotection. These data suggest that repurposing of approved/safe drugs with Sigma-1 receptor activity is a promising avenue for the treatment of chronic stroke.