Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline

Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.