EFFECTS OF THE MULTIMODAL COMPOUND HBK-15 ON HIPPOCAMPAL CYTOARCHITECTURE IN A MOUSE MODEL OF IMPAIRED EXCITATORY SIGNALING

Multimodal compounds targeting monoaminergic signaling represent a promising strategy for addressing the pathophysiology of central nervous system disorders. HBK-15 is a multimodal compound with the highest affinity for 5-HT1A, 5-HT7, and sigma-1 receptors. In this study, we evaluate its potential to mitigate hippocampal deficits in a mouse model of NMDA receptor hypofunction induced by MK-801 administration.
Adult mice received daily i.p. injections of HBK-15 (0.625, 1.25, or 2.5 mg/kg) followed by MK-801 (0.15 mg/kg) for 8 days. We examined the dentate gyrus using immunohistochemistry for doublecortin to identify immature neurons, the glial fibrillary acid protein for astrocytes, and Iba1 for microglia. Synaptic integrity was assessed via PSD95 and vGlut1 expression.
Preliminary analysis indicates that MK-801 administration trends toward a reduction in the area occupied by microglia and a decrease in young neurons. Co-treatment with HBK-15 appeared to attenuate glial and neurogenic deficits. However, synaptic analysis suggests a complex dose-response pattern: lower doses trended toward preserving integrity, and higher doses associated with reduced PSD95 expression and colocalization with vGlut1.
Our data suggest that HBK-15 protects against alterations in glial and neurogenic niches induced by excitatory hypofunction. However, the observed variation in synaptic markers at higher doses suggests a potential therapeutic window, underscoring the need to further explore dosage precision in multimodal pharmacology.
Funding: Erasmus+ programme Partnership for Cooperation (2023-1-PL01-KA220-HED-000160284). Science and Innovation Spanish Ministry (PID2022-140525NB-I00 and PID2022-140456NB-I00). Strategic plans and strategic research programmes of excellence from the Regional Government of Castile and León, co-funded by the ERDF Operational Programme (CLU-2023-1-01).