Sigma-1-targeting multimodal compound HBK-15 reverses memory deficits and restores hippocampal plasticity under NMDA hypofunction
PMC12976527
· 10.1016/j.neurot.2025.e00774
Gap Declaration
We tested the effects of both single and short repeated doses (up to six days), but longer treatment durations are necessary to evaluate the longevity and clinical significance of HBK-15's cognitive benefits. While the present work centered on NMDA receptor hypofunction associated with psychiatric disorders, the anti-amnesic effects of HBK-15 warrant exploration in neurodegenerative settings. Future studies should establish whether its procognitive activity extends to models characterized by NMDA receptor overactivation and excitotoxicity. Addressing these limitations in future studies will enhance the translational relevance of our results. In conclusion, the multimodal compound HBK-15 emerges as a sigma-1 receptor agonist capable of restoring recognition and spatial memory under NMDA receptor hypofunction. [...] While the present work centered on NMDA receptor hypofunction associated with psychiatric disorders, the anti-amnesic effects of HBK-15 warrant exploration in neurodegenerative settings. Future studies should establish whether its procognitive activity extends to models characterized by NMDA receptor overactivation and excitotoxicity. Addressing these limitations in future studies will enhance the translational relevance of our results. In conclusion, the multimodal compound HBK-15 emerges as a sigma-1 receptor agonist capable of restoring recognition and spatial memory under NMDA receptor hypofunction. By rescuing hippocampal LTP and stabilizing oscillatory coordination, it engages both synaptic and network-level plasticity to counteract MK-801-induced impairments.
Abstract
Memory impairment is among the most disabling features of depression and schizophrenia, yet remains largely untreated by available pharmacotherapies. NMDA receptor hypofunction is strongly implicated in these deficits, while sigma-1 receptors, by stabilizing calcium signaling and supporting glutamatergic plasticity, have emerged as a promising therapeutic target. HBK-15, a methoxyphenylpiperazine derivative with a multimodal receptor profile, had previously shown preliminary anti-amnesic activity in rodents, prompting us to test its efficacy under NMDA receptor hypofunction. We therefore investigated whether HBK-15 engages sigma-1 receptors and restores memory in a mouse model of MK-801-induced impairment. HBK-15 bound sigma-1 receptors with high affinity and showed functional agonist acti…
Conclusions / Discussion
Discussion We found that HBK-15 reversed memory impairments induced by NMDA receptor hypofunction, a mechanism strongly implicated in the cognitive symptoms of depression and schizophrenia. The compound restored both recognition and spatial memory across acquisition and retrieval phases. These effects critically depended on sigma-1 receptor activation and were accompanied by restoration of hippocampal LTP and partial normalization of hippocampal theta-gamma coupling. Together, these findings suggest that HBK-15 stabilizes plasticity at both synaptic and network levels, positioning it as a promising candidate for treating memory disturbances in neuropsychiatric disorders. Despite their profound impact on functional outcome, cognitive deficits in depression and schizophrenia remain largely unaddressed by current pharmacotherapies. Existing treatments primarily target mood or psychotic symptoms, leaving cognitive impairments unresolved and contributing to relapses, poor functional recovery, and chronic disability. This therapeutic gap underscores the need for agents that can directly modulate memory processes. In our earlier work, we identified HBK-15, a methoxyphenylpiperazine deriva…
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