Sigma-1 receptor involvement in the paradigm-dependent anti-amnesic effects of multimodal HBK-10 under NMDA receptor hypofunction, with accompanying hippocampal ERK1/2 and BDNF modulation.

Cognitive impairment is a clinically relevant yet inadequately treated dimension of depression. N-methyl-D-aspartate (NMDA) receptor hypofunction disrupts hippocampal plasticity and contributes to learning and memory deficits. Sigma-1 receptors regulate glutamatergic neurotransmission and neuronal plasticity and therefore represent a promising target for cognitive rescue. We investigated whether HBK-10, a multimodal methoxyphenylpiperazine derivative with antidepressant-like activity, engages sigma-1 receptors and counteracts memory impairment associated with NMDA receptor hypofunction. Sigma-1 receptor interaction was assessed by radioligand binding and sigma-1 receptor/binding immunoglobulin protein (BiP) dissociation assays. Neuroprotection was evaluated in amyloid-β25-35 (Aβ25-35)-exposed SH-SY5Y cells, and cognitive efficacy in MK-801-treated mice using recognition, spatial, and aversive memory paradigms. Extracellular signal-regulated kinase 1/2 (ERK1/2) and brain-derived neurotrophic factor (BDNF) were measured ex vivo, and dorsal hippocampal ERK1/2 dynamics were monitored in vivo using Förster resonance energy transfer (FRET)-based fiber photometry. HBK-10 bound to sigma-1 receptors, promoted sigma-1 receptor/BiP dissociation, and protected against amyloid-β25-35-induced cytotoxicity in a sigma-1 receptor-sensitive manner. In vivo, HBK-10 improved recognition memory and spatial learning and retention, but not aversive non-spatial memory. Its recognition-memory effect was attenuated by the sigma-1 receptor antagonist. Behavioral efficacy was accompanied by normalization of hippocampal phosphorylated ERK1/2 (pERK1/2) and increased BDNF after Morris water maze, whereas acute administration did not evoke a detectable ERK1/2 response. These findings indicate that HBK-10 combines sigma-1 receptor engagement with paradigm-dependent anti-amnesic efficacy and post-behavioral changes in hippocampal plasticity-related markers, supporting its further pharmacokinetic and mechanistic characterization as a multimodal compound with potential relevance for cognitive dysfunction associated with disrupted glutamatergic signaling.