Sigma-1 receptor activation ameliorates age-related postoperative cognitive dysfunction by attenuating endoplasmic reticulum stress and neuroinflammation

Postoperative Cognitive Dysfunction (POCD), a key phenotype within the broader spectrum of Postoperative Neurocognitive Disorders (PND), represents a significant neurological complication, predominantly affecting elderly individuals and resulting in cognitive impairment and diminished quality of life. The Sigma-1 receptor (Sigma-1R), a critical modulator of cellular stress endowed with neuroprotective properties, has emerged as a potential therapeutic target. This investigation aimed to elucidate the role of Sigma-1R in age-related susceptibility to POCD and to assess the therapeutic efficacy of the Sigma-1R agonist, PRE-084. Employing an exploratory laparotomy mouse model of POCD, we evaluated age-dependent variations in hippocampal Sigma-1R expression, its specific cellular localization, and the effects of PRE-084 administration on cognitive performance and associated molecular pathways in aged mice. Our findings revealed significantly lower basal hippocampal Sigma-1R levels in aged mice compared to their adult counterparts. Subsequent to surgical intervention, adult mice demonstrated a robust upregulation of Sigma-1R, which correlated with preserved cognitive function. In contrast, aged mice exhibited a blunted Sigma-1R response (a non-significant trend towards an increase), correlating with more pronounced cognitive deficits. Immunohistochemical analysis confirmed predominant Sigma-1R expression within hippocampal neurons. Post-surgical administration of PRE-084 to aged mice resulted in a substantial amelioration of cognitive function, as assessed by the Morris water maze. These salutary effects were associated with an attenuation of endoplasmic reticulum (ER) stress, evidenced by reduced levels of BIP and p-eIF2α, mitigation of neuroinflammation, indicated by decreased microglial and astrocytic activation, inhibition of NF-κB activation, and promotion of CREB phosphorylation. In conclusion, this study underscores the pivotal role of a differential Sigma-1R response to surgical stress in the pathogenesis of age-related POCD. PRE-084 demonstrates promise as a therapeutic agent, exerting neuroprotection by alleviating neuronal ER stress, which in turn curtails secondary neuroinflammation and recalibrates critical NF-κB and CREB signaling pathways.