Sigma-1 receptor modulation by fluvoxamine ameliorates valproic acid-induced autistic behavior in rats: Involvement of chronic ER stress modulation, enhanced autophagy and M1/M2 microglia polarization

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2025-01, Vol.136, p.111192, Article 111192
• Main Authors: Mohamed, Ahmed F., El-Gammal, Mohamad A., EL-Yamany, Mohammed F., Khodeir, Ahmed E.
• Format: Article
• Language: English
• Subjects: Autism; ER stress; Fluvoxamine; Microglial cells; Sigma-1 receptor
• ISSN: 0278-5846; 1878-4216; 1878-4216
• DOI: 10.1016/j.pnpbp.2024.111192

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. While, fluvoxamine (FVX) is an antidepressant and widely prescribed to ASD patients, clinical results are inconclusive and the mechanism of FVX in the management of ASD is unclear. This study determined the potential therapeutic impact of FVX, a sigma-1 receptor (S1R) agonist, against the valproic acid (VPA)-induced model of autism. On gestational day 12.5, Wistar pregnant rats were given a single intraperitoneal (i.p.) injection of either VPA (600 mg/kg) or normal saline (10 mL/kg, vehicle-control). Starting on postnatal day (PND) 21 to PND 50, FVX (30 mg/kg, P·O. daily) and NE-100, (S1R) antagonist, (1 mg/kg, i.p. daily) were given to male pups. Behavior tests and histopathological changes were identified at the end of the experiment. In addition, the cerebellum biomarkers of endoplasmic reticulum (ER) stress and autophagy were assessed. Microglial cell polarization to M1 and M2 phenotypes was also assessed. FVX effectively mitigated the histopathological alterations in the cerebellum caused by VPA. FVX enhanced sociability and stereotypic behaviors in addition to its noteworthy impact on autophagy enhancement, ER stress deterioration, and controlling microglial cell polarization. The current investigation confirmed that the S1R agonist, FVX, can lessen behavioral and neurochemical alterations in the VPA-induced rat model of autism. Graphical abstract illustrating the mechanistic pathway by which FVX, sigma-1 receptor agonist, alleviated prenatal valproate-induced autism in rats. In autistic rats, cerebellar synaptophysin and PSD-95 were decreased as well as glutamate/GABA ratio was increased that caused behavioral alteration, especially anxiety, sociability, and stereotypic behaviors. Autophagy was also deteriorated that caused increasing the level of unfolded protein and ER stress. ER stress increased microglial M1 cells polarization rather than M2 cells. On the other hand, FVX, sigma-1 receptor agonist, improved the behaviors of rats by inhibition of ER stress and induction of autophagy as well as increasing microglial M2 cells polarization rather than M1 cells [Display omitted] •ASD is a neurological disorder characterized by impairment in sociability, repetitive behaviors, and memory.•FVX ameliorated the main symptoms of ASD as sociability deficits and enhance motor learning and memory.•FVX alleviated unfolded protein levels in neurons by increasing autophagy.•FVX suppressed ER stress