A potential strategy for improving offspring behavior in maternal immune activation: Amantadine-mediated suppression of neuroinflammation.

BACKGROUND: Maternal viral infection during pregnancy can lead to maternal immune activation (MIA), increasing the risk of neurodevelopmental disorders in offspring. Amantadine (AMA) exhibits antiviral activity and is widely employed in the management of neurologic conditions. Nevertheless, the efficacy of AMA in treating MIA is currently not established. METHODS: MIA was induced by polyinosinic acid-polycytidylic acid (poly(I:C)); AMA was administered from embryonic (E) day 11.5 for 3 days. BV-2 cells were stimulated using poly(I:C) and treated with AMA. Behavior was assessed via open field test, elevated plus maze test, three-chamber sociability test, and marble burying test. Neuronal morphology was vizualized using Nissl stain; apoptosis via TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) stain; protein expression (Iba1, NeuN, CD68, TNF-α [tumor necrosis factor-alpha], IL-1β [interleukin-1β]) using immunofluorescence (IF); interleukin-6 (IL-6) levels using enzyme-linked immunosorbent assay; reactive oxygen species using staining; Iba1, NeuN, Bcl-2, Bax, and cleaved caspase 3 using Western blot; and gene expression changes using RNA-seq. RESULTS: AMA treatment reduced the levels of IL-6 in maternal blood, improved autism-like behaviors in MIA offspring, and effectively prevented neuronal damage and neuroinflammation. In vitro cellular studies have demonstrated that AMA effectively downregulates the expression levels of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β. RNA-seq analysis indicated that AMA mitigates abnormal activation of microglia by modulating inflammatory pathways associated with IL-6. CONCLUSION: AMA can prevent the development of neuropsychiatric disorders in MIA offspring. This effect may be related to its ability to attenuate neuronal damage, reduce neuronal apoptosis, and inhibit neuroinflammation, indicating that the antiviral drug AMA may be a potential treatment for MIA.