Therapeutic effect of bismuth subsalicylate in a propionic acid-induced autism model

Abstract

Inflammation-induced oxidative stress in macrophages and microglia is associated with excessive production of reactive oxygen species, initiating a damaging cycle of neuroinflammation and cellular injury. These processes are significant contributors to the pathophysiology of autism spectrum disorders, which involve neuronal dysfunction, cell loss, and behavioral impairments. Under conditions of oxidative stress, activated microglia release pro-inflammatory mediators, further intensifying neuronal damage. Bismuth subsalicylate (BSS), a compound with well-documented anti-inflammatory and antioxidant properties, has shown potential in mitigating such neurodegenerative processes. This study aimed to evaluate the effects of BSS in reducing neuroinflammation and oxidative stress in a propionic acid (PPA)-induced autism model, alongside its impact on behavioral outcomes. The study utilized 30 male Wistar albino rats, with PPA administered intraperitoneally at 250 mg/kg/day for 5 days to induce an autism-like phenotype. Rats were divided into three groups: Group 1 (Normal control, n = 10); Group 2 (PPA + saline, PPAS, n = 10); and Group 3 (PPA + BSS, PPAB, n = 10). Treatments were administered for 15 days. Behavioral performance was assessed through three-chamber sociability, open field, and passive avoidance learning tests, followed by biochemical and histological evaluations of brain tissues. Biochemical analysis revealed a significant increase in malondialdehyde, tumor necrosis factor-alpha, and interleukin-17 levels in the PPAS group, indicating heightened oxidative stress and inflammation. Treatment notably reduced these markers, suggesting its efficacy in mitigating oxidative damage and inflammatory responses. Immunohistochemical results demonstrated reduced glial activation and enhanced neuronal preservation in the hippocampal and cerebellar regions of treated rats. Additionally, behavioral impairments in social interaction, exploration, and memory were significantly improved with BSS therapy. These results suggest that BSS may confer neuroprotective effects through attenuation of oxidative stress and neuroinflammation, potentially contributing to improved neuronal function and behavioral performance in a PPA-induced autism model.

Keywords: Autism; Bismuth subsalicylate; Neuroinflammation; Oxidative stress; Propionic acid.

Fig. 1

Demonstration of pre-test session and sociability test with three-chamber sociability test

Fig. 2

CA3 and CA1 of hippocampus × 40 magnification. Astrogliosis was characterized by GFAP immunostaining (Brown staining). A1–A3 Normal control group male rats CA3 and CA1. B1–B3 PPA and saline group male rats have increased glial activity and decreased neural count and dysmorphological changes CA3 and CA1 pyramidal neuron (arrow and asterisk) (*p < 0.05 vs Control). C1–C3 PPA and BSS group male rats have decreased glial activity and increased count and improved neural morphology changes CA3 and CA1 (hash) pyramidal neuron (#p < 0.05 vs PPA group). Vertical bars showing the thickness in selected demonstrative parts. Statistical significance symbols are overlaid on the images. Quantitative data are presented in corresponding bar graphs. Statistical analysis: one-way ANOVA with Bonferroni post-hoc test

Fig. 3

Cerebellum × 40 magnification. Astrogliosis was characterized by GFAP immunostaining (Brown staining). A1, A2 Normal control group male rats. B1, B2 PPA and saline group male rats have increased glial activity and decreased and dysmorphological changes in cerebellum Purkinje Neuron (arrow and asterisk) (*p < 0.05 vs Control). C1, C2 PPA and BSS group male rats have decreased glial activity and increased count and improved Purkinje Neuron morphology changes in cerebellum (arrow and hash) structure (#p < 0.05 vs PPA group). Statistical markers are shown on image panels. Data were analyzed using one-way ANOVA followed by Bonferroni correction