Malathion-induced neurological alterations associated with dysregulation of RORγt/STAT3/IL-17 and FOXP3/STAT5/IL-10 pathways: potential neuroprotective effects of BCG

Despite their effectiveness in agriculture to control a variety of pests, organophosphorus compounds (OPC) such as malathion were linked with neurological dysfunctions and possibly death. The present study aimed to investigate the impact of OPC exposure on neuroinflammation via disrupting the equilibrium between pro-inflammatory (RORγt/STAT3/IL-17/IL-22) and anti-inflammatory (FOXP3/STAT5/IL-10) pathways. The study extended to evaluate the potential of BCG vaccination in alleviating neuroinflammation. Rats were distributed into four groups: control, malathion-intoxicated group, BCG-treated group, and scopolamine-treated group. Behavioral tests and histopathological investigations of the cerebral cortex were done. FOXP3, RORγt, STAT3, and STAT5 were estimated using qRT-PCR. Acetylcholine (Ach), BDNF, IL-10, IL-17, IL-22, BCL2, and BAX were estimated using ELISA, whereas GFAP and IL-1β were estimated via immunohistochemical analysis. The malathion-intoxicated group revealed higher gene expression of RORγt and STAT3, along with lower gene expression of FOXP3 and STAT5, compared with the control group. Moreover, the concentrations of IL-17, IL-22, and BAX were higher, along with lower concentrations of BDNF, IL-10, and BCL2, compared with the control group. Furthermore, GFAP and IL-1β showed marked positive cytoplasmic expression. However, the BCG-treated group reversed all the abovementioned findings. Collectively, the study highlights that malathion induces neuroinflammation via skewing the balance between the proinflammatory (RORγt/STAT3/IL-17/IL-22) and the antiinflammatory (FOXP3/STAT5/IL-10), leading to behavioral fluctations and brain's histological disruption. This imbalance resulted in cytokine production, neuronal apoptosis, and neurodegeneration. BCG administration alleviates these effects owing to its anti-inflammatory and neuroprotective effects.