Risperidone ameliorated 1,2-Diacetylbenzene-induced cognitive impairments in mice via activating prolactin signaling pathways.

Cognitive impairment and organic solvent exposure have been becoming public health concerns due to an increasingly aging population, increased life expectancy, urbanization, and industrialization. Converging evidence indicates the link between 1,2-diacetylbenzene (DAB), prolactin (PRL), risperidone, and cognitive impairment. However, these relationships remain unclear. We investigated the therapeutic properties of risperidone in DAB-induced cognitive impairment using both in vivo and in silico methods. Risperidone alleviated DAB-induced cognitive impairment in hippocampal mice, possibly by inhibiting GSK-3β, β-amyloid, CDK5, BACE, and tau hyperphosphorylation. Risperidone also attenuated the activation of TREM-1/DAP12/NLRP3/caspase-1/IL-1β, and TLR4/NF-κB pathways caused by DAB. Furthermore, risperidone inhibited DAB-induced oxidative stress, advanced glycation end products, and proinflammatory cytokines, as well as increased the expression of Nrf2, IL-10, Stat3, MDM2, and catalase activity. On the other hand, risperidone activated the expression of IRS1, PI3K, AKT, BDNF, Drd2, Scna5, and Trt as well as reduced the Bax/Bcl2 ratio and Caspase-3 levels. In silico analyses identified the prolactin signaling pathway, miR-155-5p, miR-34a-5p, and CEBPB as the main molecular mechanisms involved in the pathophysiology of DAB-induced cognitive impairment and targeted by risperidone. Our results suggest that risperidone could be used to treat cognitive impairment caused by organic solvents, especially DAB.