Isopropoxate Exerts Neurotoxicity by Crossing the Blood-Brain Barrier and Mediating through Inflammation-Neurotransmitter Signaling Pathways.

Isopropoxate (IPPO), an emerging imidazole ester-type new psychoactive substance, poses potential risks to public health and the environment, yet its neurotoxic mechanisms remain poorly understood. In this study, 8-week-old C57BL/6J mice were used to evaluate the effects of IPPO on the blood-brain barrier (BBB), oxidative stress, neuroinflammation, and neurotransmitter receptor systems through UPLC-MS/MS-based tissue distribution analysis, quantitative real-time PCR, TUNEL staining, and molecular docking. At a dose of 3mg/kg, IPPO accumulated in brain tissue and induced cerebral edema. Marked reductions in the tight-junction proteins Occludin and Claudin-5, together with decreased expression of the efflux transporter genes Abcb1a and Abcb1b, indicated impairment of blood-brain barrier (BBB) integrity. In brain tissue, malondialdehyde (MDA) increased by approximately 30%, catalase (CAT) activity decreased by approximately 20%, and glutathione (GSH) content declined by approximately 8%, demonstrating enhanced lipid peroxidation (LPO) and weakened antioxidant defenses. IPPO exposure also upregulated components of the NLRP3 inflammasome and the pro-inflammatory mediators IL-1β, IL-6, and TNF, while reducing the anti-inflammatory cytokine IL-10 by approximately 26%, indicating disruption of the pro-/anti-inflammatory balance. Within neurotransmitter systems, DRD1 and GABRA1 protein levels increased, Taar1 expression decreased, and the immediate-early genes Fos and Arc were markedly upregulated, consistent with dysregulation of dopaminergic, GABAergic, and neuronal activity-related signaling. Molecular docking further indicated stable interactions of IPPO with GABAA and DRD1 receptors, supporting a potential direct influence on neurotransmission through key receptor targets. Transcriptomic profiling corroborated suppression of tight-junction-related genes and disturbance of neurotransmitter-associated pathways. Collectively, these findings identify a coordinated neurotoxic mechanism in which IPPO disrupts the BBB, promotes oxidative stress and neuroinflammation, and alters neurotransmitter receptor signaling.