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

Authors

Renjuan Cao, Zien Chen, Jihong Cai, Pengfei Mei, Xin Liu, Yuan Ren, Chao Liu

Published in

Toxicology. Pages 154561. Aug 08, 2026. Epub Aug 08, 2026.

Abstract

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 GABA_A 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.

PMID:
42570856
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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