Mepirapim, a novel synthetic cannabinoid, induces Parkinson’s disease-related behaviors by causing maladaptation of the dopamine system in the brain

• Published in: Archives of toxicology 2023-02, Vol.97 (2), p.581-591
• Main Authors: Hur, Kwang-Hyun, Lee, Youyoung, Donio, Audrey Lynn, Lee, Jae-Gyeong, Lee, Bo-Ram, Kim, Seon-Kyung, Yoon, Seolmin, Lee, Yong-Sup, Kim, Hyoung-Chun, Lee, Seok-Yong, Jang, Choon-Gon
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain; Cannabinoids; Cognition Disorders; Cognitive ability; Dopamine; Environmental Health; Health risks; Male; Mice; Mice, Inbred ICR; Movement disorders; Neurodegenerative diseases; Neurotoxicity; Neurotoxicity Syndromes; Occupational Medicine/Industrial Medicine; Organ Toxicity and Mechanisms; Parkinson Disease; Parkinson's disease; Pharmacology/Toxicology; Public health; Signs and symptoms; Synuclein; Tyrosine; Tyrosine 3-monooxygenase
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-022-03414-y

Mepirapim is a novel synthetic cannabinoid that first appeared on the illicit drug market in 2013. In recent years, recreational abuse of Mepirapim has caused serious emergencies, posing a threat to public health. However, there are no legal regulations to prohibit the use of Mepirapim, as there is no scientific evidence for the dangerous pharmacological effects of the drug. In the present study, we investigated the dangerous neurotoxic effects of Mepirapim through behavioral and molecular experiments in mice (ICR/CD1, male, 25–30 g). In particular, based on a previous study that Mepirapim activates the dopamine system, we evaluated whether high-dose Mepirapim [single (15, 30, or 60 mg·kg −1 , i.p.) or multiple (8, 15, or 30 mg·kg −1 , i.p. × 4 at 2 h intervals)] treatment causes Parkinson’s disease-related symptoms through damage to the dopamine system. In the result, we found that Mepirapim treatment caused comprehensive Parkinson’s disease-related symptoms, including motor impairment, cognitive deficits and mood disorders. Furthermore, we confirmed the maladaptation in dopamine-related neurochemicals, including decreased dopamine levels, decreased tyrosine hydroxylase expression, and increased α-synuclein expression, in the brains of mice treated with Mepirapim. Taken together, these results indicate that Mepirapim has dangerous neurotoxic effects that induces Parkinson’s disease-related behaviors by causing maladaptation of the dopamine system in the brain. Based on these findings, we propose the strict regulation of recreational abuse and therapeutic misuse of Mepirapim.