Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia

Abstract

Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the U.S. Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevents the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, but not in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos + /preproenkephalin + striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect-pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.

Neuroprotection by arbutin against haloperidol-induced Tardive Dyskinesia in rats and reducing neurotoxicity in SHSY-5Y cells

“…Furthermore, several studies have found that haloperidol treatment causes dopamine receptor hypersensitivity by inhibiting the dopamine D2 receptors speci cally located in the striatum. As a result, there is an increase in oxidative stress that leads to neurodegeneration [5,34]. Another study reported higher levels of free radical formation in TD patients compared to those who do not have the illness [35].…”

Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway

“…BP cases were defined according to the ICD10 system, based on BP-related symptoms ( Supplemental Table 3 ). To produce a time-series analysis of MarketScan data, the software packages “survival” ( 13 ) and “MatchIt” ( 14 ) in R software v4.1.2 and RStudio (2022.07.1 Build 554 software, R Foundation for Statistical Computing) were used as previously described ( 9 ). The incidence of BP associated with the use of DPP4 inhibitors was first evaluated via Poisson regression analysis, and the obtained results were expressed as incidence rate ratio (IRR), along with the 95% confidence interval (CI) and Z scores.…”

“…In previous studies, data obtained from the FDA Adverse Event Reporting System (FAERS) database, which is the largest self-reported adverse event database, were analyzed to identify concomitant drugs that reduce the incidence of adverse events ( 7 , 8 ). Furthermore, the causal relationships between concomitant drug use and incidence of adverse events have also been demonstrated using insurance claims databases ( 9 , 10 ).…”

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

“…First, they successfully showed that acetaminophen and the acetaminophen metabolite AM404 are valid options for alleviation of TD. They also showed that TRPV1 is a crucial component in the mechanism of acetaminophen action since the anti-dyskinetic effect was lost in the TRPV1 knock-out animals if compared to wild-type rats ( Nagaoka et al, 2021 ). Furthermore, in a monkey model of TD induced by haloperidol, monkeys treated with haloperidol without TD had a higher expression of the transcription factor NUR77.…”