MCH-02, a synthetic macamide analog with in vitro FAAH-inhibitory activity, modulates hippocampal endocannabinoid system and BK channel expression without preventing PTZ-induced progressive seizure susceptibility in rats
Year: 2026
Type: article
Abstract: Epilepsy remains a major neurological disorder, with about 30% of patients showing drug resistance despite the availability of multiple antiseizure medications. The endocannabinoid system (ECS) has emerged as a promising therapeutic target due to its role in regulating neuronal excitability. This study examined the effects of a new macamide-derived fatty acid amide hydrolase (FAAH) inhibitor, N -(8Z-heptadecen-1-yl)- O -(3-pyridylmethyl) carbamate (MCH-02), on seizure development, cognition, and hippocampal molecular markers in a chronic pentylenetetrazol (PTZ) kindling model in rats. Behavioral measures (Racine scale, survival, Barnes maze, and novel object recognition) and molecular analyses (RT-qPCR and Western blot of CA1, CA3, and dentate gyrus) were conducted. MCH-02 did not prevent PTZ-induced progressive seizure susceptibility and initially worsened seizure severity. Survival probability did not differ significantly among groups, and we observed no evidence of a protective effect on survival. On a molecular level, MCH-02 increased FAAH, Cnr1, and Napepld mRNA levels in the CA1 region. It altered CB1 receptor and BKα1 subunit protein levels in the hippocampus, suggesting ECS remodeling and changes in potassium channel regulation. Despite these molecular changes, behavioral protection was inconsistent, suggesting a complex and context-dependent relationship between ECS function and intrinsic excitability. Overall, MCH-02 modulates molecular pathways associated with hippocampal endocannabinoid signaling and BK channel remodeling but does not demonstrate antiepileptogenic efficacy in the PTZ-kindling model. However, the surprising worsening of seizures highlights the importance of further research incorporating electrophysiological and pharmacokinetic studies to determine optimal dosing and therapeutic timing for FAAH inhibitors in chronic epilepsy models.
Source: Frontiers in Neurology
Institutions: Universidad Andina del Cusco, Universidade de São Paulo
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222475151