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
- 1Laboratorio de Investigación en Neurociencias, Instituto Científico, Universidad Andina del Cusco
- 2Multidisciplinary Research Center, School of Arts, Sciences and Humanities, University of São Paulo
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.
Related
- Endocannabinoid System Genes in Dementia: A Systematic Mendelian Randomization Study of Functional Variants and Tissue-Specific Expression Across Clinical, Molecular, and Neuroimaging Phenotypes
- Hippocampal circuit remodeling in post-traumatic epileptogenesis: inhibitory dysfunction, glial homeostatic failure, and therapeutic opportunities
- Progressive Hippocampal Volume Reduction Beyond Normal Aging in Temporal Lobe Epilepsy: A Longitudinal MRI Study.
- Relative inhibitory activities of taniborbactam and xeruborbactam against KPC variants conferring reduced susceptibility or resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam
- Naringenin Enhances the Inhibitory Effect of Regorafenib on HepG2 Hepatocellular Carcinoma Cell Viability with Modulation of E-Cadherin and MRP1 Gene Expression
BibTeX
@article{yaurihuaman2026mch02,
title = {{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}},
author = {Yessenia Yauri-Huaman and Rodrigo Caceres-Robles and Christell Becerra Flores and Miguel Garay-Malpartida and Carlos Medina-Saldivar and Luis F. Pacheco-Otalora},
journal = {Frontiers in Neurology},
year = {2026},
month = oct,
doi = {10.3389/fneur.2026.1843264},
url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1843264/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Yessenia Yauri-Huaman
AU - Rodrigo Caceres-Robles
AU - Christell Becerra Flores
AU - Miguel Garay-Malpartida
AU - Carlos Medina-Saldivar
AU - Luis F. Pacheco-Otalora
PY - 2026
DA - 2026/10/16
JO - Frontiers in Neurology
DO - 10.3389/fneur.2026.1843264
UR - https://www.frontiersin.org/articles/10.3389/fneur.2026.1843264/full
AB - 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.
SN - 1664-2295
ER -