Mikkelsen_2024_Neurochem.Int__105717

OBJECTIVES: Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase considered a potential novel drug target for the treatment of CNS disorders including epilepsy. Here we examined MAGL levels in a rat model of epilepsy. METHODS: Autoradiography has been used to validate the binding properties of the MAGL radiotracer, [(3)H]T-401, in the rat brain, and to explore spatial and temporal changes in binding levels in a model of temporal lobe epilepsy model using unilateral intra-hippocampal injections of kainic acid (KA) in rats. RESULTS: Specific and saturable binding of [(3)H]T-401 was detected in both cortical grey and subcortical white matter. Saturation experiments revealed a K(D) in the range between 15 nM and 17 nM, and full saturation was achieved at concentrations around 30 nM. The binding could be completely blocked with the cold ligand (K(i) 44.2 nM) and at higher affinity (K(i) 1.27 nM) with another structurally different MAGL inhibitor, ABD 1970. Bilateral reduction in [(3)H]T-401 binding was observed in the cerebral cortex and the hippocampus few days after status epilepticus that further declined to a level of around 30% compared to the control. No change in binding was observed in either the hypothalamus nor the white matter at any time point. Direct comparison to [(3)H]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A), another protein localized in the pre-synapse, revealed that while binding to MAGL remained low in the chronic phase, SV2A was increased significantly in some cortical areas. SIGNIFICANCE: These data show that MAGL is reduced in the cerebral cortex and hippocampus in a chronic epilepsy model and indicate that MAGL inhibitors may further reduce MAGL activity in the treatment resistant epilepsy patient.