Anti-Epileptic Action of ABHD6 Inhibitors as Treatment for Dravet Syndrome

摘要 新发现的酶，α/β-水解酶结构域6(ABHD6)，控制着2-羟色胺的含量。 花生四烯酸甘油(2-AG)，大脑中含量最丰富的内源性大麻素(ECB)。我们最近发现， 在体内，ABHD6抑制降低了几种癫痫小鼠模型的癫痫发生率，这 治疗反应不会耐受，也不会产生明显的副作用。这些结果 提示ABHD6抑制可能是一种新的抗癫痫治疗方法。 在这份R21拨款提案中，我们将测试一种新型ABHD6抑制剂KT-182在 SCN1A+/-小鼠，一种准确模拟这种毁灭性的Drave氏综合征的临床前小鼠模型 从婴儿期开始的顽固性癫痫。我们的假设是，ABHD6的抑制将显著减少 Scn1a+/-小鼠癫痫发作严重程度，无明显副作用和耐受性。为了检验这一假设，我们 将实现三个目标： 1.ABHD6抑制对热惊厥的影响 2.ABHD6抑制对自发性癫痫发作和过早死亡的影响 3.ABHD6抑制对脑电和神经元兴奋性的影响 通过这笔R21赠款收集的结果将为未来旨在 开发ABHD6抑制剂作为治疗Drave氏综合征的新疗法。这项研究将 也增加了我们对内源性2-AG信号转导的分子机制的基本理解 控制突触传递和癫痫发生率。

Summary The newly discovered enzyme, α/β-hydrolase domain 6 (ABHD6), controls the amount of 2- arachidonoylglycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain. We recently found that in vivo ABHD6 inhibition decreases seizure incidence in several mouse models of epilepsy, and that this therapeutic response does not undergo tolerance nor does it produce overt side effects. These results suggest that ABHD6 inhibition might represent a novel anti-epileptic therapeutic approach. In this R21 grant proposal, we will test the therapeutic efficacy of a novel inhibitor of ABHD6, KT-182, in Scn1a+/- mice, a preclinical mouse model of Dravet Syndrome that accurately mimics this devastating intractable epilepsy that begins in infancy. Our hypothesis is that ABHD6 inhibition will significantly reduce seizure severity in Scn1a+/- mice without producing overt side effect and tolerance. To test this hypothesis, we will address three aims: 1. Effect of ABHD6 inhibition on thermally-induced seizures 2. Effect of ABHD6 inhibition on spontaneous seizures and premature death 3. Effect of ABHD6 inhibition on EEG and neuronal excitability The results gathered through this R21 grant will provide a solid foundation for future research aimed at developing ABHD6 inhibitors as new therapeutics for the treatment of Dravet Syndrome. This research will also increase our basic understanding of the molecular mechanisms by which endogenous 2-AG signalling controls synaptic transmission and seizure incidence.