Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Department of Hygiene, Kawasaki Medical School, Kurashiki 701-0192, Japan.
Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299.
Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs.
神经元兴奋受能量代谢调控，耐药性癫痫可通过特殊饮食抑制。在此，我们报告称，通过抑制代谢途径（即通过乳酸脱氢酶（LDH），星形胶质细胞-神经元乳酸穿梭的组成部分）可减少癫痫发作和癫痫样活动。抑制该酶可使神经元超极化，而其下游代谢产物丙酮酸可逆转这种超极化。LDH 抑制也可抑制癫痫小鼠模型中的癫痫发作。我们进一步发现，临床上使用的抗癫痫药物 stiripentol 是一种 LDH 抑制剂。通过修饰其化学结构，我们鉴定出一种以前未知的 LDH 抑制剂，其在体内可有效抑制癫痫发作。我们得出结论，LDH 抑制剂是一种很有前途的新型抗癫痫药物。
