Durie Dylan, McDonald Tanya S, Borges Karin
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia.
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia.
Epilepsy Res. 2018 Sep;145:77-81. doi: 10.1016/j.eplepsyres.2018.06.004. Epub 2018 Jun 15.
A recent report has found that glucose oxidation and the activity of pyruvate dehydrogenase (PDH) are reduced in the chronic stage of the pilocarpine mouse epilepsy model. This is likely caused by increased phosphorylation by PDH kinase of the E1α subunit of PDH, downregulating its activity. Inhibition of this phosphorylation has not yet been explored as a possible approach to treat epilepsy. Chronic dichloroacetate (DCA, 50 and 100 mg/kg/day) treatment was tested in acute seizure and the chronic pilocarpine models. We also determined the effects on phosphorylation state, activity and protein levels of PDH in the chronic stage of the pilocarpine model. DCA treatment did not increase latencies to seizures in the acute flurothyl seizure test and was slightly proconvulsant in the 6 Hz test. The latencies to seizures in a second-hit flurothyl test were decreased in SE vs. No SE mice in the chronic stage, but were not restored by DCA. In mice that had experienced pilocarpine-induced SE and were in the chronic "epileptic" stage of the model, PDH activity was reduced by 65% compared to "healthy" No SE mice. This was partially alleviated with DCA treatment. Also, PDH protein levels were decreased by 37% and phosphorylation at Ser of PDH was increased by 52% in SE mice, but were not significantly changed with DCA. Moreover DCA treatment decreased the amounts of total PDH by 23% in No SE mice, which may explain the proconvulsant effects in the 6 Hz test. The reduction in PDH protein levels during the chronic epileptic stage suggests increased degradation of the protein, which may contribute to the deficient glucose oxidation found in epilepsy. Taken together, DCA did not have any anti-convulsant effects in the tested models. Future studies utilising other PDH kinase inhibitors are required to determine whether this treatment approach is viable.
最近的一份报告发现，毛果芸香碱小鼠癫痫模型的慢性期葡萄糖氧化和丙酮酸脱氢酶（PDH）的活性降低。这可能是由于PDH激酶对PDH的E1α亚基磷酸化增加，下调了其活性。抑制这种磷酸化作为一种治疗癫痫的可能方法尚未得到探索。在急性癫痫发作和慢性毛果芸香碱模型中测试了慢性二氯乙酸（DCA，50和100mg/kg/天）治疗。我们还确定了在毛果芸香碱模型慢性期对PDH的磷酸化状态、活性和蛋白质水平的影响。DCA治疗在急性氟烷癫痫试验中没有增加癫痫发作的潜伏期，并且在6Hz试验中略有促惊厥作用。在慢性期，第二次氟烷试验中癫痫发作的潜伏期在癫痫持续状态（SE）小鼠中比无癫痫持续状态（No SE）小鼠缩短，但未被DCA恢复。在经历过毛果芸香碱诱导的癫痫持续状态并处于模型慢性“癫痫”期的小鼠中，与“健康”的无癫痫持续状态小鼠相比，PDH活性降低了65%。DCA治疗部分缓解了这种情况。此外，SE小鼠中PDH蛋白水平降低了37%，PDH丝氨酸磷酸化增加了52%，但DCA治疗后没有显著变化。此外，DCA治疗使无癫痫持续状态小鼠中总PDH量减少了23%，这可能解释了在6Hz试验中的促惊厥作用。慢性癫痫期PDH蛋白水平的降低表明该蛋白降解增加，这可能导致癫痫中发现的葡萄糖氧化不足。综上所述，DCA在测试模型中没有任何抗惊厥作用。需要利用其他PDH激酶抑制剂进行进一步研究，以确定这种治疗方法是否可行。
