Meidenbauer Joshua J, Roberts Mary F
Biology Department, Boston College, Chestnut Hill, MA 02467, USA.
Chemistry Department, Boston College, Chestnut Hill, MA 02467, USA.
Epilepsy Behav. 2014 Oct;39:48-54. doi: 10.1016/j.yebeh.2014.08.007. Epub 2014 Sep 7.
Dietary therapy has been used to treat many individuals with epilepsy whose seizures are refractory to antiepileptic drugs. The mechanisms for how dietary therapy confers seizure protection are currently not well understood. We evaluated the acute effects of glucose and β-hydroxybutyrate (the major circulating ketone body) in conferring seizure protection to the EL mouse, a model of multifactorial idiopathic generalized epilepsy. EL mice were fed either an unrestricted standard diet or a calorie-restricted standard diet to achieve a body weight reduction of 20-23%. D-Glucose, 2-deoxy-D-glucose, and β-hydroxybutyrate were supplemented in the drinking water of calorie-restricted mice for 2.5 h prior to seizure testing to simulate the effect of increased glucose availability, decreased glucose utilization, and increased ketone availability, respectively. Seizure susceptibility, body weight, plasma glucose, and β-hydroxybutyrate were measured over a nine-week treatment period. Additionally, excitatory and inhibitory amino acids were measured in the brains of mice using (1)H NMR. Glutamate decarboxylase activity was also measured to evaluate the connection between dietary therapy and brain metabolism. We found that lowering of glucose utilization is necessary to confer seizure protection with long-term (>4 weeks) calorie restriction, whereas increased ketone availability did not affect seizure susceptibility. In the absence of long-term calorie restriction, however, reduced glucose utilization and increased ketone availability did not affect seizure susceptibility. Brain excitatory and inhibitory amino acid content did not change with treatment, and glutamate decarboxylase activity was not associated with seizure susceptibility. We demonstrated that reduced glucose utilization is necessary to confer seizure protection under long-term calorie restriction in EL mice, while acute ketone supplementation did not confer seizure protection. Further studies are needed to uncover the mechanisms by which glucose utilization influences seizure susceptibility.
饮食疗法已被用于治疗许多癫痫患者，这些患者的癫痫发作对抗癫痫药物难治。目前，饮食疗法赋予癫痫保护作用的机制尚不清楚。我们评估了葡萄糖和β-羟基丁酸（主要的循环酮体）对EL小鼠（一种多因素特发性全身性癫痫模型）的急性癫痫保护作用。给EL小鼠喂食不受限制的标准饮食或热量限制的标准饮食，以使体重减轻20-23%。在癫痫测试前2.5小时，向热量限制小鼠的饮用水中补充D-葡萄糖、2-脱氧-D-葡萄糖和β-羟基丁酸，分别模拟葡萄糖可用性增加、葡萄糖利用减少和酮可用性增加的效果。在为期九周的治疗期间，测量癫痫易感性、体重、血糖和β-羟基丁酸。此外，使用（1）H NMR测量小鼠大脑中的兴奋性和抑制性氨基酸。还测量了谷氨酸脱羧酶活性，以评估饮食疗法与脑代谢之间的联系。我们发现，长期（>4周）热量限制赋予癫痫保护作用需要降低葡萄糖利用，而酮可用性增加并不影响癫痫易感性。然而，在没有长期热量限制的情况下，葡萄糖利用减少和酮可用性增加并不影响癫痫易感性。脑兴奋性和抑制性氨基酸含量随治疗没有变化，谷氨酸脱羧酶活性与癫痫易感性无关。我们证明，在EL小鼠长期热量限制下，降低葡萄糖利用是赋予癫痫保护作用所必需的，而急性补充酮并不能赋予癫痫保护作用。需要进一步研究以揭示葡萄糖利用影响癫痫易感性的机制。
