Cheng Clara M, Hicks Kristin, Wang Jie, Eagles Douglas A, Bondy Carolyn A
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
J Neurosci Res. 2004 Jul 15;77(2):270-6. doi: 10.1002/jnr.20144.
The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.
生酮饮食是一种碳水化合物含量极低、脂肪含量高的饮食，用于治疗难治性癫痫。我们推测这种饮食可能通过增加谷氨酸脱羧酶（GAD）的表达来发挥作用，GAD是γ-氨基丁酸（GABA）合成中的限速酶。因此，我们在一个成熟的、能抑制癫痫发作的生酮饮食啮齿动物模型中评估了脑内GAD水平。由于该饮食在适度（约10%）限制热量的情况下效果最佳，我们研究了三组动物：自由采食标准大鼠饲料的大鼠（自由采食-标准组）；热量限制的标准饲料组（CR-标准组）；以及等热量、热量限制的生酮饮食组（CR-生酮组）。我们发现，与对照组相比，两个CR饮食组的下丘、上丘和小脑皮质中的GAD67 mRNA均显著增加（例如，上丘增加45%，小脑皮质增加71%；P<.001）。与自由采食对照组相比，CR-标准组和CR-生酮组的上丘和颞叶皮质中GAD65 mRNA选择性增加。唯一明显的CR-生酮组特异性效应是纹状体中GAD67 mRNA增加30%（P = 0.03）。检测到GAD免疫反应性增强与mRNA变化平行。这些数据清楚地表明，热量限制可增加几个脑区的脑GAD65和GAD67表达，与生酮效应无关。这些观察结果可能解释了为什么热量限制可提高生酮饮食治疗癫痫的疗效，并表明饮食调整可能有助于治疗许多以GAD或GABA活性受损为特征的脑部疾病。
