The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid
The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid
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DOI：
10.1111/j.1528-1167.2007.01026.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.6
通讯作者：
Rogawski, Michael A.
中科院分区：
文献类型：
--
作者：
Gasior, Maciej;French, Amy;Rogawski, Michael A.
背景：丙酮是生酮饮食治疗过程中升高的主要酮体之一，表现出抗惊厥特性，可能有助于通过饮食保护癫痫发作。丙酮的抗惊厥作用机制尚不清楚，但它被代谢成几种可能发挥作用的生物活性物质。方法：在两种小鼠惊厥模型上，评价丙酮及其主要代谢物--丙醇、1，2-丙二醇、甲基乙二醛和丙酮酸的抗惊厥活性。不同剂量的药物均能提高静脉注射戊四氮(PTZ)所致阵挛发作的阈值，并对皮下注射4-氨基吡啶(4-AP)所致的强直性癫痫发作具有保护作用。结果：丙酮(1~32 mmol/kg，ip)可剂量依赖性地提高PTZ阈值，并对4-AP惊厥具有保护作用(ED50，26.3 mmol/kg)。在倒屏试验中，有效剂量的丙酮(10-32 mmol/kg)没有引起运动损伤(TD50，45.7 mmol/kg)。在PTZ模型中，当剂量超过丙酮最低有效剂量(3.2 mmol/kg)10倍时，代谢物丙醇、1，2-丙二醇和丙酮酸都是不活跃的。在导致运动障碍的较高剂量下，丙醇和1，2-丙二醇(但不包括丙酮酸)确实提高了PTZ阈值。甲基乙二醛既有催眠作用，又有抗惊厥作用，而且有很大的毒性，会导致呼吸窘迫、运动障碍和死亡。结论：本研究证实了丙酮的广谱抗惊厥作用，提示丙酮的抗癫痫作用不太可能来源于其主要代谢产物。
Background: Acetone, one of the principal ketone bodies elevated during treatment with the ketogenic diet, exhibits anticonvulsant properties that may contribute to the seizure protection conferred by the diet. The anticonvulsant mechanism of acetone is unknown, but it is metabolized to several bioactive substances that could play a role.Methods: Acetone and its major metabolites-acetol, 1,2-propanediol, methylglyoxal, and pyruvic acid-were assessed for anticonvulsant activity in two mouse seizure models. Various doses of the substances administered intraperitoneally were characterized for their ability to elevate the threshold for clonic seizures induced by intravenous infusion of pentylenetetrazol (PTZ) and for protection against tonic seizures induced by subcutaneous bolus administration of 4-aminopyridine (4-AP). The inverted-screen test was used to assess acute neurological toxicity.Results: Acetone (1-32 mmol/kg, i.p.), in a dose-dependent fashion, elevated the PTZ threshold and conferred protection against 4-AP seizures (ED50, 26.3 mmol/kg). Effective doses of acetone (10-32 mmol/kg) did not cause motor impairment in the inverted-screen test (TD50, 45.7 mmol/kg). In doses 10-fold greater than the minimally effective dose of acetone (3.2 mmol/kg), the metabolites acetol, 1,2-propanediol, and pyruvic acid were inactive in the PTZ model. At higher doses that produced motor impairment, acetol and 1,2-propanediol (but not pyruvic acid) did elevate the PTZ threshold. Methylglyoxal had both proconvulsant and anticonvulsant actions, and had substantial toxicity, producing respiratory distress, motor impairment, and death. None of the acetone metabolites protected against 4-AP seizures.Conclusions: This study confirms the broad-spectrum anticonvulsant properties of acetone and indicates that the seizure protection conferred is unlikely to result from its major metabolic products.