Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models.
Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models.
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DOI：
10.1002/ana.21603
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发表时间：
2009-04
影响因子：
11.2
通讯作者：
Sutula, Thomas P.
中科院分区：
文献类型：
--
作者：
Stafstrom, Carl E.;Ockuly, Jeffrey C.;Murphree, Lauren;Valley, Matthew T.;Roopra, Avtar;Sutula, Thomas P.
传统的抗惊厥药通过影响离子通道和突触功能来降低神经元的兴奋性。生酮饮食的抗惊厥机制仍不完全清楚。由于生酮饮食患者的碳水化合物受到限制，我们在癫痫发作和癫痫的实验模型中评估了通过使用糖酵解抑制剂2-脱氧-D-葡萄糖（2DG）减少糖酵解来限制碳水化合物可用性的影响。在体外用7.5mM [K+]o，4-氨基吡啶（4-AP）或荷包牡丹碱灌注大鼠海马脑片，并在体内对小鼠中由6 Hz刺激诱发的癫痫发作、Fring小鼠中的听源性刺激以及大鼠中最大电休克和皮下Metrazol诱发的癫痫发作评估2DG的急性抗惊厥作用。2DG（10 mM）可减少高[K+]o、4-AP和荷包牡丹碱诱发的发作间期癫痫样爆发和高[K+]o诱发的海马CA 3区电图癫痫发作。2DG可减少6 Hz电刺激诱发的小鼠癫痫发作（ED_（50）= 79.7mg/kg）和Fring小鼠听源性电刺激诱发的癫痫发作（ED_（50）= 206.4mg/kg）。2DG通过增加穿支通路（但不是嗅球）点燃的后放电阈值发挥慢性抗癫痫作用，并在两个刺激部位引起点燃癫痫发作进展减慢2倍。2DG对最大电休克或Metrazol癫痫发作无保护作用。糖酵解抑制剂2DG发挥急性抗惊厥和慢性抗癫痫作用，并在临床前筛选模型中具有新的有效性模式。这些结果确定代谢调节作为抑制癫痫发作和修改癫痫发生的潜在治疗靶点。
Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Since carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine (4-AP), or bicuculline and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring’s mice, and maximal electroshock and subcutaneous Metrazol in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. 2DG (10mM) reduced interictal epileptiform bursts induced by high [K+]o, 4-AP and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6 Hz stimulation in mice (ED50 = 79.7 mg/kg) and audiogenic stimulation in Fring’s mice (ED50 = 206.4 mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a 2-fold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis.
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影响因子：
3.6
作者：
HUTTENLOCHER, PR
通讯作者：
HUTTENLOCHER, PR
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作者：
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作者：
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作者：
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