Stringer J L, Lothman E W
Department of Neurology, University of Virginia Medical Center, Charlottesville 22908.
Ann Neurol. 1988 Mar;23(3):281-6. doi: 10.1002/ana.410230311.
Recently, a theoretical scheme offered mechanisms by which phenytoin exerts its antiepileptic effects. Two predictions arising from this proposal are that phenytoin would suppress alterations in the potency of excitatory neurotransmission engendered by repetitive neural activation and that this effect would be augmented by displacing the extracellular concentration of K+ ([K+]0) away from its normal resting level. In the present study, we tested these predictions by examining the effects of phenytoin on short- and long-term functional plasticity in vitro in the hippocampus. Extracellular field potentials were recorded in the CA1 region of the rat hippocampal slice in response to stimulation of the Schaeffer collaterals. Phenytoin (20 micrograms/ml) did not affect baseline excitatory neurotransmission as measured by input-output curves (population spike amplitude versus stimulus intensity) obtained at low stimulus rates. The drug also had no effect on either frequency potentiation (2.5 Hz) or long-term potentiation (50 Hz, 500 msec; or 400 Hz, 20 msec). When [K+]0 was raised to levels seen during seizures, the drug still did not alter frequency potentiation or long-term potentiation induced by either type of stimulus train. Phenytoin also had no effect on either stimulus-locked or spontaneous epileptiform bursts that appear in conjunction with elevated [K+]0 or on stimulus-locked bursts that appear in the presence of 0.75 mM extracellular calcium. These results, showing that certain forms of functional synaptic plasticity are not affected by phenytoin, suggest a means by which phenytoin could exert its antiepileptic action without interfering with normal brain function.
最近，一个理论方案提出了苯妥英发挥抗癫痫作用的机制。该提议产生的两个预测是，苯妥英会抑制由重复性神经激活引起的兴奋性神经传递效能的改变，并且这种效应会因将细胞外钾离子浓度（[K⁺]₀）从其正常静息水平移开而增强。在本研究中，我们通过检查苯妥英对海马体体外短期和长期功能可塑性的影响来检验这些预测。在大鼠海马体切片的CA1区域记录细胞外场电位，以响应施affer侧支的刺激。苯妥英（20微克/毫升）对低刺激率下获得的输入-输出曲线（群体峰电位幅度与刺激强度）所测量的基线兴奋性神经传递没有影响。该药物对频率增强（2.5赫兹）或长期增强（50赫兹，500毫秒；或400赫兹，20毫秒）也没有影响。当[K⁺]₀升高到癫痫发作时所见的水平时，该药物仍然不会改变由任何一种刺激序列诱导的频率增强或长期增强。苯妥英对与[K⁺]₀升高相关出现的刺激锁定或自发性癫痫样爆发，或对存在0.75毫摩尔细胞外钙时出现的刺激锁定爆发也没有影响。这些结果表明某些形式的功能性突触可塑性不受苯妥英影响，这提示了一种苯妥英可以在不干扰正常脑功能的情况下发挥其抗癫痫作用的方式。
