PRENATAL AED EXPOSURE AND SEIZURE SUSCEPTIBILITY

拟议的实验旨在确定产前的影响。 抗癫痫药物(AED)对惊厥行为的影响 在大鼠体内的后代。有效的假设是，暴露于 在非致畸的剂量下，大脑对这些药物的发育可以 诱导中枢神经系统的长期变化，从而改变癫痫的敏感性。 苯巴比妥、丙戊酸钠和氯硝西潘将用于大鼠 在妊娠15-21天，服用产生人体血清水平的剂量 治疗范围。在第一系列实验中，后代将被 接受戊四氮(PTZ)诱导的癫痫发作以确定1)是否 孕晚期产前暴露于抗癫痫药物可保护胎儿 来自这种化学惊厥剂的后代或使其对这种化学惊厥剂的作用敏感； 2)这个变化区的个体发育参数是什么；3)如果预暴露 在子宫内改变这些药物的抗炎效果；4)或 抽搐行为中未被观察到的变化是性二态的；以及 5)如果外周代谢酶的变化是导致 PTZ所致惊厥行为的改变。 第二系列实验将调查母体和母体的作用 癫痫发作与抗癫痫药在动物惊厥发生中的作用 癫痫易感性由基因决定的模型：听源性 癫痫易感性(AGSS)大鼠。在确定了行为 AED的疗效、AGS的成熟参数和疗效 针对这些在我们殖民地的缉获，我们将调查 怀孕前或怀孕期间经治疗和未经治疗的惊厥 子代的癫痫易感性。在两个系列的实验中 苯巴比妥、氯硝西潘和丙戊酸盐的血浆浓度以及血浆 将在怀孕期间和在女性体内检测蛋白质 出生后的后代。 这些实验应该提供有关漏洞的信息 对AEDs和随后的癫痫敏感性的影响 后代。它们还可以决定基因和基因的贡献 确定癫痫发作阈值的环境因素并提供 妊娠期癫痫的治疗指南。

The proposed experiments are designed to determine the effects of prenatal exposure to antiepiletic drugs (AED) on the convulsive behavior of the offspring in rat. The working hypothesis is that exposure of the developing brain to these agents, in doses that are not teratogenic, can induce long-term changes in the CNS which alter seizure susceptibility. Phenobarbital, sodium valproate and clonazepam will be administered to rats on gestation days 15-21 in doses that produce serum levels in the human therapeutic range. In the first series of experiments offspring will be subjected to pentylene-tetrazole (PTZ)-induced seizures to determine 1) if prenatal exposure to AEDs during the third trimester can protect the offspring from or sensitize them to the action of this chemical convulsant; 2) what the ontogenetic parameters of this change area; 3) if pre-exposure in utero alters the anticovulsant efficacy of these drugs; 4) whether or not observed alterations in convulsive behavior are sexually dimorphic; and 5) if changes in peripheral metabolizing enzymes are responsible for changes in PTZ-induced convulsive behavior. A second series of experiments will investigate the role of both maternal seizure activity and AEDs on the development of convulsions in an animal model whose seizure susceptibility is genetically determine: the audiogenic seizure susceptibility (AGSS) rats. After determining the behavioral response, the maturational parameters of AGS, and the efficacy of AED against these seizures in our colony, we will investigate the effects of treated and untreated convulsions prior to or during pregnancy on the seizure susceptibility in the offspring. In both series of experiments plasma levels of phenobarbital, clonazepam, and valproate as well as plasma proteins will be determined in females during pregnancy and in the offspring after birth. These experiments should provide information concerning the vulnerability of the developing brain to AEDs and subsequent seizure susceptibility in the offspring. They may also determine the contribution of genetic and environmental factors in determining seizure thresholds and provide guidelines for the management of epilepsy in pregnancy.