Velísková J, Velísek L, Galanopoulou A S, Sperber E F
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Epilepsia. 2000;41 Suppl 6:S30-5. doi: 10.1111/j.1528-1157.2000.tb01553.x.
Estrogens have neuroprotective effects in ischemia, stroke, and other conditions leading to neuronal cell death (e.g., Alzheimer's disease). The present study examined whether estrogens may have neuroprotective effects after seizures.
The kainic acid model was used to determine if estrogens protect hippocampal cells after status epilepticus in adult female rats. Rats were ovariectomized 1 week before hormone replacement. beta-Estradiol benzoate (EB; 2 microg in 0.1 mL of oil) was injected subcutaneously 48 and 24 hours before seizure testing. We administered kainic acid (16 mg/kg intraperitoneally) and behaviorally monitored the rats for 5 hours. After this time, all rats were injected with pentobarbital (50 mg/kg intraperitoneally) irrespective of seizure severity. Some rats received two additional doses of EB, one immediately and one 24 hours after the seizures. Another group of rats received only these two doses of EB after the seizures, and yet another group of rats received pretreatment with the intracellular EB receptor antagonist tamoxifen before each of four EB injections. Control rats received oil instead of EB. Rats were killed 48 hours after seizures. Neuronal damage was evaluated in silver-impregnated and Nissl-stained sections.
Estrogen treatment before kainic acid administration significantly delayed the onset of kainic acid-induced clonic seizures, whereas it did not change the onset of status epilepticus compared with oil-treated controls. Furthermore, estrogen treatment significantly protected against kainic acid-induced seizure-related mortality. In control rats, examination of Nissl-stained and silver-impregnated slides revealed severe neuronal damage in the vulnerable pyramidal neurons of the hippocampal CA3 subfield and in the hilus of the dentate gyrus. Estrogen pretreatment, as well as the combination of pretreatment and posttreatment, significantly reduced the number of argyrophilic neurons in both the CA3 and the dentate gyrus. Posttreatment only had no protective effects. The data indicate that intracellular EB receptors mediate this type of neuroprotective effect, because the tamoxifen pretreatment abolished EB neuroprotection.
Our results suggest that estrogens can be beneficial in protecting against status epilepticus-induced hippocampal damage. Hormonal conditions may have differential effects on underlying epileptic state in some patients. Therefore, more studies are necessary to determine the prospective therapeutic advantage of hormonal treatment in seizure-related damage.
雌激素在缺血、中风及其他导致神经元细胞死亡的病症（如阿尔茨海默病）中具有神经保护作用。本研究旨在探讨雌激素在癫痫发作后是否可能具有神经保护作用。
采用海藻酸模型来确定雌激素对成年雌性大鼠癫痫持续状态后海马细胞是否具有保护作用。在激素替代前1周对大鼠进行卵巢切除术。在癫痫测试前48小时和24小时皮下注射苯甲酸雌二醇（EB；2μg溶于0.1mL油中）。腹腔注射海藻酸（16mg/kg），并对大鼠进行5小时的行为监测。此后，无论癫痫严重程度如何，所有大鼠均腹腔注射戊巴比妥（50mg/kg）。一些大鼠在癫痫发作后立即和24小时后额外接受两剂EB。另一组大鼠在癫痫发作后仅接受这两剂EB，还有一组大鼠在四次EB注射前均用细胞内EB受体拮抗剂他莫昔芬进行预处理。对照大鼠接受油而非EB。癫痫发作48小时后处死大鼠。在银染和尼氏染色切片中评估神经元损伤。
在给予海藻酸前进行雌激素治疗可显著延迟海藻酸诱导的阵挛性癫痫发作的起始，而与用油处理的对照相比，其并未改变癫痫持续状态的起始。此外，雌激素治疗可显著预防海藻酸诱导的癫痫相关死亡率。在对照大鼠中，尼氏染色和银染切片检查显示海马CA3亚区易损锥体细胞和齿状回门区存在严重的神经元损伤。雌激素预处理以及预处理和后处理的联合应用均显著减少了CA3和齿状回中嗜银神经元的数量。仅后处理无保护作用。数据表明细胞内EB受体介导了这种神经保护作用，因为他莫昔芬预处理消除了EB的神经保护作用。
我们的结果表明，雌激素在预防癫痫持续状态诱导的海马损伤方面可能有益。激素状况可能对某些患者的潜在癫痫状态有不同影响。因此，需要更多研究来确定激素治疗在癫痫相关损伤中的潜在治疗优势。
