The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical. The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).

中文翻译：

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雷洛昔芬增强氟西汀抗小鼠最大电击诱发的癫痫发作的作用。

缺乏指导临床医生就目前的抗癫痫药物（AED）进行理疗的证据，目前的实践建议很大程度上是经验性的。现有AED联合治疗的药物负荷过大与神经毒性加剧有关，无法避免药物耐受性癫痫发作的出现。为寻求基于机制证据的组合疗法中新AED的明智选择，对雷洛昔芬，氟西汀，溴隐亭及其低剂量组合的标准剂量对最大电击（MES）引起的强直性后肢延伸（THLE）的影响进行了实验测试在小鼠中。进行了海马神经肽Y（NPY）水平，氧化应激和组织病理学研究。结果表明，4 mg / kg雷洛昔芬对14 mg / kg氟西汀的抗MES诱导的THLE有增强作用，否则用4 mg / kg雷洛昔芬的单药治疗无法产生效果。结果还显示比标准的AED卡马西平（20 mg / kg）有更好的疗效。最深刻的是，MES诱导的海马NPY水平显着（P <0.001）降低，但使用二重奏药物组合却没有显着提高，表明在缓解电击诱发的癫痫发作方面有其他机制。这些结果随后通过评估氧化应激和神经元损伤的测定得到证实。总之，结果证明了双药低剂量组合药物具有良好的治疗效果。雷洛昔芬和氟西汀，