Evaluation Of Novel Epilepsy Treatment Approaches

新型癫痫治疗方法的评价

• 批准号: 6842958
• 负责人: MICHAEL A. ROGAWSKI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6842958
• 关键词: anticonvulsants; brain disorder chemotherapy; disease /disorder proneness /risk; drug screening /evaluation; epilepsy; female; hormone therapy; human subject; human therapy evaluation; menstrual cycle; neurohormones; neuropharmacology; patient oriented research; physiologic stressor; steroid hormone; stress

The overall goal of this project is to investigate strategies for the drug treatment of epilepsy through pharmacological studies in animal models and clinical investigation in human subjects. Research was continued evaluating the role of neuroactive steroids in epilepsy and their possible uses in epilepsy therapy. Neuroactive steroids are endogenous steroid hormones (and their synthetic analogs) that rapidly alter the excitability of neurons by direct actions on membrane ion channels, including GABA-A and NMDA receptors. In prior reporting periods, we confirmed that the reproductive hormone progesterone has powerful anticonvulsant activity and we demonstrated that this results from its conversion to the neuroactive steroid allopregnanolone. We proposed that perimenstrual catamenial epilepsy, the increase in seizure frequency that many women with epilepsy experience near the time of menstruation (when progesterone levels fall) may, in part, be related to withdrawal of allopregnanolone. At present, there is no specific treatment for catamenial epilepsy. However, our studies with an animal model of catamenial epilepsy suggested that neurosteroid replacement could be useful. We have initiated clinical studies to validate the neurosteroid withdrawal hypothesis of catamenial epilepsy and we plan a clinical trial to evaluate the utility of neurosteroid replacement. In addition, we have investigated the role of neurosteroids in stress-induced alterations in seizure susceptibility, focusing specifically on tetrahydrodeoxycorticosterone (DOC), an adrenal steroid whose synthesis is enhanced during stress. Our results demonstrated that DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to neurosteroids with modulatory actions on GABA-A receptors including THDOC and possibly also dihydrodeoxycorticosterone (DHDOC). Our results further suggest a role for neuroactive steroids as a treatment approach for stress-related seizures. In the present reporting period we developed an in vitro model to assess neurosteroid effects on seizure susceptibility in the absence of confounding factors such as differences in absorption, metabolism, and brain accessibility. The neurosteroids allopregnanolone and its 5beta-epimer pregnanolone, and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by picrotoxin (PTX) and 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice. At a low concentration, allopregnanolone partially reduced PTX-induced bursting and at higher concentrations completely suppressed bursting. In contrast, pregnanolone failed to alter the discharge frequency. Allopregnanolone depressed 4-AP-induced bursting with similar potency as in the PTX model; pregnanolone was also partially effective. In the 4-AP model, allopregnanolone inhibited both the more frequent predominantly positive-going potentials as well as the less frequent negative-going potentials that may be generated by synchronous GABAergic interneuron firing. PS enhanced the PTX bursting frequency and, in the 4-AP model, increased the frequency of negative potentials but did not alter the frequency of positive potentials. By itself, PS did not induce bursting. The effects of the steroids in the in vitro seizure models largely correspond with their activities on GABA-A receptors; suppression of discharges may occur as a result of direct activation of these receptors rather than modulation of GABA-mediated synaptic responses. We conclude that PTX and 4-AP-induced bursting in the hippocampal slice are useful models for directly assessing neurosteroid effects on seizure susceptibility under conditions that eliminate the factor of brain bioavailability.

该项目的总体目标是通过动物模型中的药理学研究和人类受试者的临床研究来研究癫痫药物治疗的策略。研究继续评估神经活性类固醇在癫痫中的作用及其在癫痫疗法中的可能用途。神经活性类固醇是内源性类固醇激素（及其合成类似物），它们通过在包括GABA-A和NMDA受体在内的直接作用来迅速改变神经元的兴奋性。在先前的报告期间，我们证实了生殖激素孕酮具有强大的抗惊厥活性，我们证明了这是由于其转化为神经活性类固醇异源性异烷醇的结果。我们提出，绝经性癫痫，癫痫发作频率的增加，许多患有癫痫病的女性在月经时（孕酮水平下降）可能部分与撤回异源性同种素有关。目前，尚无针对性癫痫的具体治疗方法。然而，我们对诊断癫痫动物模型的研究表明，神经固醇的替代可能是有用的。我们已经开始了临床研究，以验证神经固醇戒断的假设，并计划一项临床试验来评估神经类固醇替代的效用。此外，我们还研究了神经类固醇在应激诱导的癫痫敏感性改变中的作用，专门针对四氢去氧化脱氧核心酮（DOC），这是一种肾上腺类固醇，其合成在胁迫下的合成增强。我们的结果表明，DOC是急性应激的生理作用的中介，这可能会导致压力引起的癫痫发作易感性的变化，通过转换为神经类固醇，对GABA-A受体进行调节作用，包括THDOC，包括Dihydrodoxyoxyoxyoxyoxyoxyoxyoxyoxycosterone（DHDOC）。我们的结果进一步表明神经活性类固醇作为与压力相关的癫痫发作的治疗方法的作用。在本报告期间，我们开发了一个体外模型，以评估神经类固醇对癫痫发作易感性的影响，在没有混杂因素（例如吸收，代谢和大脑可及性的差异）的情况下。 检查神经蛋白酶及其5beta- epimer妊娠酮和硫酸妊娠硫酸盐（PS），以对自发性癫痫样放电（PICrototoxin（PTX）和4-氨基吡啶（4- AP）诱导的自发性癫痫样放电作用。在较低的浓度下，Allopregnanolone部分降低了PTX诱导的爆发，并且在较高的浓度下完全抑制了爆发。相比之下，妊娠酮未能改变放电频率。 Allopregnanolone抑制4AP诱导的爆发，其效力与PTX模型相似。妊娠醇也是部分有效的。在4-AP模型中，Allopregnanolone抑制了更频繁的主要积极潜力，以及同步GABAergic Interneuron射击可能产生的频率较低的负面电位。 PS增强了PTX爆发频率，在4-AP模型中，PS提高了负电势的频率，但并没有改变正势的频率。就其本身而言，PS并没有引起破裂。类固醇在体外癫痫发作模型中的影响很大程度上与它们在GABA-A受体上的活性相对应。由于这些受体的直接激活而不是对GABA介导的突触反应的调节，可能会导致排放的抑制。我们得出的结论是，海马切片中的PTX和4-AP诱导的爆发是在消除消除脑生物利用度因素的条件下直接评估神经固醇对癫痫敏感性的影响的有用模型。