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的药理学研究和人类受试者的临床研究来研究癫痫的药物治疗策略。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治疗中的可能用途。神经活性类固醇是内源性类固醇激素（及其合成类似物），通过直接作用于膜离子通道（包括GABA-A和NMDA受体）迅速改变神经元的兴奋性。在以前的报告期间，我们证实，生殖激素孕酮具有强大的抗惊厥活性，我们证明，这是由于其转化为神经活性类固醇allopregnanolone。我们提出，月经期月经癫痫，癫痫发作频率的增加，许多妇女的经验，月经时间（当孕酮水平下降）可能，部分，是与撤回allopregnanolone。目前，对于月经性癫痫还没有特效的治疗方法。然而，我们对月经性癫痫动物模型的研究表明，神经类固醇替代可能是有用的。我们已经启动了临床研究，以验证神经类固醇戒断假说的月经性癫痫，我们计划进行临床试验，以评估效用的神经类固醇替代。此外，我们还研究了神经类固醇在应激诱导的癫痫发作易感性改变中的作用，特别关注四氢脱氧皮质酮（DOC），一种肾上腺类固醇，其合成在应激过程中增强。我们的研究结果表明，DOC是急性应激的生理效应，可能有助于通过其转换为神经甾体与GABA-A受体，包括THDOC和可能也二氢脱氧皮质酮（DHDOC）的调节作用，在癫痫发作易感性的应激诱导的变化的介质。我们的研究结果进一步表明神经活性类固醇作为应激相关癫痫发作的治疗方法的作用。在本报告期内，我们开发了一种体外模型，以评估神经类固醇对癫痫发作易感性的影响，不存在混杂因素，如吸收，代谢和大脑可及性的差异。 本文观察了神经甾体别孕烯醇酮及其5 β-差向异构体孕烯醇酮和硫酸双烯醇酮（PS）对印防己毒素（PTX）和4-氨基吡啶（4-AP）诱发的大鼠海马脑片CA_3区自发性痫样放电的影响。在低浓度下，allopregnanolone部分减少PTX诱导的爆裂，并在较高浓度下完全抑制爆裂。相反，孕烯醇酮未能改变放电频率。别孕烯醇酮抑制4-AP诱导的爆发与PTX模型中的效力相似;孕烯醇酮也部分有效。在4-AP模型中，别孕烯醇酮既抑制更频繁的主要正向电位，也抑制可能由同步GABA能中间神经元放电产生的频率较低的负向电位。PS增强PTX爆发频率，在4-AP模型中，增加负电位的频率，但不改变正电位的频率。PS本身不会引起爆破。类固醇在体外癫痫发作模型中的作用在很大程度上与其对GABA-A受体的活性相对应;放电抑制可能是由于这些受体的直接激活而不是GABA介导的突触反应的调节。我们的结论是，PTX和4-AP诱导的海马切片爆裂是有用的模型，直接评估神经类固醇的癫痫发作易感性的条件下，消除脑生物利用度的因素。