Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.
Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.
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DOI：
10.1016/j.yebeh.2016.11.006
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Whalley BJ
中科院分区：
文献类型：
--
作者：
Rosenberg EC;Patra PH;Whalley BJ
大麻中的离散植物大麻素的分离和鉴定重新引起了人们对分析临床病例研究和轶事中大麻的历史治疗主张的兴趣。特别是，早在11世纪和15世纪就有消息称大麻粗提取物在治疗惊厥性疾病方面具有功效，这促使植物大麻素在癫痫治疗潜力方面的临床前研究领域变得特别活跃。从那时起，积累了大量文献，描述了超过100种植物大麻素中的几种在癫痫发作、癫痫、癫痫发生和癫痫相关神经保护的临床前模型中的作用。我们调查了文献中关于这种植物大麻素作用的相关报道，并对他们的发现进行了批判性的审查。我们发现，在啮齿动物急性癫痫发作的简单模型中，急性CB 1 R激动通常产生抗惊厥作用，而CB 1 R拮抗剂在相同的模型中产生匡威的作用。然而，当在更复杂的癫痫、癫痫发生和神经保护模型中研究这些配体的作用时，出现了一种不那么简单的叙述。在这里，（i）给定模型中涉及的大脑区域之间的复杂相互作用，（ii）内源性大麻素信号对这些区域突触传递调节的相对贡献，（iii）多靶点效应，（iv）大麻素1型和2型受体信号相互作用，以及，（v）时机，（vi）配体给药的持续时间和（vii）配体给药的定位表明，在上和下-中枢神经系统中内源性大麻素信号的调节。受体脱敏和所用配体的特异性药理学等因素（例如，完全与部分激动剂和中性拮抗剂与反向激动剂）似乎也在报告的效应中发挥重要作用。此外，几种植物大麻素（最著名的是大麻二酚（CBD）和大麻素（CBDV））在癫痫发作、癫痫、癫痫发生和神经保护模型中的作用不那么模糊，并且与这些化合物的治疗有益作用的报道一致。临床研究。然而，关于CBD/CBDV的治疗分子机制的可靠信息的持续缺乏突出了该领域研究的持续需要，以确定尚未开发的药物开发靶点，并提高我们对难治性癫痫的理解。最近在两项治疗难治性癫痫的III期临床试验中报告了大麻二酚治疗的积极结果，为一种植物大麻素在癫痫中的临床疗效提供了关键证据。此外，与在儿科癫痫中使用未经许可的含有大麻提取物的Δ9-THC相关的风险和/或益处仍然知之甚少。因此，鉴于这些范式变化的临床事件，本综述的研究结果旨在推动未来的药物开发新确定的目标和适应症，确定动物模型在癫痫中植物大麻素作用研究中的重要局限性，并将未来的研究重点放在这一领域关于癫痫内源性大麻素信号传导复杂性的具体，未回答的问题上。
The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review's findings aim to drive future drug development for newly-identified targets and indications, identify important limitations of animal models in the investigation of plant cannabinoid effects in the epilepsies, and focuses future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid signaling in epilepsy.
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