Department of Neurosciene, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20123 Milano, Italy.
Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.
Curr Pharm Des. 2017;23(37):5569-5576. doi: 10.2174/1381612823666170926113754.
The lack of treatments which can prevent epilepsy development or improve disease prognosis represents an unmet and urgent clinical need. The development of such drugs requires a deep understanding of the mechanisms underlying disease pathogenesis. In the last decade, preclinical studies in models of acute seizures and of chronic epilepsy highlighted that neuroinflammation arising in brain areas of seizure onset and generalization is a key contributor to neuronal hyper-excitability underlying seizure generation. Microglia and astrocytes are pivotal cells involved in both the induction and perpetuation of the inflammatory response to epileptogenic injuries or seizures; other cell contributors are neurons, cell components of the blood brain barrier and leukocytes.
From the clinical standpoint, neuroinflammation is now considered an hallmark of epileptogenic foci in various forms of focal onset pharmacoresistant epilepsies. Moreover, pharmacological studies in animal model with drugs targeting specific inflammatory molecules, and changes in intrinsic seizure susceptibility of transgenic mice with perturbed neuroinflammatory mechanisms, have demonstrated that neuroinflammation is not a bystander phenomenon but has a pathogenic role in seizures, cell loss and neurological co-morbidities. Understanding the role of neuroinflammation in seizure pathogenesis is instrumental for a mechanism-based discovery of selective therapies targeting the epilepsy causes rather than its symptoms, thereby allowing the development of novel disease-modifying treatments. Notably, clinical translation of laboratory findings may take advantage of anti-inflammatory drugs already in medical use for peripheral autoinflammatory or autoimmune disorders.
This review reports key preclinical and clinical findings supporting a role for brain inflammation in the pathogenesis of seizures. It also highlights the emerging proof-of-concept studies showing signs of clinical efficacy of target-specific anti-inflammatory interventions in epilepsies of differing etiologies. We will discuss the need for biomarkers and novel clinical trial designs for anti-inflammatory therapies that have a mechanism of action very different than standard antiepileptic drugs.
缺乏能够预防癫痫发作或改善疾病预后的治疗方法，这是一个未满足的、紧迫的临床需求。这类药物的开发需要深入了解疾病发病机制的机制。在过去的十年中，急性发作和慢性癫痫模型中的临床前研究强调，起源于发作起始和泛化脑区的神经炎症是导致发作发生的神经元过度兴奋的关键因素。小胶质细胞和星形胶质细胞是参与致痫性损伤或发作引起的炎症反应诱导和持续的关键细胞；其他细胞贡献者包括神经元、血脑屏障的细胞成分和白细胞。
从临床角度来看，神经炎症现在被认为是各种局灶性起始药物难治性癫痫的致痫灶的一个标志。此外，针对特定炎症分子的动物模型的药理学研究，以及神经炎症机制改变的转基因小鼠内在发作易感性的变化，表明神经炎症不是旁观者现象，而是在发作、细胞丢失和神经合并症中具有致病作用。了解神经炎症在发作发病机制中的作用对于基于机制的选择性治疗方法的发现至关重要，这些方法针对的是癫痫的病因而不是其症状，从而允许开发新的疾病修饰治疗方法。值得注意的是，实验室发现的临床转化可以利用已经用于治疗外周自身炎症或自身免疫性疾病的抗炎药物。
本综述报告了支持脑炎症在发作发病机制中起作用的关键临床前和临床发现。它还强调了新兴的概念验证研究，这些研究显示了针对不同病因癫痫的靶向特异性抗炎干预措施具有临床疗效的迹象。我们将讨论针对具有与标准抗癫痫药物作用机制非常不同的抗炎治疗方法的生物标志物和新的临床试验设计的需求。
