Radu Beatrice Mihaela, Epureanu Florin Bogdan, Radu Mihai, Fabene Paolo Francesco, Bertini Giuseppe
Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Italy; Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Romania.
Department of Pharmacology and Pharmacognosy, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Romania.
Epilepsy Res. 2017 Mar;131:15-27. doi: 10.1016/j.eplepsyres.2017.02.003. Epub 2017 Feb 9.
Current antiepileptic drugs have limited efficacy and provide little or no benefits in 30% of the patients. Given that a role for brain inflammation in epilepsy has been repeatedly reported in recent years, the potential of anti-inflammatory drugs should be explored in depth, as they may provide new therapeutical approaches in preventing or reducing epileptogenesis. Here, we review preclinical (both in vivo and in vitro) and clinical epilepsy studies in which nonsteroidal antiinflammatory drugs (NSAIDs), i.e. cyclooxygenase-2 (COX-2) selective inhibitors (COXIBs) and nonselective NSAIDs, were used for seizure control. The effects of NSAIDs are reviewed in animal models of both chemical (pilocarpine, kainic acid, pentylenetetrazol, or carbachol administration) and electrical (tetanic hippocampal stimulation, electroshock) seizure induction. In the pilocarpine model, NSAIDs are neuroprotective, reduce mossy fiber sprouting or diminish P-glycoprotein upregulation, but only rarely protect against seizures. While neuroprotective effects have also been observed in the kainic acid model, NSAIDs tend in general to worsen seizure activity. Effects of COXIB administration in the pentylenetetrazol-induced seizures model are variable, alternating from protection against seizures to null effects or even increased incidence of convulsions. Moreover, NSAIDs tested in the tetanic hippocampal stimulation model diminished the seizure-associated P-glycoprotein upregulation, but were not very effective in seizure control. NSAIDs efficacy in experimental in vivo epilepsy studies may be influenced by multiple factors, including the timing of administration (before or after status epilepticus induction), the animal model of epilepsy or some of the signaling pathways involved in cyclooxygenase induction (e.g. prostaglandins and their receptors). On the other hand, the few clinical studies on the use of NSAIDs in neurological pathologies accompanied/characterized by seizures indicate that nonselective NSAIDs (e.g. aspirin) in prolonged, low-dose treatments may offer protection against seizures and stroke-like events. No clinical trials in epileptic patients using COXIBs have been conducted so far, as several international drug-control authorities have withdrawn these drugs from the market; future studies should focus on improved COXIB formulations. We argue that, while the available evidence is still inconclusive, the potential therapeutic benefits of controlling and diminishing brain inflammation in the treatment of epilepsy should be actively explored.
目前的抗癫痫药物疗效有限，30%的患者从中几乎没有获益或完全没有获益。鉴于近年来反复报道脑炎症在癫痫中起作用，应深入探索抗炎药物的潜力，因为它们可能为预防或减少癫痫发生提供新的治疗方法。在此，我们综述了临床前（体内和体外）和临床癫痫研究，其中非甾体抗炎药（NSAIDs），即环氧合酶-2（COX-2）选择性抑制剂（COXIBs）和非选择性NSAIDs，被用于控制癫痫发作。在化学性（毛果芸香碱、 kainic 酸、戊四氮或卡巴胆碱给药）和电性（强直性海马刺激、电休克）癫痫发作诱导的动物模型中，综述了NSAIDs的作用。在毛果芸香碱模型中，NSAIDs具有神经保护作用，可减少苔藓纤维出芽或降低P-糖蛋白上调，但很少能预防癫痫发作。虽然在kainic酸模型中也观察到了神经保护作用，但NSAIDs总体上倾向于使癫痫发作活动恶化。COXIBs在戊四氮诱导的癫痫发作模型中的作用各不相同，从预防癫痫发作到无作用甚至惊厥发生率增加。此外，在强直性海马刺激模型中测试的NSAIDs减少了癫痫发作相关的P-糖蛋白上调，但在控制癫痫发作方面不是很有效。NSAIDs在实验性体内癫痫研究中的疗效可能受多种因素影响，包括给药时间（癫痫持续状态诱导之前或之后）、癫痫动物模型或环氧合酶诱导中涉及的一些信号通路（如前列腺素及其受体）。另一方面，关于NSAIDs在伴有癫痫发作/以癫痫发作为特征的神经病理学中的应用的少数临床研究表明，长期低剂量使用非选择性NSAIDs（如阿司匹林）可能对癫痫发作和中风样事件有预防作用。由于几个国际药物管制当局已将这些药物撤出市场，目前尚未对癫痫患者进行使用COXIBs的临床试验；未来的研究应集中在改进COXIB制剂上。我们认为，虽然现有证据仍然不确定，但应积极探索控制和减轻脑炎症在癫痫治疗中的潜在治疗益处。
