Commonalities in epileptogenic processes from different acute brain insults: Do they translate?
Commonalities in epileptogenic processes from different acute brain insults: Do they translate?
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DOI：
10.1111/epi.13965
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发表时间：
2018-01
期刊：
影响因子：
5.6
通讯作者：
Löscher W
中科院分区：
文献类型：
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作者：
Klein P;Dingledine R;Aronica E;Bernard C;Blümcke I;Boison D;Brodie MJ;Brooks-Kayal AR;Engel J Jr;Forcelli PA;Hirsch LJ;Kaminski RM;Klitgaard H;Kobow K;Lowenstein DH;Pearl PL;Pitkänen A;Puhakka N;Rogawski MA;Schmidt D;Sillanpää M;Sloviter RS;Steinhäuser C;Vezzani A;Walker MC;Löscher W
获得性癫痫最常见的形式出现在急性脑损伤后，如创伤性脑损伤、中风或CNS感染。治疗仅对60-70%的患者有效，尽管数十年来努力开发癫痫预防疗法，但仍有症状。最近的临床前工作集中在癫痫发生的可能主要驱动因素，即炎症，神经元丢失，可塑性和电路重组。这篇综述提出了一种途径，以确定神经元和分子靶点的临床试验的具体假设癫痫及其预防或修改。不同病因的获得性人类癫痫与动物模型有一些共同的特点。我们确定这些共性，并讨论其相关性，成功的癫痫预防或疾病的修改策略的发展。多种急性损伤病因中常见的癫痫发生风险因素包括颅内出血、血脑屏障破坏、更严重的损伤和损伤后一周内的早期癫痫发作。在不同的人类癫痫和动物模型中，癫痫发作似乎在边缘系统或丘脑皮质/皮质-皮质网络内传播。不同和大多数局灶性起源的癫痫的常见组织病理学特征是小胶质细胞活化和星形胶质细胞增生、白色物质中的异位神经元、神经元损失和存在炎性细胞浸润。星形胶质细胞在许多动物模型中表现出较小的K+电导，并且在颞叶癫痫患者的大脑皮层中失去间隙连接耦合。越来越多的证据表明，在获得性癫痫的临床前动物模型中，可以通过干扰多种急性损伤病因学共同的过程来预防或中止癫痫，例如，在局灶性癫痫的癫痫持续状态模型中，通过trkB/PLCγ1抑制剂、异氟烷或HMGB 1抗体和局部给药腺苷进行短暂治疗;在皮质流体撞击损伤模型中，通过局灶性冷却进行治疗;在白蛋白创伤后癫痫模型中，通过氯沙坦进行治疗。临床前研究进一步强调了mTOR 1通路、JAK-STAT 3、IL-1 R/TLR 4信号传导和其他炎症通路在脑损伤后癫痫发生或调节中的作用。临床前鉴定的分子靶点的共同性、多样性以及癫痫发生的可能的多维性质的丰富性主张在预防治疗中采用组合策略。展望未来，识别即将发生的癫痫生物标志物以更好地选择患者，以及与动物模型中的多中心临床前试验更好地对齐，应该指导癫痫发生及其预防的新假设的临床测试。
The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or CNS infections. Treatment is effective for only 60-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury and early seizures within a week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/cortico-cortical network. Common histopathology features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, e.g., in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin post-traumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multi-site preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.