Evidence Implicating Blood-Brain Barrier Impairment in the Pathogenesis of Acquired Epilepsy following Acute Organophosphate Intoxication.
Evidence Implicating Blood-Brain Barrier Impairment in the Pathogenesis of Acquired Epilepsy following Acute Organophosphate Intoxication.
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DOI：
10.1124/jpet.123.001836
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发表时间：
2024-01-17
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--
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中科院分区：
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有机磷（OP）中毒可引发胆碱能危象，这是一种危及生命的中毒，包括癫痫发作和癫痫持续状态。这些急性毒性反应与持续性神经炎症和自发性复发性癫痫（SRS）有关，也称为获得性癫痫。血脑屏障（BBB）损伤最近被认为是急性OP中毒与慢性不良神经功能结局相关的致病机制。在这篇综述中，我们简要地描述了血脑屏障的细胞和分子组成部分，审查证据改变血脑屏障的完整性后，急性OP中毒，并讨论了潜在的机制，急性OP中毒可能会促进血脑屏障功能障碍。我们强调神经炎症和血脑屏障功能障碍之间的复杂相互作用，这表明一个积极的前馈相互作用。最后，我们研究了不同模型和疾病状态的研究，这些模型和疾病状态表明BBB完整性的丧失可能导致癫痫发生过程的机制。总的来说，文献将BBB损伤确定为神经系统疾病的会聚机制，并证明了对急性OP中毒如何导致BBB损伤及其在SRS发病机制和潜在的其他长期神经系统后遗症中的作用的进一步机制研究是合理的。这样的研究对于评估BBB稳定作为减轻OP诱导的癫痫和可能的其他病因的癫痫发作疾病的神经保护策略是至关重要的。临床和临床前研究支持血脑屏障（BBB）功能障碍和癫痫发生之间的联系;然而，因果关系一直难以证明。描述BBB功能障碍和癫痫之间关系的机制研究可能为BBB稳定作为减轻急性有机磷（OP）中毒和非OP原因引起的癫痫以及与急性OP中毒相关的潜在其他不良神经系统疾病（如认知障碍）的神经保护策略提供新的见解。
Organophosphate (OP) poisoning can trigger cholinergic crisis, a life-threatening toxidrome that includes seizures and status epilepticus. These acute toxic responses are associated with persistent neuroinflammation and spontaneous recurrent seizures (SRS), also known as acquired epilepsy. Blood-brain barrier (BBB) impairment has recently been proposed as a pathogenic mechanism linking acute OP intoxication to chronic adverse neurologic outcomes. In this review, we briefly describe the cellular and molecular components of the BBB, review evidence of altered BBB integrity following acute OP intoxication, and discuss potential mechanisms by which acute OP intoxication may promote BBB dysfunction. We highlight the complex interplay between neuroinflammation and BBB dysfunction that suggests a positive feedforward interaction. Lastly, we examine research from diverse models and disease states that suggest mechanisms by which loss of BBB integrity may contribute to epileptogenic processes. Collectively, the literature identifies BBB impairment as a convergent mechanism of neurologic disease and justifies further mechanistic research into how acute OP intoxication causes BBB impairment and its role in the pathogenesis of SRS and potentially other long-term neurologic sequelae. Such research is critical for evaluating BBB stabilization as a neuroprotective strategy for mitigating OP-induced epilepsy and possibly seizure disorders of other etiologies. Clinical and preclinical studies support a link between blood-brain barrier (BBB) dysfunction and epileptogenesis; however, a causal relationship has been difficult to prove. Mechanistic studies to delineate relationships between BBB dysfunction and epilepsy may provide novel insights into BBB stabilization as a neuroprotective strategy for mitigating epilepsy resulting from acute organophosphate (OP) intoxication and non-OP causes and potentially other adverse neurological conditions associated with acute OP intoxication, such as cognitive impairment.
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