Jiang Chenyao, Yu Ying, Liu Jiawang, Jiang Jianxiong
Department of Pharmaceutical Sciences, College of Pharmacy, the University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Acta Pharm Sin B. 2025 May;15(5):2351-2362. doi: 10.1016/j.apsb.2025.03.024. Epub 2025 Mar 13.
Although epilepsy is first known as a disease of seizures and convulsions, most patients with epilepsy also suffer from seizure-associated behavioral abnormalities in motor functions, psychiatric status, and cognition. These neurobehavioral comorbidities may have greater impacts on the quality of life of people with epilepsy than the seizures themselves and can profoundly interfere with the treatment compliance. While repeated seizures often lead to behavioral comorbidities, certain types of comorbid conditions may potentially increase the risk for epileptic seizures, indicative of some common mechanisms that might underlie these two conditions. As such, emerging evidence supports that inflammation within the brain might represent a key component of such a shared mechanism, given that neuroinflammation can be induced by seizures and various behavioral stressors, and in turn may exacerbate both conditions. Among inflammatory pathways that arise after prolonged seizures, PGE signaling the EP2 receptor promotes cytokine induction, blood-brain barrier disruption, reactive gliosis, neuronal death, and eventually, contributes to behavioral dysfunctions. Pharmacological inhibition of EP2 by small-molecule drug-like antagonists affords broad therapeutic benefits including anti-inflammatory and neuroprotective effects in several rodent seizure models, leading to long-lasting alleviation of neurobehavioral comorbidities, particularly cognitive impairments. Targeting this key inflammatory prostaglandin receptor might provide an adjunctive strategy, along with the current anti-seizure medications, to mitigate cognitive dysfunctions associated with seizure disorders.
尽管癫痫最初被认为是一种发作和惊厥性疾病，但大多数癫痫患者还存在与发作相关的运动功能、精神状态和认知方面的行为异常。这些神经行为共病对癫痫患者生活质量的影响可能比癫痫发作本身更大，并且会严重干扰治疗依从性。虽然反复癫痫发作常导致行为共病，但某些类型的共病状况可能会增加癫痫发作的风险，这表明这两种情况可能存在一些共同的潜在机制。因此，新出现的证据支持大脑内的炎症可能是这种共同机制的关键组成部分，因为神经炎症可由癫痫发作和各种行为应激源诱导产生，进而可能使这两种情况都恶化。在长时间癫痫发作后出现的炎症通路中，前列腺素E（PGE）信号传导——通过EP2受体促进细胞因子诱导、血脑屏障破坏、反应性胶质增生、神经元死亡，并最终导致行为功能障碍。小分子药物样拮抗剂对EP2的药理学抑制在几种啮齿动物癫痫模型中具有广泛的治疗益处，包括抗炎和神经保护作用，可长期缓解神经行为共病，尤其是认知障碍。针对这一关键的炎症性前列腺素受体，可能会提供一种辅助策略，与目前的抗癫痫药物一起，减轻与癫痫疾病相关的认知功能障碍。
