School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, Zhejiang, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
J Neurol. 2024 Feb;271(2):748-771. doi: 10.1007/s00415-023-12062-w. Epub 2023 Nov 27.
Epilepsy is a complex and multifaceted neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to its diverse etiology and often-refractory nature. This comprehensive review highlights the pivotal role of AMP-activated protein kinase (AMPK), a key metabolic regulator involved in cellular energy homeostasis, which may be a promising therapeutic target for epilepsy. Current therapeutic strategies such as antiseizure medication (ASMs) can alleviate seizures (up to 70%). However, 30% of epileptic patients may develop refractory epilepsy. Due to the complicated nature of refractory epilepsy, other treatment options such as ketogenic dieting, adjunctive therapy, and in limited cases, surgical interventions are employed. These therapy options are only suitable for a select group of patients and have limitations of their own. Current treatment options for epilepsy need to be improved. Emerging evidence underscores a potential association between impaired AMPK functionality in the brain and the onset of epilepsy, prompting an in-depth examination of AMPK's influence on neural excitability and ion channel regulation, both critical factors implicated in epileptic seizures. AMPK activation through agents such as metformin has shown promising antiepileptic effects in various preclinical and clinical settings. These effects are primarily mediated through the inhibition of the mTOR signaling pathway, activation of the AMPK-PI3K-c-Jun pathway, and stimulation of the PGC-1α pathway. Despite the potential of AMPK-targeted therapies, several aspects warrant further exploration, including the detailed mechanisms of AMPK's role in different brain regions, the impact of AMPK under various conditional circumstances such as neural injury and zinc toxicity, the long-term safety and efficacy of chronic metformin use in epilepsy treatment, and the potential benefits of combination therapy involving AMPK activators. Moreover, the efficacy of AMPK activators in refractory epilepsy remains an open question. This review sets the stage for further research with the aim of enhancing our understanding of the role of AMPK in epilepsy, potentially leading to the development of more effective, AMPK-targeted therapeutic strategies for this challenging and debilitating disorder.
癫痫是一种复杂且多方面的神经障碍，其特征是自发性和反复发作的癫痫发作。由于其病因多样且经常具有难治性，因此给治疗带来了重大挑战。本综述重点介绍了 AMP 激活的蛋白激酶（AMPK）的关键作用，AMPK 是一种参与细胞能量平衡的关键代谢调节剂，可能是癫痫的有前途的治疗靶标。目前的治疗策略，如抗癫痫药物（ASMs），可以缓解癫痫发作（高达 70%）。然而，30%的癫痫患者可能发展为难治性癫痫。由于难治性癫痫的复杂性，其他治疗选择，如生酮饮食、辅助治疗，以及在有限的情况下，手术干预，都被采用。这些治疗选择仅适用于一部分患者，并且有其自身的局限性。目前癫痫的治疗方法需要改进。新出现的证据强调了大脑中 AMPK 功能障碍与癫痫发作之间的潜在关联，促使深入研究 AMPK 对神经兴奋性和离子通道调节的影响，这两者都是癫痫发作中涉及的关键因素。在各种临床前和临床环境中，通过二甲双胍等药物激活 AMPK 已显示出有希望的抗癫痫作用。这些作用主要是通过抑制 mTOR 信号通路、激活 AMPK-PI3K-c-Jun 途径和刺激 PGC-1α 途径来实现的。尽管 AMPK 靶向治疗具有潜力，但仍有几个方面需要进一步探索，包括 AMPK 在不同脑区中的作用的详细机制、AMPK 在神经损伤和锌毒性等各种条件下的影响、慢性使用二甲双胍治疗癫痫的长期安全性和疗效，以及涉及 AMPK 激活剂的联合治疗的潜在益处。此外，AMPK 激活剂在难治性癫痫中的疗效仍然是一个悬而未决的问题。本综述为进一步研究奠定了基础，旨在提高我们对 AMPK 在癫痫中的作用的认识，从而有可能开发出更有效的、针对 AMPK 的治疗策略，以应对这一具有挑战性和使人衰弱的疾病。
