Wheless James W, Rho Jong M
Division of Pediatric Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Department of Neurosciences, Pediatrics and Pharmacology, University of California San Diego School of Medicine, San Diego, California, USA.
Epilepsia. 2025 Jan;66(1):33-46. doi: 10.1111/epi.18174. Epub 2024 Nov 2.
Cholesterol is a critical molecule in the central nervous system, and imbalances in the synthesis and metabolism of brain cholesterol can result in a range of pathologies, including those related to hyperexcitability. The impact of cholesterol on disorders of epilepsy and developmental and epileptic encephalopathies is an area of growing interest. Cholesterol cannot cross the blood-brain barrier, and thus the brain synthesizes and metabolizes its own pool of cholesterol. The primary metabolic enzyme for brain cholesterol is cholesterol 24-hydroxylase (CH24H), which metabolizes cholesterol into 24S-hydroxycholesterol (24HC). Dysregulation of CH24H and 24HC can affect neuronal excitability through a range of mechanisms. 24HC is a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors and can increase glutamate release via tumor necrosis factor-α-dependent pathways. Increasing cholesterol metabolism can lead to dysfunction of excitatory amino acid transporter 2 and impair glutamate reuptake. Finally, overstimulation of NMDA receptors can further activate metabolism of cholesterol, leading to a vicious cycle of overactivation. All of these mechanisms increase extracellular glutamate and can lead to hyperexcitability. For these reasons, the cholesterol pathway represents a new potential mechanistic target for antiseizure medications. CH24H inhibition has been shown to decrease seizure behavior and improve survival in multiple animal models of epilepsy and could be a promising new mechanism of action for the treatment of neuronal hyperexcitability and developmental and epileptic encephalopathies.
胆固醇是中枢神经系统中的一种关键分子，脑胆固醇合成与代谢的失衡会导致一系列病理状况，包括与过度兴奋相关的病症。胆固醇对癫痫以及发育性和癫痫性脑病的影响是一个日益受到关注的领域。胆固醇无法穿过血脑屏障，因此大脑会自行合成和代谢自身的胆固醇池。脑胆固醇的主要代谢酶是胆固醇24 - 羟化酶（CH24H），它将胆固醇代谢为24S - 羟胆固醇（24HC）。CH24H和24HC的失调可通过一系列机制影响神经元兴奋性。24HC是N - 甲基 - D - 天冬氨酸（NMDA）受体的正变构调节剂，可通过肿瘤坏死因子 - α依赖途径增加谷氨酸释放。胆固醇代谢增加可导致兴奋性氨基酸转运体2功能障碍并损害谷氨酸再摄取。最后，NMDA受体的过度刺激可进一步激活胆固醇代谢，导致过度激活的恶性循环。所有这些机制都会增加细胞外谷氨酸水平，并可能导致过度兴奋。基于这些原因，胆固醇途径代表了抗癫痫药物的一个新的潜在作用机制靶点。在多种癫痫动物模型中，抑制CH24H已被证明可减少癫痫发作行为并提高生存率，对于治疗神经元过度兴奋以及发育性和癫痫性脑病而言，这可能是一种有前景的新作用机制。
