Chen Qian, Deng Congshuang, Huang Xiaoshan, Wang Aili, Xu Nan, Cao Kaixun, Yang Min, Li Shang, Lu Qiumin, Gong Guiyi, Lee Simon Ming-Yuen
Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China.
Shenzhen Academy of Environmental Sciences, Shenzhen, 518022, Guangdong, China.
Arch Toxicol. 2025 Sep 26. doi: 10.1007/s00204-025-04164-3.
Epilepsy is a prevalent neurological disorder characterized by recurrent and unprovoked seizures. Despite the availability of anti-epileptic drugs (AEDs), a significant number of patients are still suffering from drug-resistant epilepsy. Neuropeptide Y (NPY) signaling system has emerged as a potential target for the development of anti-epileptic drugs due to its modulation of epileptic activity. In this study, we investigated the therapeutic potential of our previously discovered Scleractinia-derived NPY-like peptide (TpNPY) in seizure disorders. The anticonvulsant effects of TpNPY were evaluated using PTZ-induced seizures in zebrafish and mice in vivo. Furthermore, the underlying molecular mechanisms of TpNPY were assessed using glutamate-induced excitotoxicity models in HT22 mouse hippocampal cells in vitro. Our findings indicated that TpNPY could alleviate PTZ-induced seizure behavior, reduce the expression of seizure-associated immediate-early genes and the production of Reactive Oxygen Species (ROS) in zebrafish. In mice, TpNPY improved seizure behaviors, decreased inflammatory cytokine levels, and ameliorated abnormal glial activation in a PTZ kindling epileptic model. Besides, the administration of TpNPY could attenuate the PTZ-induced anxiety levels and improve recognition memory deficits. Moreover, TpNPY promotes neurogenesis and neural synaptic plasticity through the BDNF/TrkB signaling pathway. Additionally, TpNPY restored cell injury and attenuated oxidative stress in glutamate-challenged HT22 cells through the Nrf2/HO-1 signaling pathway. These results highlight the potential therapeutic efficacy of TpNPY in the treatment of seizures and provide new insights into the development of coral-derived anti-epileptic peptide-based drugs.
癫痫是一种常见的神经系统疾病，其特征为反复出现且无诱因的癫痫发作。尽管有抗癫痫药物（AEDs）可用，但仍有相当数量的患者患有耐药性癫痫。神经肽Y（NPY）信号系统因其对癫痫活动的调节作用，已成为抗癫痫药物开发的潜在靶点。在本研究中，我们调查了我们之前发现的源自石珊瑚的NPY样肽（TpNPY）在癫痫疾病中的治疗潜力。使用戊四氮诱导的斑马鱼和小鼠体内癫痫发作来评估TpNPY的抗惊厥作用。此外，在体外使用谷氨酸诱导的HT22小鼠海马细胞兴奋性毒性模型评估TpNPY的潜在分子机制。我们的研究结果表明，TpNPY可以减轻戊四氮诱导的斑马鱼癫痫发作行为，降低癫痫发作相关即刻早期基因的表达以及活性氧（ROS）的产生。在小鼠中，TpNPY改善了癫痫发作行为，降低了炎症细胞因子水平，并改善了戊四氮点燃癫痫模型中的异常胶质细胞激活。此外，给予TpNPY可以减轻戊四氮诱导的焦虑水平并改善认知记忆缺陷。此外，TpNPY通过BDNF/TrkB信号通路促进神经发生和神经突触可塑性。另外，TpNPY通过Nrf2/HO-1信号通路恢复了谷氨酸刺激的HT22细胞中的细胞损伤并减轻了氧化应激。这些结果突出了TpNPY在癫痫治疗中的潜在治疗效果，并为基于珊瑚源抗癫痫肽的药物开发提供了新的见解。
