全球近16%的人口受到神经系统疾病的影响,包括神经退行性疾病和脑神经免疫疾病,由急性或慢性炎症引发。神经炎症被认为是包括阿尔茨海默病在内的一系列神经系统疾病中的常见致病机制。帕金森病,术后认知功能障碍,中风,创伤性脑损伤,和多发性硬化症。中枢神经系统(CNS)的炎症过程可导致神经元损伤和神经元凋亡,从而加剧这些疾病。衣结糖酯,来自三羧酸循环的免疫调节代谢物,抑制神经炎症和调节CNS免疫反应。新兴的人体研究表明,血浆和脑脊液中的衣康酸酯水平可能是与神经系统疾病中炎症反应相关的生物标志物。临床前研究表明,衣康酸酯及其高度细胞渗透性衍生物是预防和治疗神经炎症相关神经系统疾病的有希望的候选者。其潜在机制可能涉及调节中枢神经系统免疫细胞和神经炎症相关的信号通路和分子,包括Nrf2/KEAP1信号通路,活性氧,和NLRP3炎性体。这里,介绍了衣康酸酯的代谢和功能及其衍生物的合成和发展。我们总结了衣康酸酯及其衍生物对脑免疫细胞和相关信号通路和分子的潜在影响和治疗潜力。基于各种神经系统疾病模型的临床前证据。我们还讨论了临床翻译的挑战和潜在解决方案,以促进对衣康酸酯及其衍生物用于神经炎症相关神经系统疾病的进一步研究。
Almost 16 % of the global population is affected by neurological disorders, including neurodegenerative and cerebral neuroimmune diseases, triggered by acute or chronic inflammation. Neuroinflammation is recognized as a common pathogenic mechanism in a wide array of neurological conditions including Alzheimer\'s disease, Parkinson\'s disease, postoperative cognitive dysfunction, stroke, traumatic brain injury, and multiple sclerosis. Inflammatory process in the central nervous system (CNS) can lead to neuronal damage and neuronal apoptosis, consequently exacerbating these diseases.
Itaconate, an immunomodulatory metabolite from the tricarboxylic acid cycle, suppresses neuroinflammation and modulates the CNS immune response. Emerging human studies suggest that
itaconate levels in plasma and cerebrospinal fluid may serve as biomarkers associated with inflammatory responses in neurological disorders. Preclinical studies have shown that
itaconate and its highly cell-permeable derivatives are promising candidates for preventing and treating neuroinflammation-related neurological disorders. The underlying mechanism may involve the regulation of immune cells in the CNS and neuroinflammation-related signaling pathways and molecules including Nrf2/KEAP1 signaling pathway, reactive oxygen species, and NLRP3 inflammasome. Here, we introduce the metabolism and function of
itaconate and the synthesis and development of its derivatives. We summarize the potential impact and therapeutic potential of
itaconate and its derivatives on brain immune cells and the associated signaling pathways and molecules, based on preclinical evidence via various neurological disorder models. We also discuss the challenges and potential solutions for clinical translation to promote further research on itaconate and its derivatives for neuroinflammation-related neurological disorders.