Zhou Gui-Juan, Tang Yi-Yun, Zuo Jin-Xi, Yi Tao, Tang Jun-Peng, Zhang Ping, Zou Wei, Tang Xiao-Qing
The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China; Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China.
Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 42100, Hunan, PR China.
Biochem Pharmacol. 2022 Aug;202:115137. doi: 10.1016/j.bcp.2022.115137. Epub 2022 Jun 11.
β-microglobulin (BM) has been established to impair cognitive function. However, no treatment is currently available for BM-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates BM-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated BM-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of BM-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against BM-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in BM-exposed rats. These findings demonstrated that Itaconate alleviates BM-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond BM-associated neurocognitive disorders.
β-微球蛋白（BM）已被证实会损害认知功能。然而，目前尚无针对BM诱导的认知功能障碍的治疗方法。衣康酸是三羧酸（TCA）循环的中间产物，在几种神经系统疾病中发挥神经保护作用。氨基-β-羧基粘康酸半醛脱羧酶（ACMSD）/吡啶甲酸（PIC）途径是犬尿氨酸途径（KP）中一个关键的神经保护分支。本研究旨在探讨衣康酸是否能减轻BM诱导的认知障碍，并研究海马ACMSD/PIC途径的介导作用。我们证明4-辛基衣康酸（OI，一种衣康酸衍生物）显著减轻了BM诱导的认知功能障碍和海马神经发生损伤。OI处理还增加了ACMSD的表达，提高了PIC的浓度，并降低了BM暴露大鼠海马中3-HAA的水平。此外，TES-991对ACMSD的抑制显著消除了衣康酸对BM诱导的认知障碍和神经发生缺陷的保护作用。海马中补充外源性PIC也改善了BM暴露大鼠的认知表现和海马神经发生。这些发现表明，衣康酸通过上调海马ACMSD/PIC途径减轻了BM诱导的认知障碍。这是第一项将衣康酸记录为改善认知障碍的有前景治疗剂的研究。此外，对ACMSD/PIC途径的机制性见解增进了我们对其作为BM相关神经认知障碍以外神经系统疾病潜在治疗靶点的理解。
