Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
Oxid Med Cell Longev. 2021 Jul 9;2021:5590745. doi: 10.1155/2021/5590745. eCollection 2021.
Multi-infarct dementia (MID), a prominent subtype of vascular dementia (VD), is responsible for at least 15 to 20 percent of dementia in the elderly. Mitochondrial dysfunctions and glutamate neurotoxicity due to chronic hypoperfusion and oxidative stress were regarded as the major risk factors in the pathogenesis. (KXS), a classic prescription of , was applied to treatment for "amnesia" and has been demonstrated to alleviate the cognitive deficit in a variety of dementias, including MID. However, little is known whether mitochondria and glutamate are associated with the protection of KXS in MID treatment. The aim of this study was to investigate the role of KXS in improving the cognitive function of MID rats through strengthening mitochondrial functions and antagonizing glutamate neurotoxicity via the Shh/Ptch1 signaling pathway. Our data showed that KXS significantly ameliorated memory impairment and hippocampal neuron damage in MID rats. Moreover, KXS improved hippocampal mitochondrial functions by reducing the degree of mitochondrial swelling, increasing the mitochondrial membrane potential (MMP), and elevating the energy charge (EC) and ATP content in MID rats. As expected, the concentration of glutamate and the expression of p-NMDAR1 were significantly reduced by KXS in the brain tissue of MID rats. Furthermore, our results showed that KXS noticeably activated the Shh/Ptch1 signaling pathway which was demonstrated by remarkable elevations of Ptch1, Smo, and Gli1 protein levels in the brain tissue of MID rats. Intriguingly, the inhibition of the Shh signaling pathway with cyclopamine significantly inhibited the protective effects of KXS on glutamate-induced neurotoxicity in PC12 cells. To sum up, these findings suggested that KXS protected MID rats from memory loss by rescuing mitochondrial functions as well as against glutamate neurotoxicity through activating Shh/Ptch1 signaling pathway.
多发性梗死性痴呆（MID）是血管性痴呆（VD）的一个主要亚型，占老年人痴呆症的至少 15%至 20%。慢性灌注不足和氧化应激引起的线粒体功能障碍和谷氨酸神经毒性被认为是发病机制中的主要危险因素。（KXS）是经典的方剂，用于治疗“健忘症”，并已被证明可减轻多种痴呆症（包括 MID）的认知缺陷。然而，对于 KXS 是否与 MID 治疗中的线粒体和谷氨酸的保护有关知之甚少。本研究旨在通过增强线粒体功能和通过 Shh/Ptch1 信号通路拮抗谷氨酸神经毒性来探讨 KXS 在改善 MID 大鼠认知功能中的作用。我们的数据表明，KXS 可显著改善 MID 大鼠的记忆障碍和海马神经元损伤。此外，KXS 通过降低线粒体肿胀程度、增加线粒体膜电位（MMP）以及提高 MID 大鼠的能量电荷（EC）和 ATP 含量来改善海马线粒体功能。不出所料，KXS 可显著降低 MID 大鼠脑组织中谷氨酸的浓度和 p-NMDAR1 的表达。此外，我们的结果表明，KXS 明显激活了 Shh/Ptch1 信号通路，这表现在 MID 大鼠脑组织中 Ptch1、Smo 和 Gli1 蛋白水平的显著升高。有趣的是，用环巴胺抑制 Shh 信号通路可显著抑制 KXS 对谷氨酸诱导的 PC12 细胞毒性的保护作用。总之，这些发现表明，KXS 通过挽救线粒体功能以及通过激活 Shh/Ptch1 信号通路来抵抗谷氨酸神经毒性，从而保护 MID 大鼠免受记忆丧失。
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