Mitochondrial Protection and Against Glutamate Neurotoxicity via Shh/Ptch1 Signaling Pathway to Ameliorate Cognitive Dysfunction by Kaixin San in Multi-Infarct Dementia Rats.

Xiaoqiong Li,Hao Chen,Ying Fu,Wen Wen,Fushun Wang,Shijun Xu,Ping Li,Yuan Dai,Xu Wu

doi:10.1155/2021/5590745

Abstract

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. Kaixin San (KXS), a classic prescription of Beiji Qianjin Yaofang, 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.

Highlights

Multi-infarct dementia (MID) is a prominent subtype of vascular dementia (VD) and is responsible for at least 15 to 20 percent of dementia in the elderly
We investigated the effects of Kaixin San (KXS) on rescuing cognitive damage in MID rats based on its effects on regulating mitochondrial function and glutamate neurotoxicity via activating the sonic hedgehog (Shh)/Ptch1 signaling pathway
A typical highperformance liquid chromatography (HPLC) profile was developed for KXS extracts (Figure 1), which served as an index for the identification of KXS

Summary

Introduction

Multi-infarct dementia (MID) is a prominent subtype of vascular dementia (VD) and is responsible for at least 15 to 20 percent of dementia in the elderly. Cerebral ischemia caused by chronic hypoperfusion could induce cerebral hypoxic and result in the production of reactive oxygen species (ROS) and excitatory amino acid (EAA), such as glutamate [6], which directly impair mitochondrial homeostasis and energy production [4, 7]. The hippocampal structure in the brain is the core division for spatial cognitive activity, and its mitochondria are very sensitive to ROS and energy deficit, hippocampal mitochondrial dysfunction plays a key role in cerebral ischemia-induced cognitive impairment [8]. Glutamate outflow and excessive extracellular glutamate accumulation resulted from the death of nerve cells due to energy deficit in turn could lead to ischemic neuronal death and cognitive disorder [9, 10]. Previous studies suggested that cognitive deficit could be alleviated by reversing brain mitochondrial dysfunction and reducing excessive glutamate content in MID rats [4, 11, 12]

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