Chrysophanol Suppressed Glutamate-Induced Hippocampal Neuronal Cell Death via Regulation of Dynamin-Related Protein 1-Dependent Mitochondrial Fission

Abstract

Chrysophanic acid, or chrysophanol, is an anthraquinone found in Rheum palmatum, which was used in the preparation of oriental medicine in ancient China. The hippocampus plays a major role in controlling the activities of the short- and long-term memory. It is one of the major regions affected by excessive cell death in Alzheimer's disease. Therefore, neuronal cell-death modulation in the hippocampus is important for maintaining neuronal function. We investigated chrysophanol's effects on glutamate-induced hippocampal neuronal cell death. Chrysophanol reduced glutamate-induced cell death via suppression of proapoptotic factors and reactive oxygen species generation. Furthermore, it downregulated glutamate-induced mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) dephosphorylation. Thus, chrysophanol suppressed hippocampal neuronal cell death via inhibition of Drp1-dependent mitochondrial fission, and can be used as a therapeutic agent for treating neuronal cell death-mediated neurodegenerative diseases.

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

“…[ 38 ] Chrysophanol can inhibit neuronal cell death by regulating anti‐apoptotic and pro‐apoptotic factors in hippocampal neurons, down‐regulate Drp1 (S637) dephosphorylation and intracellular ROS accumulation. [ 39 ] Our study found that Chrysophanol could improve memory ability of d ‐galactose and Aβ 25‐35 induced AD rat model correlating with inhibiting tau hyperphosphorylation and the CaM‐CaMKIV signal pathway in hippocampus. [ 40 ] Chrysophanol exerts neuroprotective effects by reducing the neurological deficits, cerebral oedema and BBB destruction, and down‐regulating the levels of NALP3, caspase‐1 and IL‐1β, which might be involve in the inhibition of NALP3 inflammasome activation.…”

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics

“…found that chrysophanol (10 μ m ) inhibited LPS‐induced BV‐2 murein microglial cell inflammatory response by down‐regulating dynamin‐related protein 1 (Drp1) (S637) dephosphorylation to inhibit the production of pro‐inflammatory mediators and cytokines via regulation of mitogen‐activated protein kinase (MAPK), nuclear factor‐jB (NF‐jB)and reactive oxygen species (ROS) generation. Similarly, for treating AD, researchers have found that chrysophanol could prevent excessive mitochondrial division in hippocampal neurons by inhibiting dephosphorylation of Drp1 . Moreover, Wang et al .…”

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

“…Other reports suggest that dephosphorylation of Drp1 at Ser‐637 can trigger increased mitochondrial division by calcium‐calmodulin kinase (CaMKIIα) after the hypoxic precondition and glutamate treatment leading to necroptosis in CA1 neurons, suggesting that dephosphorylation of Drp1 at Ser‐637 reverses the protective effect toward mitochondrial fission, which was mediated by phosphorylation at Ser‐637, indicating the same function in mitochondrial dynamics with phosphorylation at Ser‐40, 44, 579, 585, 592, and 616. Hence, it is necessary to elucidate whether the stimulative role of the Siah2/AKAP1 pathway in mitochondrial division and neuronal cell apoptosis was mediated by dephosphorylation at Ser‐637, but this remains unclear (Chae et al, ; Chen et al, ; Flippo et al, ; H. Kim et al, ; Zhan et al, ). The function of phosphorylation at Ser‐656 is much similar to Ser‐637, because Slupe et al found that the PKA‐mediated phosphorylation of Drp1 at Ser‐656 can decrease the Drp1 activity which denotes decreased mitochondrial fission events of mitochondria causing a protective effect of the neuronal system, whereas dephosphorylation of Drp1 at Ser‐656 mediated by protein phosphatase 2A (PP2A)/calcineurin (CaN) increases the activity of Drp1 causing neuronal death after oxygen‐glucose deprivation (OGD) treatment.…”

“…According to Kim et al's report,Siah2 (a ubiquitin ligase) can inhibit the expression of AKAP1 by decreasing the expression of protein kinase A (PKA) and FIS1-Drp1 interaction causing increased mitochondrial division finally leading to neural cell apoptosis. Other reports suggest that dephosphorylation of Drp1 at Ser-637 can trigger increased mitochondrial division by calciumcalmodulin kinase (CaMKⅡα) after the hypoxic precondition and glutamate treatment leading to necroptosis in CA1 neurons, suggesting that dephosphorylation of Drp1 at Ser-637 reverses the protective effect toward mitochondrial fission, which was mediated by phosphorylation at Ser-637, indicating the same function in mitochondrial dynamics with phosphorylation at 44,579,585,592,and 616. Hence, it is necessary to elucidate whether the stimulative role of the Siah2/AKAP1 pathway in mitochondrial division and neuronal cell apoptosis was mediated by dephosphorylation at Ser-637, but this remains unclear (Chae et al, 2017;Chen et al, 2015;Flippo et al, 2018; H. Kim et al, 2011;Zhan et al, 2018). The function of phosphorylation (Table 1) effect in the neural system (Dickey & Strack, 2011;Slupe et al, 2013; Table 1).…”