A Novel Tetramethylpyrazine Derivative Protects Against Glutamate-Induced Cytotoxicity Through PGC1α/Nrf2 and PI3K/Akt Signaling Pathways

Abstract

Glutamate-induced excitotoxicity is one of the main causes of neuronal cell death in stroke. Compound 22a has been previously reported as a promising neuroprotective compound derived from tetramethylpyrazine, which is a widely used active ingredient of traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franchat). Compound 22a can protect neurons from oxidative stress-induced PC12 cell death and alleviates the infarct areas and brain edema in a rat permanent middle cerebral artery occlusion model. In the current work, we further investigated the neuroprotective effects and underlying mechanisms of compound 22a against glutamate-induced excitotoxicity in primary culture of rat cerebellar granule neurons (CGNs). We found that pretreatment with compound 22a prevented glutamate-induced neuronal damage by maintaining mitochondrial membrane potential and attenuating cellular apoptosis. Compound 22a could also enhance peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) transcriptional activity and induce nuclear accumulation of Nrf2 in PC12 cells. Accordingly, pretreatment with compound 22a reversed the glutamate-induced down-regulation of expression of the proteins PGC1α, transcriptional factor NF-E2-related factor 2 (Nrf2), and hemooxygenase 1 (HO-1). In addition, compound 22a increased the phosphorylation of phosphoinositide 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and glycogen synthase kinase 3β (p-GSK3β). Meanwhile, the small interfering RNA-mediated silencing of PGC1α expression and selective inhibitors targeting PI3K/Akt (LY294002 and Akt-iv) could significantly attenuate the neuroprotective effect of compound 22a. Taken together, compound 22a protected against glutamate-induced CGN injury possibly in part through regulation of PGC1α/Nrf2 and PI3K/Akt pathways.

Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γ/Bcl-2

“…Many studies have shown that TMP and its derivatives or compatibility with salvianic acid A/resveratrol possess functional cardioprotection/neuroprotection after myocardial ischemia-reperfusion/ischaemic stroke through interfering with PI3K/Akt/GSK3 β , PGC1 α /Nrf2, BDNF/Akt/CREB pathway, up-regulating Nrf-2 and HO-1 expression, maintaining Ca 2+ homeostasis, and inhibiting inflammatory reaction, etc. [18–20, 50–52]. Some researchers have shown that TMP and prescriptions as mentioned above can attenuate injury Dox-induced cardiotoxicity and nephrotoxicity by inhibiting oxidative stress, cell autophagy and apoptosis [53, 54].…”

Unique indolizidine alkaloid securinine is a promising scaffold for the development of neuroprotective and antitumor drugs

“…Ligustrazine is one of the main biologically active components known from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franchat), widely used for the clinical treatment of cardiovascular diseases, [95][96][97] and has pronounced antitumor 98 and neuroprotective properties. [99][100][101] Numerous series of derivatives have been synthesized on the basis of ligustrazine including dimeric ones. 100,102,103 The patent 94 describes in detail the synthesis of bivalent compounds based on ligustrazine and securinine (Scheme 15) with the preliminary production of 2,5-bis(bromomethyl)-3,6dimethylpyrazine and aminosecurinine followed by their combination into a bivalent derivative.…”

Attenuated glutamate induced ROS production by antioxidative compounds in neural cell lines

“…Glutamate-induced cytotoxicity is one of the leading causes of neuronal cell death. 35 In this study, we rst compared the cytotoxicity among different neural cells. The cell viability experiment was performed to four typical neural cells, including PC22, SH-SY5Y, HT22 and primary astrocytes.…”