A Novel Tetramethylpyrazine Derivative Prophylactically Protects against Glutamate-Induced Excitotoxicity in Primary Neurons through the Blockage of N -Methyl-D-aspartate Receptor

Frontiers in Pharmacology
Shengquan HuYifan Han

Abstract

The over-activation of NMDA receptor via the excessive glutamate is believed to one of the most causal factors associated with Alzheimer's disease (AD), a progressive neurodegenerative brain disorder. Molecules that could protect against glutamate-induced neurotoxicity may hold therapeutic values for treating AD. Herein, the neuroprotective mechanisms of dimeric DT-010, a novel derivative of naturally occurring danshensu and tetramethylpyrazine, were investigated using primary rat cerebellar granule neurons (CGNs) and hippocampal neurons. It was found that DT-010 (3-30 μM) markedly prevented excitotoxicity of CGNs caused by glutamate, as evidenced by the promotion of neuronal viability as well as the reversal of abnormal morphological changes. While its parent molecules did not show any protective effects even when their concentration reached 50 μM. Additionally, DT-010 almost fully blocked intracellular accumulation of reactive oxygen species caused by glutamate and exogenous oxidative stimulus. Moreover, Western blot results demonstrated that DT-010 remarkably attenuated the inhibition of pro-survival PI3K/Akt/GSK3β pathway caused by glutamate. Ca2+ imaging with Fluo-4 fluorescence analysis further revealed that DT-010 greatl...Continue Reading

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Citations

Jan 1, 2020·Metabolic Engineering Communications·Thomas EngAindrila Mukhopadhyay
Dec 4, 2020·Acta Pharmacologica Sinica·Feng ZhangWei-Dong Le
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pedro Cruz-VicenteEugenia Gallardo
Aug 6, 2021·Neurotoxicity Research·Zeyu MengShengxi Meng
Aug 17, 2021·Oxidative Medicine and Cellular Longevity·Musbau Adewumi AkanjiOluyomi Stephen Adeyemi

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Methods Mentioned

BETA
X-ray
phase
transfection

Software Mentioned

Leica LAS X
QuickPrep
Origin Pro
MOE

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