Dataset Information

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

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 ?M) 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 ?M. 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/GSK3? pathway caused by glutamate. Ca2+ imaging with Fluo-4 fluorescence analysis further revealed that DT-010 greatly declined glutamate-induced increase in intracellular Ca2+. Most importantly, with the use of whole-cell patch clamp electrophysiology, DT-010 directly inhibited NMDA-activated whole-cell currents in primary hippocampal neurons. Molecular docking simulation analysis further revealed a possible binding mode that inhibited NMDA receptor at the ion channel, showing that DT-010 favorably binds to Asn602 of NMDA receptor via arene hydrogen bond. These results suggest that DT-010 could be served as a novel NMDA receptor antagonist and protect against glutamate-induced excitotoxicity from blocking the upstream NMDA receptors to the subsequent Ca2+ influx and to the downstream GSK3? cascade.

SUBMITTER: Hu S

PROVIDER: S-EPMC5816056 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Hu Shengquan S Hu Huihui H Mak Shinghung S Cui Guozhen G Lee Mingyuen M Shan Luchen L Wang Yuqiang Y Lin Huangquan H Zhang Zaijun Z Han Yifan Y

Frontiers in pharmacology 20180212

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 gra ...[more]

PMID: 29483871

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Project description:Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 μm length and 100 μm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.

Dataset Information

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

Publications

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

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