A Novel Ligustrazine Derivative T-VA Prevents Neurotoxicity in Differentiated PC12 Cells and Protects the Brain against Ischemia Injury in MCAO Rats.

Guoliang Li,Penglong Wang,Yuzhong Zhang,Yingzhi Hao,Haimin Lei,Yufei Tian,Ying Hong,Chunxiao Chen

doi:10.3390/ijms160921759

Guoliang Li, Penglong Wang + Show 6 more

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https://doi.org/10.3390/ijms160921759

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Abstract

Broad-spectrum drugs appear to be more promising for the treatment of acute ischemic stroke. In our previous work, a new ligustrazine derivative (3,5,6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (T-VA) showed neuroprotective effect on injured PC12 cells (EC50 = 4.249 µM). In the current study, we show that this beneficial effect was due to the modulation of nuclear transcription factor-κB/p65 (NF-κB/p65) and cyclooxygenase-2 (COX-2) expressions. We also show that T-VA exhibited neuroprotective effect in a rat model of ischemic stroke with concomitant improvement of motor functions. We propose that the protective effect observed in vivo is owing to increased vascular endothelial growth factor (VEGF) expression, decreased oxidative stress, and up-regulation of Ca2+–Mg2+ ATP enzyme activity. Altogether, our results warrant further studies on the utility of T-VA for the potential treatment of ischemic brain injuries, such as stroke.

Highlights

Stroke is the second most common cause of death and major cause of disability worldwide, in the elderly [1]
The results showed that ligustrazine-benzoic acid derivatives presented neuroprotective effects, on injured differentiated PC12 cells, of which, T-VA (C24H28N4O4) (Figure 1) displayed promising protective effect on the injured PC12 cells (EC50 = 4.249 μM) [14,15,16]
With treatment of differentiated PC12 cells with CoCl2, the cell viability was reduced to 42.9% of the nerve growth factor (NGF) group value (100%), and NMDP increased model cell viability to 90.1%

Summary

Introduction

Stroke is the second most common cause of death and major cause of disability worldwide, in the elderly [1]. Most strokes (80%) are ischemic and the disease relates with both cerebrovascular system and cranial nerves [2]. Ischemic stroke has exerted neurological disturbances, nerve damage and microcirculation damage in the brain, including oxidative stress, inflammatory response, and intracellular rise of Ca2+ [3,4]. In the light of recent knowledge, strategies such as antioxidants, calcium antagonists and angiogenesis appear to be effective in neuron damage, and drugs with these categories will likely be more appropriate as adjunctive interventions for the treatment of acute ischemic stroke [5,6]. Justifying TCM use in ischemic stroke patients is principally based on the synergic effect of their multi-categories [8,9]

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Discussion

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