Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats

Abstract

Background: Activated astrocytes release matrix metalloproteinase-2/9 (MMP-2/9) to induce central sensitization and maintain neuropathic pain. However, the mechanisms involved in the activation of MMP-2/9 on astrocytes during pain remain poorly understood. Meanwhile, there is a lack of effective treatment to inhibit the activation of MMP-2/9 on astrocytes. In this study, we aim to investigate the effect of tetramethylpyrazine (TMP), a natural compound with analgesic effects but unknown mechanisms, on MMP-2/9 in neuropathic pain. Methods: The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 6). Cell signaling was assayed using western blotting (n = 6) and immunohistochemistry (n = 5). The astrocyte cell line C8-D1A was cultured to investigate the in vitro effects. Results: TMP significantly attenuated the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain, inhibited the activation of astrocytes, and decreased the expression of MMP-2/9. Furthermore, our results indicated that TMP could selectively suppress JNK activity but had no notable effects on ERK and p38. Our study also revealed that the effect of TMP may be dependent on the inhibition of TAK1.

α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

“… 68 – 70 As one of the most important members of the MAPK family, JNK was also found to be activated in neuropathic pain. 71 – 73 Our data illustrated that the alleviation of activated glia and pain behavior was ameliorated by the activation of α7nAChR. Therefore, we hypothesized that the effect might proceed through this complex downstream signaling pathway.…”

Chuanxiong Formulae for Migraine: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials

“…TMP and FA inhibit the activity of NADPH oxidase via ERK signaling pathway and NF-κB pathway respectively (Wong et al, 2007 ; Cao et al, 2015 ). (2) Antiinflammatory effects: TMP, senkyunolide A and ligustilide could down regulate the activation and proliferation of astrocytic, the production and bioactivity of tumor necrosis factor α (TNF-α), and the expression of cyclooxygenase-2 (COX-2) protein (Liu et al, 2005 ; Chung et al, 2012 ; Feng et al, 2012 ; Jiang et al, 2017 ). (3) Antiapoptotic effects: Ligustilide prevented neuronal apoptosis in both parietal cortex and hippocampus through regulation of mitochondrion metabolism (Feng et al, 2012 ) TMP could decrease the levels of miR-214-3p and increase the expression level of Bcl2l2 (Fan and Wu, 2017 ).…”

Identification of the key genes associated with neuropathic pain

“…Double labeling with the tracers fast blue and horseradish peroxidase-labeled gold underwent retrograde transport from the site of injury and revealed that c-Jun protein expression was confined to injured neurons ( 34 ). Activated c-Jun in the dorsal root ganglion (DRG) contributes to the pathogenesis of neuropathic pain induced by CCI ( 35 ), and neuropathic pain is alleviated by inhibiting the mitogen-activated protein kinase 8 (JNK)/c-Jun signal pathway ( 36 , 37 ). Furthermore, Plau mRNA is abundantly expressed by many neurons in the peripheral and central nervous system ( 38 ).…”