Experimental Study On The Effect Of Tetramethylpyrazine On Astrocyte Disorders To Attenuate Chronic Pain

BackgroundChronic pain is a rising health problem that is predicted to affect up to 30%of adults worldwide.Due to its complex causes,the pathogenesis is not clear,the treatment is very difficult.Management of neuropathic pain remains a clinical challenge:current treatments for chronic pain have been greatly limited by an incomplete understanding of its pathogenesis.Convincing evidence shows that nerve injury induces the profound activation of glial cells,including microglia and astrocytes,in the spinal cord Microglia and astrocytes both play important roles in neuropathic pain.The continuous search for a safer and more effective compound is urgently needed.The preliminary results of this laboratory and the forefront of neuroscience research have suggested that tetramethylpyrazine(TMP),the bioactive component extracted from Chuanxiong(Ligusticum chuanxiong hort).chuanxiong,a Chinese traditional medicine,has been used for treating chronic pain for more than one hundred years.TMP has been widely used for three decades in clinical treatments,including ischemic and cerebral infarction diseases of the central nervous system to suppress neuroinflammation.TMP for chronic pain have been greatly limited by an incomplete understanding of its pathogenesis.In the current study,we examined how TMP improve neuropathic pain.Methods(1)Chronic constriction injury(CCI)of the scistic nerve model was established in rats.Mechanical allodynia of CCI rats were tested to evaluate the analgesia effect of TMP(i.p.)while single administration,consistent administration(2)Western blot was performed to measure the effects of TMP(single and consistent administration)on CCI induced upregulation of MAPK family proteins including p-JNK.Immunofluorescence was performed to determine the effects of TMP(consistent administration)on GFAP in CCI rats’ spinal cord dorsal horn.(3)The activity of MMP-9/2 of spinal cord was evaluated by gelatin zymography while TMP was given in vivo.(4)Western blot was performed to measure the effects of TMP(single administration)on CCI induced upregulation of p-PKCy,p-NRl and IL-1 activation.(5)Western blot was used to detect the effect of the effects of p-TAK1 on CCI and measure the level of p-TAK1 by treatment with TAK1 and JNK inhibitor in the spinal cord.Result(1)TMP significantly attenuated the maintenance of chronic constrictive injury(CCI)-induced neuropathic pain and inhibited the activation of astrocytes.(2)Gelatin Zymography results showed that single administration or consistent administration of TMP significantly inhibited CCI induced activation of MMP-9/2 in rats’ spinal cord.(3)TMP could selectively suppress JNK activity TMP significantly inhibited CCI-induced IL-1β cleavage,PKCγ and NR1 phosphorylation.(4)TMP selectively suppressed the JNK signal pathway to inhibit the activation of astrocytes and then attenuated neuropathic pain via downregulation of TAK1 phosphorylation.ConclusionsTetramethylpyrazine attenuates neuropathic pain by selective suppressing the activity of CaMKⅡ-TAK1-JNK-MMP2/9 signal pathway.