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Neuropathic pain releasing calcitonin gene related peptide protects against stroke in rats.

ABSTRACT: Neuropathic pain (NPP) is deemed as a potential risk of stroke; however, recent pieces of evidence showed that calcitonin gene-related peptide is involving in pain progression as well as organ protection. The mechanisms underlying the neuroprotection of calcitonin gene-related peptide are yet poorly described with respect to stroke. The present study showed that the elevated level of calcitonin gene-related peptide-induced by NPP exerts a protective effect against stroke in rats, which was further confirmed in vivo and vitro via mitigation of inflammatory response, inhibition of neuronal cell apoptosis, and increase in regional cerebral blood flow. Repetitive transcranial magnetic stimulation at trigeminal ganglion was performed to simulate to facilitate the release of calcitonin gene-related peptide for a similar neuroprotective effect. Together, these findings posit that the release of calcitonin gene-related peptide-induced by NPP or repetitive transcranial magnetic stimulation protects against stroke in rats. Thus, repetitive transcranial magnetic stimulation could have high application prospects for the prevention and treatment of stroke.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7013228 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Neuropathic pain releasing calcitonin gene related peptide protects against stroke in rats.

Wang Yida Y Liu Zhenxiu Z Ge Xinyu X Hu Xinyu X Cao Xiangyuan X Li Lei L Xia Jianhua J Li Fulong F Gao Liang L

American journal of translational research 20200115 1

Neuropathic pain (NPP) is deemed as a potential risk of stroke; however, recent pieces of evidence showed that calcitonin gene-related peptide is involving in pain progression as well as organ protection. The mechanisms underlying the neuroprotection of calcitonin gene-related peptide are yet poorly described with respect to stroke. The present study showed that the elevated level of calcitonin gene-related peptide-induced by NPP exerts a protective effect against stroke in rats, which was furth ...[more]

PMID: 32051737

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Project description:BackgroundCalcitonin gene-related peptide (CGRP) as a mediator of microglial activation at the transcriptional level may facilitate nociceptive signaling. Trimethylation of H3 lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) is an epigenetic mark that regulates inflammatory-related gene expression after peripheral nerve injury. In this study, we explored the relationship between CGRP and H3K27me3 in microglial activation after nerve injury, and elucidated the underlying mechanisms in the pathogenesis of chronic neuropathic pain.MethodsMicroglial cells (BV2) were treated with CGRP and differentially enrichments of H3K27me3 on gene promoters were examined using ChIP-seq. A chronic constriction injury (CCI) rat model was used to evaluate the role of CGRP on microglial activation and EZH2/H3K27me3 signaling in CCI-induced neuropathic pain.ResultsOverexpressions of EZH2 and H3K27me3 were confirmed in spinal microglia of CCI rats by immunofluorescence. CGRP treatment induced the increased of H3K27me3 expression in the spinal dorsal horn and cultured microglial cells (BV2) through EZH2. ChIP-seq data indicated that CGRP significantly altered H3K27me3 enrichments on gene promoters in microglia following CGRP treatment, including 173 gaining H3K27me3 and 75 losing this mark, which mostly enriched in regulation of cell growth, phagosome, and inflammation. qRT-PCR verified expressions of representative candidate genes (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) and real-time cell analysis (RTCA) verified microglial proliferation. Additionally, CGRP treatment and CCI increased expressions of ITGAM, ADAM10, MCP-1, and CX3CR1, key mediators of microglial activation in spinal dorsal horn and cultured microglial cells. Such increased effects induced by CCI were suppressed by CGRP antagonist and EZH2 inhibitor, which were concurrently associated with the attenuated mechanical and thermal hyperalgesia in CCI rats.ConclusionOur findings highly indicate that CGRP is implicated in the genesis of neuropathic pain through regulating microglial activation via EZH2-mediated H3K27me3 in the spinal dorsal horn.

Project description:Background: Clinical studies have shown that applying pulsed radiofrequency (PRF) to the neural stem could relieve neuropathic pain (NP), albeit through an unclear analgesic mechanism. And animal experiments have indicated that calcitonin gene-related peptide (CGRP) expressed in the dorsal root ganglion (DRG) is involved in generating and maintaining NP. In this case, it is uncertain whether PRF plays an analgesic role by affecting CGRP expression in DRG. Methods: Rats were randomly divided into four groups: Groups A, B, C, and D. In Groups C and D, the right sciatic nerve was ligated to establish the CCI model, while in Groups A and B, the sciatic nerve was isolated without ligation. After 14 days, the right sciatic nerve in Groups B and D re-exposed and was treated with PRF on the ligation site. Thermal withdrawal latency (TWL) and hindpaw withdrawal threshold (HWT) were measured before PRF treatment (Day 0) as well as after 2, 4, 8, and 14 days of treatment. At the same time points of the behavioral tests, the right L4-L6 DRG was sampled and analyzed for CGRP expression using RT-qPCR and an enzyme-linked immunosorbent assay (ELISA). Results: Fourteen days after sciatic nerve ligation, rats in Groups C and D had a shortened TWL (P<0.001) and a reduced HWT (P<0.001) compared to those in Groups A and B. After PRF treatment, the TWL of the rats in Group D gradually extended with HWT increasing progressively. Prior to PRF treatment (Day 0), CGRP mRNA expressions in the L4-L6 DRG of Groups C and D increased significantly (P<0.001) and were 2.7 and 2.6 times that of Group A respectively. ELISA results showed that the CGRP content of Groups C and D significantly increased in comparison with that of Groups A and B (P<0.01). After PRF treatment, the mRNA expression in the DRG of Group D gradually decreased and the mRNA expression was 1.7 times that of Group A on the 4th day(P> 0.05). On the 8th and 14th days, the mRNA levels in Group D were restored to those of Groups A and B. Meanwhile, the CGRP content of Group D gradually dropped over time, from 76.4 pg/mg (Day 0) to 57.5 pg/mg (Day 14). Conclusions: In this study, we found that, after sciatic nerve ligation, rats exhibited apparent hyperalgesia and allodynia, and CGRP mRNA and CGRP contents in the L4-L6 DRG increased significantly. Through lowering CGRP expression in the DRG, PRF treatment might relieve the pain behaviors of NP.

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Neuropathic pain releasing calcitonin gene related peptide protects against stroke in rats.

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Neuropathic pain releasing calcitonin gene related peptide protects against stroke in rats.

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