Background
CGRP 8-37 (human)is a highly selective CGRP receptor antagonists.
CGRP significantly suppressed the level of reactive oxygen species (ROS) generated by NADPH oxidase in Ang II-induced VSMCs. The Ang II-stimulated activation of both Src and the downstream transcription factor, STAT3, was abrogated by CGRP. However, the antioxidative effect of CGRP was lost following the expression of constitutively activated Src or STAT3. Pre-treatment with H-89 or CGRP 8-37 (human) also blocked the CGRP inhibitory effects against Ang II-induced oxidative stress[1].
CGRP 8-37 (human) is effective in abolishing mechanical and thermal allodynia produced by spinal hemisection[2].When explored the effects of calcitonin gene-related peptide (CGRP) and its antagonist CGRP 8-37 (human) on the latency to hindpaw withdrawal responses induced by both thermal and mechanical stimulation in rats. CGRP 8-37 (human) (5nM or 10nM) induced a significant increase in hindpay withdrawal latency[3,5].Intrathecal administration of CGRP 8-37 (human) can reversed the SP-induced decrease in latency to both withdrawal responses ,besides,it can mediated a significant increase in response latency [6].When performed to investigate the effects of intrathecal administration of CGRP 8-37 (human) on the HWL and HWT in rats with unilateral hindpaw inflammation induced by subcutaneous injection of carrageenin.Intrathecal administration of 10 nmol of CGRP8-37 induced a significant bilateral increase in the HWL and HWT in rats with experimentally induced inflammation[4]. CGRP 8-37 (human) could enhance ALI induced by LPS in the rat model, and regulate the expression levels of AQP-1 and AQP-5 by affecting inflammatory cytokines[7]. CGRP8-37 and Endomorphin-1 alone, and in combinated administration, as bolus and continues dose.Endomorphin-1and CGRP 8-37 (human) injections were able to reduce neuropathic pain after spinal cord compression injury[8]. The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was investigated. CGRP and its receptor antagonists, olcegepant and CGRP 8-37 (human), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP 8-37 (human) decreased them[9].
参考文献:
[1]. Luo HM, Wu X, et,al. Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway. J Cell Mol Med. 2020 Jun;24(11):6426-6437. doi: 10.1111/jcmm.15288. Epub 2020 May 5. PMID: 32372557; PMCID: PMC7294141.
[2]. Bennett AD, Chastain KM, Hulsebosch CE. Alleviation of mechanical and thermal allodynia by CGRP(8-37) in a rodent model of chronic central pain. Pain. 2000 May;86(1-2):163-75. doi: 10.1016/s0304-3959(00)00242-6. PMID: 10779673.
[3]. Yu LC, Hansson P, et,al. The calcitonin gene-related peptide antagonist CGRP8-37 increases the latency to withdrawal responses in rats. Brain Res. 1994 Aug 8;653(1-2):223-30. doi: 10.1016/0006-8993(94)90393-x. Erratum in: Brain Res 1994 Dec 15;666(2):295. PMID: 7526959.
[4]. Yu LC, Hansson P, et,al. Intrathecal CGRP8-37-induced bilateral increase in hindpaw withdrawal latency in rats with unilateral inflammation. Br J Pharmacol. 1996 Jan;117(1):43-50. doi: 10.1111/j.1476-5381.1996.tb15152.x. PMID: 8825341; PMCID: PMC1909388.
[5]. L?fgren O, Yu LC, et,al. Intrathecal CGRP(8-37) results in a bilateral increase in hindpaw withdrawal latency in rats with a unilateral thermal injury. Neuropeptides. 1997 Dec;31(6):601-7. doi: 10.1016/s0143-4179(97)90006-8. PMID: 9574827.
[6]. Yu LC, Hansson P, et,al. Opioid antagonists naloxone, beta-funaltrexamine and naltrindole, but not nor-binaltorphimine, reverse the increased hindpaw withdrawal latency in rats induced by intrathecal administration of the calcitonin gene-related peptide antagonist CGRP8-37. Brain Res. 1995 Nov 6;698(1-2):23-9. doi: 10.1016/0006-8993(95)00752-c. PMID: 8581488.
[7]. Hong-Min F, Chun-Rong H, et,al.CGRP 8-37 enhances lipopolysaccharide-induced acute lung injury and regulating aquaporin 1 and 5 expressions in rats. J Physiol Biochem. 2016 Aug;73(3):381-386. doi: 10.1007/s13105-017-0563-3. Epub 2017 May 4. Erratum in: J Physiol Biochem. 2017 Oct 5;: PMID: 28470555.
[8]. Janzadeh A, Karami Z, et,al.The role of CGRP receptor antagonist (CGRP8-37) and Endomorphin-1 combination therapy on neuropathic pain alleviation and expression of Sigma-1 receptors and antioxidants in rats. J Chem Neuroanat. 2020 Jul;106:101771. doi: 10.1016/j.jchemneu.2020.101771. Epub 2020 Feb 21. PMID: 32092447.
[9].Pozo-Rosich P, Storer RJ, et,al. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia. 2015 Dec;35(14):1298-307. doi: 10.1177/0333102415576723. Epub 2015 Mar 19. PMID: 25792688.
CGRP 8-37 (human)是一种高选择性的CGRP受体拮抗剂。
CGRP 显着抑制 Ang II 诱导的 VSMC 中 NADPH 氧化酶产生的活性氧 (ROS) 水平。 Ang II 刺激的 Src 和下游转录因子 STAT3 的激活被 CGRP 消除。然而，随着组成型激活的 Src 或 STAT3 的表达，CGRP 的抗氧化作用丧失。用 H-89 或 CGRP 8-37（人）预处理也阻断了 CGRP 对 Ang II 诱导的氧化应激的抑制作用[1]。
CGRP 8-37（人）可有效消除脊髓半切产生的机械性和热性异常性疼痛[2]。当探索降钙素基因相关肽 (CGRP) 及其拮抗剂 CGRP 的作用时8-37（人类）关于大鼠热刺激和机械刺激引起的后爪退缩反应的潜伏期。 CGRP 8-37（人）（5nM 或 10nM）可显着增加 hindpay 退缩潜伏期[3,5]。CGRP 8-37（人）的鞘内给药可逆转 SP 诱导的减少在两种戒断反应的潜伏期中，此外，它可以介导反应潜伏期的显着增加[6]。在研究鞘内注射 CGRP 8-37（人）对 HWL 和皮下注射角叉菜胶诱导单侧后爪炎症大鼠的 HWT 鞘内注射 10 nmol CGRP8-37 可显着增加实验性炎症大鼠的 HWL 和 HWT[4]。 CGRP 8-37 (human)可增强大鼠LPS诱导的ALI，并通过影响炎性细胞因子调节AQP-1和AQP-5的表达水平[7]。 CGRP8-37 和 Endomorphin-1 单独给药，以及联合给药，作为推注和持续剂量。Endomorphin-1 和 CGRP 8-37（人）注射液能够减轻脊髓压迫损伤后的神经性疼痛[8]。研究了降钙素受体样受体 (CLR) 和受体活性修饰蛋白 1 (RAMP1) 的存在。将 CGRP 及其受体拮抗剂 olcegepant 和 CGRP 8-37（人）显微注射到 vlPAG 中，同时监测三叉神经颈复合体 (TCC) 中神经反应的变化。在将荷包牡丹碱显微注射到 vlPAG 后，TCC 对刺激硬脑膜传入神经和眼部皮肤感受野的反应的抑制表明 vlPAG 和 TCC 神经元之间存在联系。 CGRP 促进了这些 TCC 反应，而 olcegepant 和 CGRP 8-37（人类）降低了它们[9]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Rat VSMCs
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Preparation Method
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Cells were pre-treated with or without test compounds for the indicated time periods and then stimulated with or without Ang II for 30 minutes and CGRP for 60 minutes. In some experiments, CGRP 8-37 (human) or H-89 was added 30 minutes, dibutyl-cAMP 60 minutes and apocynin 2 hours before CGRP treatment.
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Reaction Conditions
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CGRP 8-37 (human) (3 × 10-5 mol/L) for 30 minute
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Applications
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Pre-treatment with H-89 or CGRP 8-37 (human) also blocked the CGRP inhibitory effects against Ang II-induced oxidative stress.
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| Animal experiment [2]: |
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Animal models
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Male Sprague±Dawley rats (175±200 g)
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Preparation Method
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Rts were given a spinal hemisection or a sham surgery at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. CGRP 8-37 (human) was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 microl volumes.
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Dosage form
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CGRP 8-37 (human)as1,5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 microl volume.
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Applications
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CGRP 8-37 (human) is effective in abolishing mechanical and thermal allodynia produced by spinal hemisection.
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参考文献:
[1]. Luo HM, Wu X, et,al. Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway. J Cell Mol Med. 2020 Jun;24(11):6426-6437. doi: 10.1111/jcmm.15288. Epub 2020 May 5. PMID: 32372557; PMCID: PMC7294141.
[2]. Bennett AD, Chastain KM, et,al. Alleviation of mechanical and thermal allodynia by CGRP(8-37) in a rodent model of chronic central pain. Pain. 2000 May;86(1-2):163-75. doi: 10.1016/s0304-3959(00)00242-6. PMID: 10779673.
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