Intranasal Calcitonin Gene-Related Peptide Protects Against Focal Cerebral Ischemic Injury in Rats Through the Wnt/β-Catenin Pathway

Du, Zhimin; Zhang, Haidong; Chen, Qiang; Gao, Yue; Sun, Bo

doi:10.12659/msm.913777

Cited by 16 publications

(9 citation statements)

References 24 publications

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“…Low pH‐ and ischemia‐induced CGRP release from perivascular C‐fibers results in coronary and cerebrovascular vasodilation and restoration of circulation 10–12 . Treatment with CGRP improves and genetic ablation of CGRP worsens blood flow and outcomes after focal cerebral arterial occlusion in experimental animals 13–15 . Administration of CGRP has shown beneficial effects in peripheral and coronary artery disease 16–18 and ameliorated experimental cerebral and cardiac ischemia by preserving blood flow and the blood–brain barrier 15,19–21 .…”

Section: Introductionmentioning

confidence: 99%

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Mulder

Vries

et al. 2020

Annals of Neurology

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Objective: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRPmediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results: Olcegepant (1mg/kg, single dose) increased infarct risk after 12-to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition.

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Section: Introductionmentioning

confidence: 99%

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Mulder

Vries

et al. 2020

Annals of Neurology

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“…CGRP is one of the strongest vasoactive peptides found in vivo so far, which plays a role in relaxing and inhibiting vascular smooth muscle proliferation [ 6 , 7 ]. At the same time, CGRP can stagnate the cell cycle in G0/G1 phase and thus participate in the regulation of tumor growth [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Methylation of CALCA and CALCB in Pancreatic Ductal Adenocarcinoma

Gao

Liu

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Calcitonin gene-related peptide (CGRP) plays a diverse and intricate role in chronic low-grade inflammation and is closely related to specific cancers. It includes two subtypes, CALCA (αCGRP) and CALCB (βCGRP), of which αCGRP expression accounts for more than 90%. Here, we show that methylation of CALCA and CALCB in pancreatic ductal adenocarcinoma was significantly higher than that in paracancer. Western blot and immunohistochemistry showed that CGRP, p-AKT, and p-CREB in the tumor tissues were lower than those in the paracarcinoma tissues. In vivo, the expressions of p-AKT and p-CREB in the pancreatic tissues of CALCA-KO rats were also lower than those of wild type. Methylation of CALCA and CALCB is increased in pancreatic adenocarcinoma, and under that condition, p-AKT and p-CREB levels were decreased.

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“…The change of cell cycle is the driving force of tumor biological behavior [ 149 ], but whether it is unique in the role of cell cycle disorder in the occurrence of pancreatic cancer is still unknown. CGRP can induce G2/M phase arrest by regulating G2/M phase-related proteins [ 150 ]. Moreover, it is found that CGRP can arrest the cell cycle of pancreatic cancer stem cells in the G0/G1 stage [ 151 ].…”

Section: Cgrp and Tumor Stem Cellsmentioning

confidence: 99%

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

Chen

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Stem cells have the ability of self-replication and multidirectional differentiation, but the mechanism of how stem cells “maintain” this ability and how to “decide” to give up this state and differentiate into cells with specific functions is still unknown. The Nobel Prize in physiology and medicine in 2021 was awarded to “temperature and tactile receptor,” which made the pain receptor TRPV1-calcitonin gene-related peptide (CGRP) pathway active again. The activation and blocking technology of CGRP has been applied to many clinical diseases. CGRP gene has complex structure and transcription process, with multiple methylation and other modification sites. It has been considered as a research hotspot and difficulty since its discovery. Drug manipulation of TRPV1 and inhibition of CGRP might improve metabolism and prolong longevity. However, whether the TRPV1-neuropeptide-CGRP pathway is directly or indirectly involved in stem cell self-replication and multidirectional differentiation is unclear. Recent studies have found that CGRP is closely related to the migration and differentiation of tumor stem cells, which may be realized by turning off or turning on the CGRP gene expression in stem cells and activating a variety of ways to regulate stem cell niches. In this study, we reviewed the advances in researches concentrated on the biological effects of CGRP as a new endogenous switching of cell stemness.

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Intranasal Calcitonin Gene-Related Peptide Protects Against Focal Cerebral Ischemic Injury in Rats Through the Wnt/β-Catenin Pathway

Cited by 16 publications

References 24 publications

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Methylation of CALCA and CALCB in Pancreatic Ductal Adenocarcinoma

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

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