Calcitonin gene-related peptide protects rats from cerebral ischemia/reperfusion injury via a mechanism of action in the MAPK pathway

Yang, Shuo; Yuan, Yongjie; Jiao, Shan; Luo, Qi; Yu, Jinlu

doi:10.3892/br.2016.658

Cited by 32 publications

(22 citation statements)

References 20 publications

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“…Previous studies have investigated the function of the the MAPK signaling pathways in I/R, including ERK, c-Jun N-terminal kinase (JNK) and p38 pathways. For example, Yang et al ( 20 ) identified that CRGP effectively improved I/R injury of the brain tissue through a reduction in JNK and p38 phosphorylation and an increase in ERK phosphorylation in the MAPK pathway. Zhang et al ( 9 ) demonstrated that ROCK enhanced cardiomyocyte apoptosis in the heart I/R via promotion of JNK-mediated apoptosis-inducing factor translocation.…”

Section: Discussionmentioning

confidence: 99%

Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion

Bian

Zhou

et al. 2017

Molecular Medicine Reports

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It has been previously reported that Rho-kinase (ROCK) and poly ADP-ribose polymerase (PARP) serve critical roles in myocardial ischemia/reperfusion (I/R) injury. Studies have additionally demonstrated that the activation of ROCK and the expression of PARP are increased in I/R. However, the effect and mechanism of the two proteins remains to be fully elucidated in I/R. In addition, whether they can be influenced by each other is unclear. In the present study, it was demonstrated that ischemia followed by reperfusion resulted in a significant increase in ROCK and PARP. In addition, Y-27632 (ROCK inhibitor) and 3-aminobenzamide (3-AB; PARP inhibitor) pretreatment rescued myocardial infarction size and cardiomyocyte apoptosis. The inhibitory role of Y-27632 was observed to be superior to that of the 3-AB group. In addition, Y-27632 and 3-AB diminished extracellular signal-related kinase (ERK) phosphorylation and the production of tumor necrosis factor α and interleukin 6. Overall, the results of the present study suggested that the inhibition of ROCK leads to reduced myocardial infarction size and cardiomyocyte apoptosis via the PARP/ERK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion

Bian

Zhou

et al. 2017

Molecular Medicine Reports

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“…It is also clear that MAPK pathway members, including ERK, JNK and p38, serve important roles in neuronal cells as a response to the stress stimuli induced by I/R ( 28 ). Inhibition of ERK by U0126 or PD98059 significantly decreases the number of surviving cells in hippocampal CA1 subfield and cortex ( 29 ), whereas activation of ERK significantly ameliorates neurological deficit and histopathology alterations in rats exposed to 90 min MCAO-induced ischemia and 24 h reperfusion ( 30 , 31 ). The alterations in JNK and p38 appeared to be contrary to ERK, with the inhibition of JNK and p38 attenuating infarction volume in I/R brains in vivo ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 serves a protective role in response to ischemic‑reperfusion in the brain by promoting ERK activation

Feng

2017

Mol Med Report

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The aim of the present study was to investigate the expression and function mechanism of bone morphogenetic protein 9 (BMP9) in cerebral ischemia-reperfusion (I/R) injuries in vivo and in vitro. A total of 40 Sprague-Dawley rats were randomly divided into four groups (n=10): i) Normal control; ii) sham surgery group, the procedure without occlusion; iii) I/R group, right middle cerebral artery occlusion (MCAO) followed by reperfusion; and iv) adenoviral vector (Ad)-BMP9 + I/R group, Ad-BMP9 intracerebroventricular injection was performed 2 days prior to MCAO. Neurological deficit score and infarct volume were measured at 24 h following reperfusion. To further test the mechanism of BMP9, astrocytes were isolated and treated with Ad-BMP9, Ad-BMP9 + extracellular signal-regulated kinase (ERK) inhibitor PD098059, Ad-BMP9 + c-Jun N-terminal kinase inhibitor SP600125 and Ad-BMP9 + p38 inhibitor SB203580 for 24 h, followed by undergoing oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Cell viability and death were assessed by 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazolium and lactate dehydrogenase release, respectively. Gene expression was determined by quantitative polymerase chain reaction and western blotting. BMP9 was identified to be upregulated at mRNA and protein levels in cerebral I/R animal and cell models. BMP9 pretreatment significantly reduced the neurological score and infarct volume compared with I/R rats. In astrocytes, overexpression of BMP9 significantly decreased cell death and improved cell viability, an effect which may be mediated by the ERK signaling pathway, as ERK was activated by BMP9 and the use of PD098059 partially reversed the protective effect of BMP9. Pretreatment with BMP-9 may be a promising treatment option for prevention of cerebral I/R injuries.

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“…In the body, production and release of CGRP are likely increased by ischemia and help defend against it . Similarly, in animal models of cerebral ischemia‐reperfusion, intraperitoneal or intravenous administration of CGRP decreases the extent of tissue damage and behavioral deficit . Intravenous CGRP also decreases the lesion size in a mouse model of permanent ischemia .…”

Section: Neuroprotective Consequences Of Cgrp Outside the Blood‐brainmentioning

confidence: 97%

“…In addition, CGRP seems to reduce NMDA‐mediated excitotoxicity . By inhibiting glycogen synthase kinase‐3β, CGRP can prevent hyperphosphorylation of tau and the consequent neural degeneration .…”

Section: Neuroprotective Consequences Of Cgrp Outside the Blood‐brainmentioning

confidence: 99%

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CGRP and Brain Functioning: Cautions for Migraine Treatment

Borkum

2019

Headache

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Background Calcitonin gene‐related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long‐term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning. Methods Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology. Results Within the brain, CGRP is upregulated by stresses such as ischemia, injury, hyperthermia, and seizure, and activates neuroprotective processes. Thus, CGRP buffers intracellular calcium, triggers antiapoptotic signaling, upregulates a number of neurotrophins (including insulin‐like growth factor‐1/IGF‐1, basic fibroblast growth factor/bFGF, and nerve growth factor/NGF), reduces brain edema, and likely increases antioxidant defenses. When released outside the blood‐brain barrier, CGRP likely protects the endothelium, upregulates growth factor signaling from the endothelium to the brain parenchyma, strengthens the blood‐brain barrier, protects the immune privilege of the brain by inhibiting the movement of neutrophils and monocytes, and facilitates neurogenesis and angiogenesis at stem cell niches. Conclusions CGRP participates in a wide range of neuroprotective processes. In theory, migraineurs with comorbid brain pathology might be at increased risk from CGRP inhibition. However, the extent of compensating processes is unknown and will determine whether these risks materialize in practice.

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Calcitonin gene-related peptide protects rats from cerebral ischemia/reperfusion injury via a mechanism of action in the MAPK pathway

Cited by 32 publications

References 20 publications

Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion

Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion

Bone morphogenetic protein 9 serves a protective role in response to ischemic‑reperfusion in the brain by promoting ERK activation

CGRP and Brain Functioning: Cautions for Migraine Treatment

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