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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2021

Open Access 01-12-2021 | Hypoxic-Ischemic Brain Injury | Research

Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats

Authors: Shufeng Yu, Desislava Met Doycheva, Marcin Gamdzyk, Yijun Yang, Cameron Lenahan, Gaigai Li, Dujuan Li, Lifei Lian, Jiping Tang, Jun Lu, John H. Zhang

Published in: Journal of Neuroinflammation | Issue 1/2021

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Abstract

Background

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats.

Methods

A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted.

Results

The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI.

Conclusions

Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE).
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Metadata
Title
Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats
Authors
Shufeng Yu
Desislava Met Doycheva
Marcin Gamdzyk
Yijun Yang
Cameron Lenahan
Gaigai Li
Dujuan Li
Lifei Lian
Jiping Tang
Jun Lu
John H. Zhang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2021
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-021-02078-2

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