Evidence map›Paper›PMID 33468172›Full record

ArticleJournal of neuroinflammation2021

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

Shufeng Yu, Desislava Met Doycheva, Marcin Gamdzyk, Yijun Yang, Cameron Lenahan, Gaigai Li, Dujuan Li, Lifei Lian, Jiping Tang, Jun Lu and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed, 1 pooled it
3.0field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.

  1. Pooled it
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  8. Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
    Review
  9. An overview of benefits and risks of chronic melanocortin-1 receptor activation.Journal of the European Academy of Dermatology and Venereology : JEADV · 2025
    Review
  10. Article
  11. Article
  12. Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects.International journal of molecular sciences · 2023
    Review
  13. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 2 countries.

Shufeng YuDepartment of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, 570208, China.
Desislava Met DoychevaDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Marcin GamdzykDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Yijun YangDepartment of Hepatobiliary Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, 570208, China.
Cameron LenahanDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Gaigai LiDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Dujuan LiDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Lifei LianDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Jiping TangDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Jun LuDepartment of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, 570208, China. lu139762@163.com.
John H ZhangDepartment of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. johnzhang3910@yahoo.com.ORCID http://orcid.org/0000-0002-4319-4285
Loma Linda University · USCentral South University · CN

Funding

ER stress and neonatal hypoxia ischemia encephalopathyR01NS104083 · NINDS · LOMA LINDA UNIVERSITY · PI ZHANG, JOHN H · 2018 to 2022
$1.7M
NINDS NIH HHS NS104083NINDS NIH HHS R01 NS104083
6 · The paper itself

Abstract

backgroundMicroglia-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.

methodsA 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.

resultsThe 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.

conclusionsOur 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).

Indexed as

AnimalsAnimals, NewbornBrainCyclic AMPCyclic AMP-Dependent Protein KinasesHypoxia-Ischemia, BrainImidazolesInflammationMicrogliaNuclear Receptor Subfamily 4, Group A, Member 2RatsRats, Sprague-DawleyReceptor, Melanocortin, Type 1Signal TransductionBMS-470539Cyclic AMPCyclic AMP-Dependent Protein KinasesImidazolesNuclear Receptor Subfamily 4, Group A, Member 2Receptor, Melanocortin, Type 1BMS-470539Melanocortin-1 receptorMicroglial polarizationNeonatal hypoxia-ischemiaNeuroinflammationNurr1

Identifiers

PMID33468172
PMCPMC7814630
OpenAlexW3125869546

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.