BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model

Abstract

Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.

Sodium Butyrate Ameliorates Deoxynivalenol-Induced Oxidative Stress and Inflammation in the Porcine Liver via NR4A2-Mediated Histone Acetylation

“…17,18 Apart from mediating inflammatory processes through the activation of IL-8 and the suppression of IL-4 in T-reg, 19,20 NR4A2 (encodes the NURR1 protein) also inhibits the transcription of the OS gene. 21,22 Sodium butyrate (NaBu) is a short-chain fatty acid that increases the average daily weight gain of piglets, provides energy for intestinal epithelium, plays an immunomodulatory role, and also regulates lipid metabolism in the liver and intestine. 23 Notably, as a vital ligand of NR and a natural HDAC inhibitor, NaBu could alleviate DON- induced OS and inflammation.…”

“…Mycotoxin is tightly linked with the transcriptional processes involved in NR-mediated regulation . Increasing evidence have shown that NRs exert cardinal roles in regulating DON-induced OS and inflammatory genes through the recruitment of histone modifiers. , Apart from mediating inflammatory processes through the activation of IL-8 and the suppression of IL-4 in T-reg, , NR4A2 (encodes the NURR1 protein) also inhibits the transcription of the OS gene. , Sodium butyrate (NaBu) is a short-chain fatty acid that increases the average daily weight gain of piglets, provides energy for intestinal epithelium, plays an immunomodulatory role, and also regulates lipid metabolism in the liver and intestine . Notably, as a vital ligand of NR and a natural HDAC inhibitor, NaBu could alleviate DON-induced OS and inflammation. , Moreover, NaBu exerts anti-inflammatory effects by increasing the H3K9ac profiles at promoter regions of the pro-inflammatory genes and enhancing NR PPARA activation. − Therefore, we hypothesize NaBu resists DON-induced OS and the inflammatory response through histone acetylation recruited by NR4A2 .…”

Bioinformatic analysis of circular RNA expression profiles in a rat lumbosacral spinal root avulsion model

“…KEGG analysis showed significant enrichment of differentially expressed circRNAs in pathways related to neuronal injury, such as the "MAPK signaling pathway" and "cAMP signaling pathway". For example, previous evidence has shown that the MAPK signaling pathway plays a vital role in spinal cord injury and ischemic stroke (Tian et al, 2020;Zhang et al, 2021), while the cAMP signaling pathway is a critical regulator of neuronal apoptosis (Liu et al, 2020;Yu et al, 2022). Besides that, functional annotation also showed that the top five differentially expressed circRNAs were enriched in distinct GO and KEGG pathways, demonstrating Frontiers in Genetics frontiersin.org important roles of these circRNAs may play in LSRA.…”

Berberine alleviates ischemia reperfusion injury induced AKI by regulation of intestinal microbiota and reducing intestinal inflammation

“…Reference to previous methods, hematoxylin and eosin (HE) were used to stain the colon and kidney tissues [ 16 ]. The inflammation of colon tissue was evaluated according to the degree of infiltration of inflammatory cells.…”