NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice.
Wu. Xuan X; Fu. Siming S; Liu. Yun Y; Luo. Hansheng H; Li. Feng F; Wang. Yiying Y; Gao. Meng M; Cheng. Yuan Y; Xie. Zongyi Z
Key Findings
- NDP‑MSH activates the melanocortin‑1 receptor (MC1R) in brain cells after hemorrhage.
- Treatment reduced neuroinflammation markers (IL‑1β, TNF‑α, MMP‑9) and improved tight‑junction proteins (ZO‑1, occludin, Lama5).
- The protective effect depends on the CREB/Nr4a1 pathway and is lost when MC1R or Nr4a1 are silenced.
Practical Outcomes
- The study suggests melanotan‑I could have neuroprotective properties, but it’s only been shown in mice with a brain bleed and given by injection. For biohackers, there’s no clear dosing, safety, or oral formulation data yet, so it’s not ready for real‑world use. It does, however, highlight MC1R as a potential target for future brain‑health interventions.
Summary
In a mouse model of brain bleed, giving the peptide NDP-MSH (also called melanotan‑I) right after injury helped the animals recover better. It lowered brain swelling, reduced inflammation, and kept the blood‑brain barrier more intact by turning on a chain of signals (CREB → Nr4a1 → less NF‑κB activity). The benefits disappeared when the researchers blocked the receptor (MC1R) or a downstream protein (Nr4a1).
Abstract
Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Recently, melanocortin-1 receptor (Mc1r) activation by Nle4-D-Phe7-α-MSH (NDP-MSH) was shown to play a neuroprotective role in an experimental autoimmune encephalomyelitis (EAE) mouse model. This study aimed to investigate whether NDP-MSH could alleviate neuroinflammation and BBB disruption after experimental ICH, as well as the potential mechanisms of its neuroprotective roles. Two hundred and eighteen male C57BL/6 mice were subjected to autologous blood-injection ICH model. NDP-MSH, an agonist of Mc1r, was administered intraperitoneally injected at 1 h after ICH insult. To further explore the related protective mechanisms, Mc1r small interfering RNA (Mc1r siRNA) and nuclear receptor subfamily 4 group A member 1 (Nr4a1) siRNA were administered via intracerebroventricular (i.c.v) injection before ICH induction. Neurological test, BBB permeability, brain water content, immunofluorescence staining, and Western blot analysis were implemented. The Expression of Mc1r was significantly increased after ICH. Mc1r was mainly expressed in microglia, astrocytes, and endothelial cells following ICH. Treatment with NDP-MSH remarkably improved neurological function and reduced BBB disruption, brain water content, and the number of microglia in the peri-hematoma tissue after ICH. Meanwhile, the administration of NDP-MSH significantly reduced the expression of p-NF-κB p65, IL-1β, TNF-α, and MMP-9 and increased the expression of p-CREB, Nr4a1, ZO-1, occludin, and Lama5. Inversely, the knockdown of Mc1r or Nr4a1 abolished the neuroprotective effects of NDP-MSH. Taken together, NDP-MSH binding Mc1r attenuated neuroinflammation and BBB disruption and improved neurological deficits, at least in part through CREB/Nr4a1/NF-κB pathway after ICH.
Study Information
pubmed
2019
2019-10-28T00:00:00.000Z
10.1186/s12974-019-1591-4
88
39