Abstract
BackgroundNeuroinflammation 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.MethodsTwo 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.ResultsThe 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.ConclusionsTaken 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.
Highlights
Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH)
Melanocortin-1 receptor (Mc1r), a G protein-coupled receptor, is best known as a mediator of the synthesis of melanin pigments, and it is implicated in inflammation which is regulated by NF-κB signaling pathway [7,8,9]. α-melanocyte-stimulating hormone (α-MSH) is released from cells in the central nervous system; the chemical property of α-MSH is unstable, transformed into the protease-stable Nle4-D-Phe7-α-MSH (NDP-MSH), which has a specific higher affinity to melanocortin-1 receptor (Mc1r) [8, 10, 11]
Double immunofluorescence staining showed that Mc1r was mainly expressed in the microglia, astrocytes, and endothelial cells in the perihematoma tissue at 24 h after ICH (Fig. 2c)
Summary
Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Melanocortin-1 receptor (Mc1r) activation by Nle4D-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. Mounting evidence has demonstrated that neuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of ICH-induced brain injury, which are closely associated with poor prognosis [2]. The administration of NDP-MSH ameliorated blood-brain barrier (BBB) disruption by activating Mc1r in a model of experimental autoimmune encephalomyelitis (EAE) [13]. Despite the well-recognized roles of NDP-MSH and Mc1r on inflammation, the effects of NDP-MSH and Mc1r on neuroinflammation and BBB integrity after ICH have not been elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
