Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury*

Bitto, Alessandra; Polito, Francesca; Irrera, Natasha; Calò, Margherita; Spaccapelo, Luca; Marini, Herbert; Giuliani, Daniela; Ottani, Alessandra; Rinaldi, Mariagrazia; Minutoli, Letteria; Guarini, Salvatore; Squadrito, Francesco; Altavilla, Domenica

doi:10.1097/ccm.0b013e318236efde

Cited by 30 publications

(28 citation statements)

References 18 publications

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“…NDP-α-MSH, acting through MC4R, modulates inflammatory and apoptotic cascades in a model of global cerebral ischemia in gerbils [17] and activation of MC4R improves survival in a model of severe haemorrhagic shock in rats [18]. Furthermore, NDP-α-MSH protects against traumatic brain injury through MC4R activation [19]. These data support the notion that protective effects of melanocortins in the CNS are mediated mainly by MC4R activation.…”

Section: Introductionsupporting

confidence: 73%

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

et al. 2013

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Brain inflammation plays a central role in numerous brain pathologies. Microglia and astrocytes are the main effector cells that become activated when an inflammatory process takes place within the central nervous system. α-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with proven anti-inflammatory properties. It binds with highest affinity to the melanocortin receptor 4 (MC4R), which is present in astrocytes and upon activation triggers anti-inflammatory pathways. The aim of this research was to identify anti-inflammatory mediators that may participate in the immunomodulatory effects of melanocortins in glial cells. Since peroxisome proliferator-activated receptors (PPARs) have recently been implicated in the modulation of inflammation, we investigated the effect of an α-MSH analog, [Nle4, D-Phe7]-α-MSH (NDP-α-MSH), on PPAR-β and PPAR-γ gene and protein expression in rat primary astrocytes and microglia. We initially demonstrated that rat primary microglia express MC4R and showed that treatment with NDP-α-MSH increases PPAR-γ protein levels and strongly decreases PPAR-β levels in both astrocytes and microglia. We also showed that extracellular signal-regulated kinase 1/2 (ERK1/2)–mediated signaling is partially involved in these effects in a cell-specific fashion. Finally, we showed that NDP-α-MSH stimulates the release of the anti-inflammatory cytokines IL-10 and TGF-β from microglia and astrocytes, respectively. The presented data suggest a role for IL-10 and TGF-β in the protective action of melanocortins and a connection between MC4R pathway and that of the nuclear receptor PPAR-γ. This is the first report providing evidence that MC4R is expressed in rat primary microglia and that melanocortins modulate PPAR levels in glial cells. Our findings provide new insights into the mechanisms underlying the activation of glial MC4R and open perspectives for new therapeutic strategies for the treatment of inflammation-mediated brain diseases.

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Section: Introductionsupporting

confidence: 73%

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

et al. 2013

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“…38 Substantial neuronal cell damage is observed in the brain especially in the CA3 region of the hippocampus after CHI if the injury is severe enough (for example, 450 g × 2 m). 5,43,60 Our data that acute Cerebrolysin treatment starting 1 hour after CHI significantly decreases neuronal cell loss in the DG and CA3 support a neuroprotective effect of Cerebrolysin. Preclinical studies have shown that acute treatment with Cerebrolysin reduces cerebral infarction in rats after transient ischemia while delayed administration of Cerebrolysin promotes neurological functional recovery without reducing lesion volume.…”

Section: Discussionmentioning

confidence: 49%

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Zhang¹,

Chopp

Meng³

et al. 2013

JNS

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Object Cerebrolysin is a unique peptide preparation that mimics the action of neurotrophic factors. This study was designed to investigate the effects of acute treatment of experimental closed head injury (CHI) in rats with Cerebrolysin on neurological function. Methods Adult male Wistar rats (n = 60) were subjected to impact acceleration–induced CHI. Closed head injured rats received intraperitoneal injection of saline (n = 30) or Cerebrolysin (2.5 ml/kg, n = 30) starting 1 hour postinjury and administered once daily until they were killed (2 or 14 days after CHI). To evaluate functional outcome, the modified neurological severity score (mNSS), foot fault, adhesive removal, and Morris water maze (MWM) tests were performed. Animals were killed on Day 14 (n = 20) after injury, and their brains were removed and processed for measurement of neuronal cells, axonal damage, apoptosis, and neuroblasts. The remaining rats (n = 40) were killed 2 days postinjury to evaluate cerebral microvascular patency by fluorescein isothiocyanate (FITC)–dextran perfusion (n = 16) and to measure the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase–9 (MMP-9) by using real-time reverse transcriptase-polymerase chain reaction (RT-PCR, n = 8) and by immunohistochemical analysis (n = 16). Results At 14 days post-CHI, the Cerebrolysin treatment group exhibited significant improvements in functional outcomes (the adhesive removal, mNSS, foot-fault, and MWM tests), and significantly more neurons and neuroblasts were present in the dentate gyrus (DG) (p < 0.05) compared with the saline-treated group (p < 0.05). At 2 days post-CHI, the Cerebrolysin group exhibited a significantly higher percentage of phosphorylated neurofilament H (pNF-H)–positive staining area in the striatum (p < 0.05), a significant increase in the percentage of FITC-dextran perfused vessels in the brain cortex (p < 0.05), a significant increase in the number of VEGF-positive cells (p < 0.05), and a significant reduction in the MMP-9 staining area (p < 0.05) compared with the saline-treated group. There was no significant difference in mRNA levels of MMP-9 and VEGF in the hippocampus and cortex 48 hours postinjury between Cerebrolysin- and saline-treated rats that sustained CHI. Conclusions Acute Cerebrolysin treatment improves functional recovery in rats after CHI. Cerebrolysin is neuroprotective for CHI (increased neurons in the dentate gyrus and the CA3 regions of the hippocampus and increased neuroblasts in the dentate gyrus) and may preserve axonal integrity in the striatum (significantly increased percentage of pNF-H–positive tissue in the striatum). Reduction of MMP-9 and elevation of VEGF likely contribute to enhancement of vascular patency and integrity as well as neuronal survival induced by Cerebrolysin. These promising results suggest that Cerebrolysin may be a useful treatment in improving the recovery of patients with CHI.

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“…Other agents have also been shown to mediate IL-10 upregulation and neuroprotection. For example, the endogenous peptides, melanocortins have been shown to induce IL-10 production and reduce tissue damage after cerebral ischemia and traumatic brain injury (Bitto et al, 2012; Spaccapelo et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury

Fouda

Pillai

Dhandapani

et al. 2017

European Journal of Pharmacology

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Introduction We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine interleukin (IL)-10. Methods Wistar rats were subjected to 3 h MCA suture occlusion and treated at reperfusion with C21 (0.03 mg/kg) ± IL-10 neutralizing antibody (0.1 mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24 h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. Results C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21 induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. Conclusion C21 provides direct neuroprotection as well as indirect protection through IL-10.

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Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury*

Abstract: Our data indicate that melanocortins protect against traumatic brain injury, in a broad time window and through activation of MC4 receptors, by counteracting the main traumatic brain injury-related mechanisms of damage. These findings could have major clinical implications.

Cited by 30 publications

References 18 publications

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury

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