Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Abstract

Oxidative stress and neuronal apoptosis play crucial roles in secondary brain injury (SBI) after intracerebral hemorrhage (ICH). Recently, Nle4-D-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), a synthetic agonist of the melanocortin-1 receptor (Mc1r), has been proved to inhibit neuroinflammatory in several diseases. This study is aimed at exploring if NDP-MSH could reduce oxidative stress and neuronal apoptosis following ICH, as well as the potential mechanism. A mouse ICH model was induced by autologous blood injection. NDP-MSH was intraperitoneally injected at 1 h after ICH. Mc1r siRNA and PI3K inhibitor LY294002 were administrated to inhibit the expression of Mc1r and phosphorylation of PI3K, respectively. Neurological test, brain water content, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), immunofluorescence, and Western blot analysis were utilized in this study. The results exhibited that Mc1r was mainly expressed in neurons, and its level in the ipsilateral hemisphere was significantly elevated after ICH. NDP-MSH treatment significantly attenuated the neurological deficits and brain water content 24 hours after ICH, which was accompanied by the inhibition of oxidative stress and neuronal apoptosis. The administration of NDP-MSH after ICH significantly promoted the expression of Mc1r, p-PI3K, p-Akt, and p-Nrf2, followed by an increase of Bcl-2 and reduction of cleaved caspase-3. Conversely, downregulating the expression of Mc1r and phosphorylation of PI3K aggravated the neurological deficits and brain edema at 24 hours after ICH, meanwhile, the effect of NDP-MSH on the expression of Mc1r, p-PI3K, p-Akt, p-Nrf2, Bcl-2, and cleaved caspase 3 was also abolished. In conclusion, our data suggest that the activation of Mc1r by NDP-MSH ameliorates oxidative stress and neuronal apoptosis through the PI3K/Akt/Nrf2 signaling pathway after ICH in mice.

17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

“…Two weeks prior to ICH, bilateral ovariectomy was performed in the mice under isoflurane-induced anesthesia. ICH was induced in 20–25 g 2-month-old SRC3 −/− and WT control C57BL/6J ovariectomized mice by injection of autologous blood according to previously established protocols ( Fu et al, 2020 ). Following anesthesia by 10% chloral hydrate at a dose of 0.045 ml/kg, the mouse was placed in a prone position onto a stereotaxic device.…”

“…Water content in different brain regions was measured to determine the severity of brain edema ( Fu et al, 2020 ). Animals were deeply anesthetized with isoflurane and perfused with phosphate-buffered saline (PBS).…”

“…Among the molecular cascades involved in ICH-induced secondary injury, oxidative stress is a significant component ( Duan et al, 2016 ). Suppression of oxidative stress correlates with reduced neurological deficits in the rodent model of ICH ( Fu et al, 2020 ; Xie et al, 2020 ). We have previously shown that 17ß-estradiol (E2), an estrogen occurring naturally, played a neuroprotective effect in rats undergone ischemic brain injury through suppressing oxidative stress ( Xiao et al, 2018 ).…”

“…When regulating cell growth, SRC3 actives PI3K/Akt signaling ( Zhou et al, 2003 ). It has been shown that the PI3K/Akt signaling pathway is activated and mediates the neuroprotective effect of Nle4-D-Phe7-α-melanocyte-stimulating hormone in ICH mice ( Fu et al, 2020 ). A previous study also suggested activation of this pathway by E2 in cancer cells ( Guo et al, 2006 ).…”

The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine‐Mediated Neuronal DNA Damage

“…However, how XPD is regulated in the context of bupivacaine-mediated neuronal DNA damage remains unknown. The phosphatidyl-3-kinase (PI3K)/AKT signaling pathway is essential for protecting neuronal cells from oxidative stress [ 10 ]. According to our previous proteomics study, PI3K is inhibited in the context of bupivacaine-mediated neurotoxicity [ 7 ].…”