α-MSH Rescues Neurons from Excitotoxic Cell Death

Abstract

This study investigates the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with alpha-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 +/- 25,554 vs. 145,254 +/- 27,871). The number of viable neurons upon administration of alpha-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 +/- 33,158, KA+alpha-MSH vs. 79,587 +/- 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1beta levels was delayed by the treatment with alpha-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of alpha-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of alpha-MSH has rescuing effects on neurons subjected to excitotoxic insults.

α-Melanocyte-Stimulating Hormone Protects Retinal Vascular Endothelial Cells from Oxidative Stress and Apoptosis in a Rat Model of Diabetes

“…However, it has been shown that α-MSH or its analog can also rescue neurons from apoptosis induced by other insults, including traumatic brain injury caused by controlled cerebral impact [50], cerebral ischemia generated by common carotid artery occlusion [51], and hippocampal excitotoxicity induced by excitatory neurotransmitter glutamate [52]. Indeed, the results from another study in progress in our laboratory showed that α-MSH dose and time-dependently reduced the number of apoptotic cells induced by glutamate both in the retinal explants [53] and in retinas in vivo (unpublished data).…”

ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damagein vitro

“…Melanocortin peptides inhibit production of proinflammatory cytokines and NO by activated MG (Delgado et al, ; Galimberti et al, ). In the PNS, Schwann cells express melanocortin receptors (Dyer et al, ); melanocortin peptides decrease inflammatory signaling (Teare et al, ), and the melanocortin analog Org2766 upregulates NGF low‐affinity receptor p75, and releases neurotrophic factors (Dyer et al, ). The presence of melanocortin receptors on OL has not been specifically investigated before; our demonstration of MC4R receptors on OL raise the possibility that the protective effects of ACTH 1‐39 on OL could be direct.…”

Astrocytes: new targets of melanocortin 4 receptor actions

“…In a model of focal cerebral ischemia in gerbils, delayed treatment with a-MSH (Giuliani et al 2007) or treatment with NDP-MSH but not with the MC3R agonist g-MSH (Giuliani et al 2006) reduced neuron death. Also, NDP-MSH reduced neuron death after kainate-induced excitotoxicity (Forslin Aronsson et al 2007). NDP-MSH was shown to protect a hypothalamic cell line, which expresses MC4R, from serum deprivation-induced apoptosis (Chai et al 2006).…”