Ghrelin the Hunger Hormone Prevents Multiple Sclerosis (in mice)
Control of pathological immunity in multiple sclerosis may be accomplished (at least in part) by antigen-specific vaccination, by administration of immune modulators such as Interferon Beta, or by depletion of activated effector T cells using antibodies.
Immune modulation by hormones offers a new method of addressing multiple sclerosis. For example, it is known that mesenchymal stem cells have therapeutic effects in animal models of multiple sclerosis, and that these effects seem to be mediated both by immune modulaton but also by stimulation of regeneration. Interestingly, hormones such as progesterone have been demonstrated to stimulate immune modulatory activities of mesenchymal stem cells.
A recent paper (Theil et al. Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin. J Immunol 2009 Jul 20) described the ability of the “hunger hormone” ghrelin to inhibit the mouse model of multiple sclerosis, experimental allergic encephalomyelitis (EAE).
Ghrelin is a hormone made by the pancreas and stomach cells that stimulates the feeling of hunger. It is also known to stimulate growth hormone release. Some have compared ghrelin as the opposite of leptin, a hormone known to inhibit hunger. Interestingly leptin has been associated with induction of inflammation of autoimmunity. For example, administration of leptin has been demonstrated to augment mouse multiple sclerosis (Matarese et al. Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur J Immunol. 2001 May;31(5):1324-32).
In the paper we are discussing, EAE was induced in B6 mice by administration of MOG peptide (myelin oligodendrocyte glycoprotein 35-55) and treated groups were administered ghrelin after immunization with the autoantigen. As compared to vehicle-controls, the treated groups had a profound inhibition of EAE induction as assessed by the disease severity index. Additionally, suppression of the inflammatory triad of TNF, IL-1, and IL-6 was observed at the mRNA level in cells that have infiltrated the spinal cord, as well as resident microglial cells. In vitro treatment of microglial cells by ghrelin resulted in suppressed ability to produce inflammatory trial cytokines after stimulation with lps.
These data suggest that ghrelin itself may be useful for the treatment of multiple sclerosis, as well as the possibility of using it in combination with other agents that block microglial activation. For example, the endocannabinoid anandamide has previously been demonstrated to inhibit microglial inflammatory activity.
Suppression of microglial-based inflammation is important because the microglia are activated by cytokine producing T cells and are critical components of multiple sclerosis neurodegeneration, not only by inflammatory mediators, but also by glutamate excitotoxicity.