α-MSH: A Potential Neuroprotective and Immunomodulatory Agent for the Treatment of Stroke

Abstract

Alpha-melanocyte-stimulating hormone (MSH) is a neuropeptide with profound immunomodulatory properties; we evaluated the effects of a-MSH on stroke outcome and its ability to modulate the postischemic immune response. In Lewis rats subjected to 3 hours of middle cerebral artery occlusion (MCAO), plasma concentrations of a-MSH rapidly decreased and returned to baseline over the course of days. Exogenous administration of a-MSH (100 or 500 lg/kg) improved 24 hour outcome in animals subjected to 2 hours MCAO; a-MSH 500 lg/kg also decreased infarct volume at this time point. Both doses of a-MSH were ineffective in improving outcome or decreasing infarct volume in animals subjected to 3 hours MCAO. The splenocyte response to phytohemagglutin in animals treated with a-MSH was attenuated at 24 hours after MCAO. At 1 month after MCAO, treatment with a-MSH 500 lg/kg at the time of stoke was associated with a decrease in TH1 response to myelin basic protein (MBP) in animals subjected to 2 hours MCAO, although treatment was not associated with improved outcome at this time point. Given the early benefits of a-MSH treatment and its effect on immunologic outcome, further studies to evaluate the utility of a-MSH for the treatment of cerebral ischemia are warranted.

Plasma α-Melanocyte Stimulating Hormone Predicts Outcome in Ischemic Stroke

“…28,29 We also found that α -MSH administration decreased infarct volume and improved neurological outcome 24 hours after transient middle cerebral artery occlusion in an animal model of stroke. 7 Consistent with the known effects of α -MSH on the immune response, we found that splenocytes harvested from α -MSH–treated animals responded less well to phytohemagglutinin (a lymphocyte mitogen) than splenocytes harvested from saline-treated animals. Furthermore, the animals treated with α -MSH in this study were less likely to develop autoimmune responses to myelin basic protein, a response associated with worse stroke outcome.…”

“…To our knowledge, this is the first study that addresses endogenous changes in plasma α -MSH after ischemic stroke, although we did find a similar decrease in plasma α -MSH in an animal study of severe stroke. 7 Further, we found that higher plasma α -MSH was associated with an increased likelihood of experiencing a good clinical outcome, an effect that was most apparent at later time points after stroke and independent of stroke severity, patient age, and infection status. In contrast, the associations between cortisol and IL-6 on outcome were most robust at early time points after stroke and explained almost entirely by the fact that cortisol and IL-6 are markers of stroke severity.…”

“…Furthermore, a growing body of experimental data shows that exogenous administration of α -MSH decreases infarct volume and improves stroke outcome. 7,19–22 There are numerous mechanisms by which α -MSH (and related neuropeptides) could improve stroke outcome, and these effects are mediated through 5 different melanocortin receptors (MCRs). Potent antipyretic properties of α -MSH, which could potentially be capitalized on in the treatment of stroke, are mediated through the MCR3/MCR4 receptor complex in the brain.…”

“…Based on experimental data, however, a decrease similar to that seen in patients with traumatic brain injury is anticipated. 7 We, thus, sought to describe the time course of changes in plasma α -MSH after ischemic stroke in relation to ACTH and cortisol. Because not all cortisol production depends on ACTH, however, we also assessed plasma interleukin (IL) 6, a cytokine that activates the hypothalamic-pituitary-adrenal axis and can directly stimulate cortisol production by the adrenal gland.…”

Comparative Analysis of a Putative Tuberculosis-Susceptibility Gene, <i>MC3R</i>, and Pseudogene Sequences in Cattle, African Buffalo, Hyena, Rhinoceros and Other African Bovids and Ruminants

“…All of the finely integrated key components and upstream regulators of the melanocortin system have widespread immunologic influence modulated via their downstream targets [Xiao et al, 2003;La Cava and Matarese, 2004;Matarese and La Cava, 2004;Taub, 2008;Savos et al, 2011] and some also act as neuroimmune cotransmitters [Bedoui et al, 2003]. Cytokines are the effector molecule links between immune response and the neuroendocrine system.…”