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 α-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 α-MSH rapidly decreased and returned to baseline over the course of days. Exogenous administration of α-MSH (100 or 500 μg/kg) improved 24 hour outcome in animals subjected to 2 hours MCAO; α-MSH 500 μg/kg also decreased infarct volume at this time point. Both doses of α-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 α-MSH was attenuated at 24 hours after MCAO. At 1 month after MCAO, treatment with α-MSH 500 μg/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 α-MSH treatment and its effect on immunologic outcome, further studies to evaluate the utility of α-MSH for the treatment of cerebral ischemia are warranted.

Figure 1

Experimental design. Three different sets of experiments were performed—assays for changes in endogenous α-MSH levels after MCAO (A), determination of neuroprotective and immunomodulatory effects at 24 hours (B), and assessment of long-term outcomes (C).

Figure 2

The plasma concentration of α-MSH decreases after MCAO and is significantly less in naive animals at 3 hours after MCAO. Box plots show median, IQR, outliers (error bars), and extreme outliers (open circles); ^*P<0.05 by Kruskal–Wallis H-test. α-MSH, α-melanocyte-stimulating hormone; IQR, interquartile range; MCAO, middle cerebral artery occlusion.

Figure 3

Treatment with α-MSH at 500 μg intraperitoneal resulted in decreased infarct volume in animals undergoing 2 hours (but not 3 hours) MCAO. (A) α-MSH at a dose of 100 μg/kg intraperitoneal was not protective for either duration of ischemia. (B) In animals undergoing the shorter duration of ischemia (2 hours), the higher dose of α-MSH (500 μg/kg) also improved neurologic scores at 24 hours. Box plots show median, IQR, outliers (error bars), and extreme outliers (open circles). Differs at ^*P<0.05 or ^**P<0.001 by Kruskal–Wallis H test. α-MSH, α-melanocyte-stimulating hormone; IQR, interquartile range; MCAO, middle cerebral artery occlusion.

Figure 4

Treatment with α-MSH decreases splenocyte responsiveness to PHA. (A) There were no significant differences in the numbers of splenocytes at 24 hours after stroke among the different treatment groups. (B) Animals treated with either dose of α-MSH, however, had decreased responsiveness of the splenocytes to PHA at this time point. Box plots show median, IQR, and outliers. Differs from control group at ^*P<0.05 by Mann–Whitney U-test. α-MSH, α-melanocyte-stimulating hormone; IQR, interquartile range.