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An alpha-MSH analogue mimics ischemic preconditioning in the heart

This research implies those with overactive PDE's or defects in MC1R
signaling (like redheads) might be more prone to ischemia.  It's also
got me wondering about the link between redheads and Parkinson's.

Peptides. 2009 Sep 30;

The peptide NDP-MSH induces phenotype changes in the heart that resemble
ischemic preconditioning.
Catania A, Lonati C, Sordi A, Leonardi P, Carlin A, Gatti S.
Center for Preclinical Investigation, Fondazione IRCCS Ospedale Maggiore
Policlinico, Mangiagalli e Regina Elena, Milano, Italy.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a
pro-opiomelanocortin (POMC)-derived peptide that exerts multiple
protective effects on host cells. Previous investigations showed that
treatment with alpha-MSH or synthetic melanocortin agonists reduces
heart damage in reperfusion injury and transplantation. The aim of this
preclinical research was to determine whether melanocortin treatment
induces preconditioning-like cardioprotection. In particular, the plan
was to assess whether melanocortin administration causes phenotype
changes similar to those induced by repetitive ischemic events. The idea
was conceived because both ischemic preconditioning and melanocortin
signaling largely depend on cAMP response element binding protein (CREB)
phosphorylation. Rats received single i.v. injections of 750mug/kg of
the alpha-MSH analogue Nle(4),DPhe(7)-alpha-MSH (NDP-MSH) or saline and
were sacrificed at 0.5, 1, 3, or 5h. Western blot analysis showed that
rat hearts expressed melanocortin 1 receptor (MC1R) protein. Treatment
with NDP-MSH was associated with early and marked increase in
interleukin 6 (IL-6) mRNA. This was followed by signal transducer and
activator of transcription 3 (STAT3) phosphorylation and induction of
suppressor of cytokine signaling 3 (SOCS3). There were no changes in
expression of other cytokines of the IL-6 family. Expression of IL-10,
IL-1beta, and TNF-alpha was likewise unaltered. In hearts of rats
treated with NDP-MSH there was increased expression of the orphan
nuclear receptor Nur77. The data indicate that NDP-MSH induces phenotype
changes that closely resemble ischemic preconditioning and likely
contribute to its established protection against reperfusion injury. In
addition, the increased expression of Nur77 and SOCS3 could be part of a
broader anti-inflammatory effect.
PMID: 19799952

perinatal hypoxic-ischemic (HI; neonatal HI encephalopathy) brain injury
is a major cause of permanent neurological dysfunction in children;
24-hour carotid-artery ligation preconditioning established by delaying
the onset of hypoxia for 24 hours after permanent unilateral carotid
ligation rats markedly diminished the cerebral injury; this
carotid-artery ligation preconditioning in neonatal rats involves CREB;
ligation of the carotid artery 24 hours before hypoxia provided complete
neuroprotection and produced improved performance on the Morris water
maze compared with ligation performed 1 hour before hypoxia; carotid
artery ligation 6 hours before hypoxia produced intermediate benefit;
the 24-hour carotid-artery ligation preconditioning caused a robust and
sustained activation of CREB on its phosphorylation site on Ser133;
i.c.v. antisense CREB oligodeoxynucleotides significantly reduced the
24-hour carotid-artery ligation-induced neuroprotection effects by
decreasing CREB expressions; activation of the cAMP-CREB signal with
PDE4 inhibitor rolipram 24 hours before hypoxia protected rat pups at
behavioral and pathological levels by sustained increased CREB
phosphorylation [PMID 15470752]

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