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Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury*.

AbstractOBJECTIVE:
Treatment for traumatic brain injury remains elusive despite compelling evidence from animal models for a variety of therapeutic targets. Melanocortins have established neuroprotective effects against experimental ischemic stroke. We investigated whether melanocortin treatment of traumatic brain injury induces neuroprotection and promotes functional recovery.
DESIGN:
Randomized experiment.
SETTING:
Research laboratory at a university hospital.
SUBJECTS:
Male Sprague-Dawley rats (n = 215).
INTERVENTIONS:
Experimental rat model of diffuse traumatic brain injury, the impact-acceleration model.
MEASUREMENT AND MAIN RESULTS:
Brain tissue nitrites, phosphorylation level of extracellular signal-regulated kinases, and c-jun N-terminal kinases; and expression of active caspase-3, tumor necrosis factor-α, BAX, and Bcl-2 as well as serum levels of interleukin-6, high mobility group box-1, interleukin-10, and brain histologic damage were evaluated 24 or 48 hrs after the insult. Sensorimotor orientation and limb use were evaluated at day 7 and learning and memory at days 23-30 after injury. Posttraumatic treatment every 12 hrs with the melanocortin analog [Nle, D-Phe]-α-melanocyte-stimulating hormone (starting 3 or 6 hrs after injury) inhibited traumatic brain injury-induced upregulation of nitric oxide synthesis, phosphorylation level of extracellular signal-regulated kinases, phosphorylation level of c-jun N-terminal kinases, and active caspase-3; reduced expressions/levels of tumor necrosis factor-α, BAX, interleukin-6, and high mobility group box-1; and increased those of Bcl-2 and interleukin-10. These molecular changes were associated with a reduction in brain tissue damage, as highlighted by histopathological findings and improved functional recovery. Pretreatment with the melanocortin MC4 receptor antagonist HS024 abated the positive effects of [Nle, D-Phe]-α-melanocyte-stimulating hormone.
CONCLUSIONS:
Our data indicate that melanocortins protect against traumatic brain injury, in a broad time window and through activation of MC4 receptors, by counteracting the main traumatic brain injury-related mechanisms of damage. These findings could have major clinical implications.
AuthorsAlessandra Bitto, Francesca Polito, Natasha Irrera, Margherita Calò, Luca Spaccapelo, Herbert R Marini, Daniela Giuliani, Alessandra Ottani, Mariagrazia Rinaldi, Letteria Minutoli, Salvatore Guarini, Francesco Squadrito, Domenica Altavilla
JournalCritical care medicine (Crit Care Med) Vol. 40 Issue 3 Pg. 945-51 (Mar 2012) ISSN: 1530-0293 [Electronic] United States
PMID22036855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
Chemical References
  • Melanocortins
Topics
  • Animals
  • Brain Injuries (drug therapy, prevention & control)
  • Male
  • Melanocortins (therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Time Factors

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