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


METHODS
Randomized experiment.


METHODS
Research laboratory at a university hospital.


METHODS
Male Sprague-Dawley rats (n = 215).


METHODS
Experimental rat model of diffuse traumatic brain injury, the impact-acceleration model.


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.
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
Alessandra
A
Bitto
Francesca
F
Polito
Natasha
N
Irrera
Margherita
M
Calò
Luca
L
Spaccapelo
Herbert R
HR
Marini
Daniela
D
Giuliani
Alessandra
A
Ottani
Mariagrazia
M
Rinaldi
Letteria
L
Minutoli
Salvatore
S
Guarini
Francesco
F
Squadrito
Domenica
D
Altavilla
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D053486:Melanocortins / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013997:Time Factors
D053486:Melanocortins