Objective: Treatment for traumatic brain injury remains elusivedespite compelling evidence from animal models for a variety oftherapeutic 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 traumaticbrain 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-alpha, 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 theinsult. Sensorimotor orientation and limb use were evaluated atday 7 and learning and memory at days 23–30 after injury.Posttraumatic treatment every 12 hrs with the melanocortin analog [Nle4, D-Phe7]-alpha-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-alpha, 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 [Nle4, D-Phe7]-alpha-melanocyte-stimulating hormone.Conclusions: Our data indicate that melanocortins protectagainst traumatic brain injury, in a broad time window andthrough activation of MC4 receptors, by counteracting the maintraumatic brain injury-related mechanisms of damage. Thesefindings could have major clinical implications.

Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury / Alessandra, Bitto; Francesca, Polito; Natasha, Irrera; Margherita, Calo`; Luca, Spaccapelo; Herbert R., Marini; Giuliani, Daniela; Ottani, Alessandra; Mariagrazia, Rinaldi; Letteria, Minutoli; Guarini, Salvatore; Francesco, Squadrito; Domenica, Altavilla. - In: CRITICAL CARE MEDICINE. - ISSN 0090-3493. - STAMPA. - 40(2012), pp. 945-951. [10.1097/CCM.0b013e318236efde]

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

GIULIANI, Daniela;OTTANI, Alessandra;GUARINI, Salvatore;
2012

Abstract

Objective: Treatment for traumatic brain injury remains elusivedespite compelling evidence from animal models for a variety oftherapeutic 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 traumaticbrain 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-alpha, 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 theinsult. Sensorimotor orientation and limb use were evaluated atday 7 and learning and memory at days 23–30 after injury.Posttraumatic treatment every 12 hrs with the melanocortin analog [Nle4, D-Phe7]-alpha-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-alpha, 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 [Nle4, D-Phe7]-alpha-melanocyte-stimulating hormone.Conclusions: Our data indicate that melanocortins protectagainst traumatic brain injury, in a broad time window andthrough activation of MC4 receptors, by counteracting the maintraumatic brain injury-related mechanisms of damage. Thesefindings could have major clinical implications.
40
945
951
Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury / Alessandra, Bitto; Francesca, Polito; Natasha, Irrera; Margherita, Calo`; Luca, Spaccapelo; Herbert R., Marini; Giuliani, Daniela; Ottani, Alessandra; Mariagrazia, Rinaldi; Letteria, Minutoli; Guarini, Salvatore; Francesco, Squadrito; Domenica, Altavilla. - In: CRITICAL CARE MEDICINE. - ISSN 0090-3493. - STAMPA. - 40(2012), pp. 945-951. [10.1097/CCM.0b013e318236efde]
Alessandra, Bitto; Francesca, Polito; Natasha, Irrera; Margherita, Calo`; Luca, Spaccapelo; Herbert R., Marini; Giuliani, Daniela; Ottani, Alessandra; Mariagrazia, Rinaldi; Letteria, Minutoli; Guarini, Salvatore; Francesco, Squadrito; Domenica, Altavilla
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/703351
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