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c-Jun N-terminal kinase pathway activation in human and experimental traumatic brain injury: neuroprotective effects of its inhibition

  • F Ortolano1,
  • ER Zanier1,
  • A Colombo2,
  • A Sclip2,
  • L Longhi1,
  • C Perego2,
  • T Borsello2,
  • N Stocchetti1 and
  • MG De Simoni2
Critical Care200812(Suppl 2):P123

Published: 13 March 2008


Traumatic Brain InjuryTraumatic Brain Injury PatientPost InjuryMinute PostCerebral Contusion


c-Jun N-terminal kinase (JNK) is a regulator of many cellular events, including programmed cell death (apoptosis). The JNK pathway is activated in several models of brain injury and its inhibition confers neuroprotection. The role of JNK following traumatic brain injury (TBI) is unclear. We tested the hypothesis that JNK might be a relevant pathway following TBI in humans and in a model of cerebral contusion, and evaluated the neurobehavioral and histological effects of its pharmacological inhibition by the administration of DJNKI-1, a peptide that selectively prevents the binding between JNK and its substrates.


JNK activation was investigated by western blot analysis performed on brain samples obtained from four TBI patients who underwent surgical removal of a cerebral contusion, and on injured cortex and hippocampus of mice subjected to anesthesia followed by controlled cortical impact brain injury at 1, 4 and 48 hours post injury. In addition, at 10 minutes post injury, animals randomly received an intraperitoneal administration of either DJNKI-1 (11 mg/kg) or an equal volume of saline (100 μl). A second group of mice received identical anesthesia, surgery without injury, and saline to serve as uninjured controls. Neurobehavioral motor outcome was evaluated at 48 hours and 7 days post injury by performing the Neuroscore. Cell death was quantified by the histochemical TUNEL technique at 48 hours post injury and the contusion volume was evaluated at 7 days post injury.


We observed a robust activation of the JNK pathway both in the human pericontusional brain tissue and in the injured cortex and hippocampus of mice at 1, 4 and 48 hours post injury. At 48 hours and 7 days post injury, mice receiving DJNKI-1 showed a better motor performance compared with mice receiving saline (P < 0.05 at both time points). Moreover, mice receiving DJNKI-1 showed a significant reduction of TUNEL-positive cells in the hippocampus compared with mice receiving saline at 48 hours post injury (P < 0.05) and a reduced contusion volume at 7 days post injury (P < 0.01).


JNK is activated following human and experimental TBI. The administration of the inhibitor DJNKI-1 to injured mice induced an amelioration of neurobehavioral deficits and histological damage following controlled cortical impact brain injury.

Authors’ Affiliations

University of Milano, Milan, Italy
Mario Negri Institute, Milan, Italy


© BioMed Central Ltd 2008

This article is published under license to BioMed Central Ltd.