1. ¹Department of Critical Care Medicine, The Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennyslvania, USA
2. ²Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennyslvania, USA
3. ³Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennyslvania, USA
4. ⁴The Children's Hospital of Pittsburgh, Pittsburgh, Pennyslvania, USA
5. ⁵Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennyslvania, USA

Correspondence: Dr RSB Clark, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA. E-mail: clarkrs@ccm.upmc.edu

Received 14 July 2005; Revised 29 August 2005; Accepted 1 September 2005; Published online 19 October 2005.

Abstract

Activation of protein kinase B (PKB, also known as Akt) by phosphorylation at serine-473 and threonine-308 promotes cell survival in multiple in vitro and in vivo models where neuronal death is seen, including traumatic brain injury (TBI); however, whether PKB is activated in humans after TBI was heretofore unknown. Activated PKB inhibits apoptogenic factors and is involved in the regulation of several transcription factors. Accordingly, we examined phosphorylation of the PKB signaling pathway in humans as well as rats after TBI using phosphospecific antibodies. Increased phosphorylation of PKB and PKB substrates was detected in injured brain from both humans and rats. In humans, increased phosphorylation of the PKB signaling pathway-related proteins Bad and forkhead transcription factor (FKHR) was detected in patients with TBI versus controls. In rats, increased phosphorylation of FKHR, inhibitor of B, and cyclic adenosine monophosphate responsive element binding protein (CREB) was detected after TBI versus controls. The deoxyribonucleic acid-binding activity of CREB was also enhanced after TBI in rats. Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats. These data show increased phosphorylation of PKB, PKB substrates, and related proteins after both experimental and clinical TBI, suggesting either activation of the PKB signaling pathway or reduced phosphatase activity in both species.