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Akt (protein kinase B) and mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of cell death and cognitive outcome after cerebral contusion in mice; however, a role for Akt/mTOR in concussive brain injury has not been well characterized. In a mouse closed head injury (CHI) concussion traumatic brain injury (TBI) model, phosphorylation of Akt (p-Akt), mTOR (p-mTOR), and S6RP (p-S6RP) was increased by 24 hours in cortical and hippocampal brain homogenates (P<0.05 versus sham for each), and p-S6RP was robustly induced in IBA-1+ microglia and glial fibrillary acidic protein-positive (GFAP+) astrocytes. Pretreatment with inhibitors of Akt or mTOR individually by the intracerebroventricular route reduced phosphorylation of their respective direct substrates FOXO1 (P<0.05) or S6RP (P<0.05) after CHI, confirming the activity of inhibitors. Rapamycin pretreatment significantly worsened hidden platform (P<0.01) and probe trial (P<0.05) performance in CHI mice. Intracerebroventricular administration of necrostatin-1 (Nec-1) before CHI increased hippocampal Akt and S6RP phosphorylation and improved place learning (probe trials, P<0.001 versus vehicle), whereas co-administration of rapamycin or Akt inhibitor with Nec-1 eliminated improved probe trial performance. These data suggest a beneficial role for Akt/mTOR signaling after concussion TBI independent of cell death that may contribute to improved outcome by Nec-1. [ABSTRACT FROM AUTHOR]

AbstractTraumatic brain injury (TBI) may involve diverse injury mechanisms (e.g., focal impact vs. diffuse impact loading). Putative therapies developed in TBI models featuring a single injury mechanism may fail in clinical trials if the model does not fully replicate multiple injury subtypes, which may occur concomitantly in a given patient. We report development and characterization of a mixed contusion/concussion TBI model in mice using controlled cortical impact (CCI; 0.6 mm depth, 6 m/sec) and a closed head injury (CHI) model at one of two levels of injury (53 vs. 83 g weight drop from 66 in). Compared with CCI or CHI alone, sequential CCI-CHI produced additive effects on loss of consciousness (p<0.001), acute cell death (p<0.05), and 12-day lesion size (p<0.05) but not brain edema or 48-h contusion volume. Additive effects of CHI and CCI on post-injury motor (p<0.05) and cognitive (p<0.005) impairment were observed with sequential CCI-CHI (83 g). The data suggest that concussive forces, which in isolation do not induce histopathological damage, exacerbate histopathology and functional outcome after cerebral contusion. Sequential CHI-CCI may model complex injury mechanisms that occur in some patients with TBI and may prove useful for testing putative therapies. [ABSTRACT FROM AUTHOR]

Akt and mammalian target of rapamycin (mTOR) are both activated after traumatic brain injury (TBI), however complex interplay between the two hampers deciphering their functional implications in vivo. We examined the effects of single and combination inhibitors of Akt/mTOR in a mouse controlled cortical impact (CCI) model. Following CCI, phospho-Akt-473 (p-Akt) and -S6 ribosomal protein (p-S6RP), a downstream substrate of mTOR, were increased in cortical and hippocampal brain homogenates (P<0.05 versus sham). At 24 hours, p-S6RP was detected in neurons and was robustly induced in microglia and astrocytes in injured hippocampus. In vivo activity of Akt and mTOR inhibitors administered separately was confirmed by reduced expression of p-GSK3β (P<0.01) or p-S6RP (P<0.05), respectively, after CCI. Importantly, administration of Akt and mTOR inhibitors together (but not of either alone) improved postinjury motor (P=0.02) and cognitive deficits (hidden platform trials, P=0.001; probe trials, P<0.05), decreased propidium iodide-positive cells in CA1 and CA3 (P<0.005), and unexpectedly increased p-GSK3β in hippocampus. Although the roles of Akt and mTOR in the pathogenesis of TBI remain to be fully elucidated, dual inhibition of Akt and mTOR may have therapeutic potential for TBI. [ABSTRACT FROM AUTHOR]

The apolipoprotein E4 (APOE4) gene leads to increased brain amyloid beta (Aβ) and poor outcome in adults with traumatic brain injury (TBI); however, its role in childhood TBI is controversial. We hypothesized that the transgenic expression of human APOE4 worsens the outcome after controlled cortical impact (CCI) in adult but not immature mice. Adult and immature APOE4 mice had worse motor outcome after CCI (P<0.001 versus wild type (WT)), but the Morris water maze performance was worse only in adult APOE4 mice (P=0.028 at 2 weeks, P=0.019 at 6 months versus WT), because immature APOE4 mice had performance similar to WT for up to 1 year after injury. Brain lesion size was similar in adult APOE4 mice but was decreased (P=0.029 versus WT) in injured immature APOE4 mice. Microgliosis was similar in all groups. Soluble brain Aβ40 was increased at 48 hours after CCI in adult and immature APOE4 mice and in adult WT (P<0.05), and was dynamically regulated during the chronic period by APOE4 in adults but not immature mice. The data suggest age-dependent effects of APOE4 on cognitive outcome after TBI, and that therapies targeting APOE4 may be more effective in adults versus children with TBI. [ABSTRACT FROM AUTHOR]