The protein kinase B (PKB) and protein kinase C (PKC) enzyme families participate in many cellular functions including protein synthesis. Catabolism, weight loss, and impaired developmental body and brain weight gains have been documented after pediatric traumatic brain injury (TBI). Hypothermia treatment has been shown to improve developmental brain weight in specific brain regions important in cognitive function such as the hippocampus and spatial memory after injury. However, recent study has shown that pediatric TBI alters hippocampal protein synthesis and while hypothermia improves protein synthesis recovery after cerebral ischemia, this has not been examined after TBI in either adult or immature animals. Hypothermia is a unique modulator of protein synthesis in that it depresses overall protein synthesis but selectively increases cap-independent synthesis of stress proteins via cold shock stress. Hippocampal protein synthesis after TBI is critical for neuronal survival, learning and memory, and synaptic plasticity. Pathological changes in protein synthesis mediated by dysfunction of eukaryotic initiation factor 2 (eIF2) and 4 (eIF4) pathways after pediatric TBI may impair the initiation and fidelity of protein synthesis and injury related restorative and growth responses. We have recently shown that hippocampal eIF2 and eIF4 pathway regulation is altered acutely (2- 72hrs) and possibility up to 2 wk after TBI to the 17 day postnatal (PND) rat. We have also shown moderate hypothermia reduces a key injury eIF2 pathway abnormality. Pathological changes in the phosphoinositide 3-kinase - protein kinase B (PI3K-PKB), protein kinase C (PKC), glycogen synthase 3 (GSK-3), mitogen activated protein kinase (MAPK) and target of rapamycin kinase (mTOR) pathways are all involved in our model. Protein synthesis can be modified by cap-dependent (eIF4E), cap-independent (IRES -internal ribosome entry segment), and 5TOP - 5' oligopyrimidine tract (mTOR) protein synthesis initiation. We hypothesize that post-injury hypothcrmia promotes functional recovery following pediatric TBI not primarily due to inhibition of excitotoxic glutamate release (which has already occurred), but by activating beneficial stress related IRES protein synthesis causing cold stress induced tolerance to secondary injury processes. We propose: 1) Impaired IRES protein translation occurs primarily after moderate pediatric TBI. Changes in hippocampal PI3K-PKB and mTOR kinase pathways that impair cap-binding (elF4E) and 5'TOP initiation phases of protein synthesis also occur but are of less magnitude. 2) The overall rate of protein synthesis (controlled by elF2) is reduced due to acute and chronic PKC zeta and GSK-3 inhibition of eIF2beta, and 3)That therapeutic modulation with mild hypothermia after pediatric TBI will enhance functional recovery by increasing IRES protein synthesis via cold shock stimulated production of beneficial IRES linked protein expression and elF2B recovery.
NIH ExPorter
NIH ExPorter