Protection of the developing brain with trophic factors. Signaling through serine/threonine kinase pathways

Sammanfattning: Background: Perinatal asphyxia still constitutes a clinical hazard associated withconsiderable neurologic morbidity. There is today no therapy in clinical use toprotect the brain after such insult.Aims: The overall aim was to investigate the involvement of the GH/IGF-I axis indevelopment of HI brain damage, by studying the neuroprotective effects of thetrophic factors IGF-I, GH and hexarelin in the neonatal brain, and their respectivemechanism of action in vivo. The possible involvement of serine/threonine kinasesin the development of brain injury was also addressed.Methods: Seven-day-old rats or nine-day-old mice were subjected to HI. Animalswere sacrificed at different time points for evaluation of brain damage, enzymeactivity measurements, immunoblotting, immunocytochemistry, RT-PCR andsolution hybridization assays.Results: IGF-I mRNA was increased after HI and after GH treatment. GH, IGF-Iand Hexarelin treatment all offered some degree of protection after HI. Thisindicates involvement of the GH/IGF-I axis in the development of brain damageand in neuroprotection following HI. Both pAkt and pGSK3? substantiallydecreased after HI. Treatment with IGF-I or hexarelin restored these levels andreduced the activation of the apoptotic executioner caspase-3. Moreover, micedeficient in the serine/threonine kinase JNK3 were significantly less damaged afterHI compared to wild-type. The protection was more pronounced in femalecompared to male mice.Conclusions: These results suggest a role for the GH/IGF-I axis in theneurochemical process leading to brain injury after HI. Moreover, reducedphosphorylation of Akt and GSK3? after HI indicate an effect on the PI3-kinasepathway similar to growth factor withdrawal in vitro. This could be an importantfactor in the development of neuronal death after HI with possible activation ofseveral pro-apoptotic mechanisms. Increased phosphorylation of both theseproteins after IGF-I and hexarelin treatment indicate that activation of PI3-kinasepathway is an important mediator of growth factor induced neuronal survival invivo. Reduced susceptibility to HI in JNK3-/- mice indicates involvement of thisserine/threonine kinase in the development of damage in the immature brain.