Regeneration of Peripheral Nerves. The role of protein kinases, with emphasis on neurotrophic factor stimulation

Sammanfattning: The purpose of this study was to investigate the role of protein kinases in peripheral nerve regeneration, with the use of dorsal root ganglia (DRG) and nodose ganglia explants from adult mice. The effects of neurotrophic factor stimulation and protein kinase inhibition were studied for long (days) and short term (minutes) effects. The protein kinase systems studied were protein kinase C (PKC), the cyclic nucleotide dependent protein kinases A and G (PKA, PKG) and the mitogen activated protein kinase (MAPK). When unstimulated regeneration was concerned, inhibition of either PKC or PKA and PKG showed minor or transient effects on both long- and short term axonal outgrowth. Simultaneous inhibition of PKC and PKA/PKG on both unstimulated and NGF stimulated DRG had much stronger effects, suggesting that complementary kinase systems work together during outgrowth. Inhibition of MAPK also lacked effects on unstimulated DRG or nodose ganglia. When neurotrophic factors were used on DRG, MAPK inhibition effectively inhibited both NGF and glial cell line-derived (GDNF) stimulated outgrowth. In contrast to this, neurotrophin-3 (NT-3) stimulated DRG outgrowth was further increased after inhibition of MAPK. Neurotrophin-4 (NT-4) activated MAPK and strongly stimulated axonal outgrowth from the nodose ganglion; yet MAPK inhibition was without effect on the NT-4 stimulated nodose outgrowth. The results thus show that the relative importance of MAPK varies between unstimulated and different types of stimulated growth in peripheral neurons, perhaps in a neuronal population specific way.