Activation of JNK in sensory neurons protects against sensory neuron cell death in diabetes and on exposure to glucose/oxidative stress in vitro.
Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition of this activation for the ERK and p38 groups prevents nerve damage, and agents that improve neuronal function in diabetic rats-antioxidants and aldose reductase inhibitors-also inhibit activation of ERK and p38 in dorsal root ganglia (DRG). However, these same treatments consistently increase activation of JNK. Thus, in DRG from rats with streptozotocin (STZ)-induced diabetes of 12-week duration, the p54/56 isoforms of JNK were activated by 2.75 compared to controls (P <.05). In DRG from diabetic rats treated with a gamma-linolenic acid and alpha-lipoic acid diester (GLA/LA), the activity of the p54/56 isoform was 3.75 that of controls and the p46 isoform was also increased to 1.75 that of controls (both P <.05 compared to both controls and untreated diabetics). We therefore tested the hypothesis that JNK activation is protective. Exposure of rats to diabetes increased activation of JNK in DRG, but treatment with GLA/LA increased this effect (P <.05). Specific inhibition of JNK in primary cultures of DRG neurons using a peptide inhibitor of JNK (JNKi1, 159-600-R100, 7.5 micro M, Alexis Biochemicals) increased the release of LDH and reduced MTT staining; both findings indicate an increase in neuronal damage. Taken together these findings indicate that multiple isoforms of JNK were activated in sensory neurons of diabetic rats, probably by a combination of raised glucose and oxidative stress, and that this activation of JNK serves to protect the neurons from damage.
Price
Sally A
SA
Division of Neuroscience, 1.124 Stopford Building, University of Manchester, Manchester, M13 9PT, England, United Kingdom. sally.a.price@man.ac.uk
Hounsom
Luke
L
Purves-Tyson
Tertia D
TD
Fernyhough
Paul
P
Tomlinson
David R
DR
D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D005727:Ganglia, Spinal / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009475:Neurons, Afferent / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases