Brain Advance Access originally published online on April 22, 2003
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Brain, Vol. 126, No. 7, 1671-1682,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg150
Enhanced activation of axonally transported stress-activated protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3
School of Biological Sciences, University of Manchester, Manchester, UK *Present address: Department of Neurology, Stanford University, Stanford, CA, USA
Correspondence to: Dr Paul Fernyhough, 1.124 Stopford Building, School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK E-mail: paul.fernyhough{at}man.ac.uk
The objective was to determine whether stress-activated protein kinases (SAPKs) mediated the transfer of diabetes-induced stress signals from the periphery to somata of sensory neurons. Thus, we characterized axonal transport of SAPKs in peripheral nerve, studied any alteration in streptozotocin (STZ)-diabetic rats and examined effects of neurotrophin-3 (NT-3) on diabetes-induced events. We demonstrate that c-jun N-terminal kinase (JNK) and p38 are bidirectionally axonally transported at fast rates in sciatic nerve. In STZ-diabetic rats the relative levels of retrograde axonal transport of phosphorylated (activated) JNK and p38 were raised compared with age-matched controls (all data are in arbitrary units and expressed as fold increase over control: JNK 54–56 kDa isoforms, control 1.0 ± 0.19, diabetic 2.5 ± 0.26; p38, control 1.0 ± 0.09, diabetic 2.9 ± 0.52; both P < 0.05). Transport of total enzyme levels of JNK and p38 and phosphorylated extracellular signal-regulated kinase (ERK) was not significantly altered and anterograde axonal transport of phosphorylated JNK and p38 was unaffected by diabetes. The transcription factor ATF-2, which is phosphorylated and activated by JNK and p38, also exhibited elevated retrograde axonal transport in STZ-diabetic animals (control 1.0 ± 0.07, diabetic 3.0 ± 0.41; P < 0.05). Treatment of STZ-diabetic animals with 5 mg/kg human recombinant NT-3 prevented activation of JNK and p38 in sciatic nerve (phosphorylated JNK, control 1.0 ± 0.09, diabetic 1.95 ± 0.35, diabetic + NT-3 1.09 ± 0.12; P < 0.05 diabetic versus others; phosphorylated p38, control 1.0 ± 0.16, diabetic 4.7 ± 0.9, diabetic + NT-3 1.19 ± 0.18; P < 0.05 diabetic versus others). The results show that JNK and p38 are transported axonally and may mediate the transfer of diabetes-related stress signals, possibly triggered by loss of neurotrophic support, from the periphery to the neuronal soma.
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