title: Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor.
abstract: OBJECTIVE
  This study was designed to determine whether diabetes in rats is associated with phosphorylation of c-Jun N-terminal kinase (JNK) and one of its transcription factors, c-Jun, in sensory neurones innervating the lower limb. We also sought to determine which neuronal phenotypes are affected and to examine the effect of aldose reductase inhibition on JNK and c-Jun phosphorylation.
  
  
  METHODS
  Diabetes was induced in rats using streptozotocin. Phosphorylation of JNK and c-Jun in lumbar dorsal root ganglia was determined by binding of phospho-specific antibodies using western blots and immunocytochemistry. Neuronal phenotypes were characterised by binding of N52 (an antibody that recognises the heavy neurofilament protein; for large-diameter mechanoceptors) and of calcitonin gene-related peptide and the plant glycoprotein lectin IB4 (for nociceptors). The efficacy of the aldose reductase inhibitor fidarestat was determined by measuring polyol pathway metabolites in sciatic nerve, and functionally by measuring the conduction velocity of motor and sensory nerves.
  
  
  RESULTS
  In control rats, activated JNK and c-Jun were primarily associated with mechanoceptors; in diabetes this was increased, but a greater increase was seen in nociceptors. Phosphorylation was prevented in all cells by fidarestat, which normalised polyol pathway metabolites as well as motor nerve and sensory nerve conduction velocity.
  
  
  CONCLUSIONS
  Fidarestat-sensitive phosphorylation of JNK and c-Jun occurs in fast-conduction mechanoceptors-the same class of neurones that registers the changes in sensory nerve conduction velocity-and in nociceptors. This supports the notion that mitogen-activated protein kinase phosphorylation, via the polyol pathway, may convert the direct effects of raised glucose into impaired nerve conduction and neuropathic pain. For proof of this we await the availability of specific JNK antagonists formulated for in vivo use.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: A B
authors.initials: AB
authors.lastname: Middlemas
authors.forename: S
authors.initials: S
authors.lastname: Agthong
authors.forename: D R
authors.initials: DR
authors.lastname: Tomlinson
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000201:enzymology / Q000517:prevention & control*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase; D048031:JNK Mitogen-Activated Protein Kinases