title: 12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy.
abstract: BACKGROUND
  Increased mitogen-activated protein kinase (MAPK) phosphorylation has been detected in peripheral nerve of human subjects and animal models with diabetes as well as high-glucose exposed human Schwann cells, and have been implicated in diabetic peripheral neuropathy. In our recent studies, leukocytetype 12/15-lipoxygenase inhibition or gene deficiency alleviated large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss in streptozotocin-diabetic mice.
  
  
  METHODS
  To address a mechanism we evaluated the potential for pharmacological 12/15-lipoxygenase inhibition to counteract excessive MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy. C57Bl6/J mice were made diabetic with streptozotocin and maintained with or without the 12/15-lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC). Human Schwann cells were cultured in 5.5 mM or 30 mM glucose with or without CDC.
  
  
  RESULTS
  12(S) HETE concentrations (ELISA), as well as 12/15-lipoxygenase expression and p38 MAPK, ERK, and SAPK/JNK phosphorylation (all by Western blot analysis) were increased in the peripheral nerve and spinal cord of diabetic mice as well as in high glucose-exposed human Schwann cells. CDC counteracted diabetes-induced increase in 12(S)HETE concentrations (a measure of 12/15-lipoxygenase activity), but not 12/15-lipoxygenase overexpression, in sciatic nerve and spinal cord. The inhibitor blunted excessive p38 MAPK and ERK, but not SAPK/ JNK, phosphorylation in sciatic nerve and high glucose exposed human Schwann cells, but did not affect MAPK, ERK, and SAPK/JNK phosphorylation in spinal cord.
  
  
  CONCLUSIONS
  12/15-lipoxygenase inhibition counteracts diabetes related MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy and implies that 12/15-lipoxygenase inhibitors may be an effective treatment for diabetic peripheral neuropathy.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Stavniichuk
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Obrosov
authors.forename: Viktor R
authors.initials: VR
authors.lastname: Drel
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yorek
keywords: Diabetes; Lipoxygenase; Mitogen-Activated Protein Kinase; Neuropathy; Schwann Cells