TITLE:
12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy
AUTHORS:
Roman Stavniichuk, Alexander A. Obrosov, Viktor R. Drel, Jerry L. Nadler, Irina G. Obrosova, Mark A. Yorek
KEYWORDS:
Diabetes; Lipoxygenase; Neuropathy; Schwann Cells; Mitogen-Activated Protein Kinase
JOURNAL NAME:
Journal of Diabetes Mellitus,
Vol.3 No.3,
July
17,
2013
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 in5.5 mMor30 mMglucose 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. Conclusion:
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.