Evidence for the important role of arachidonic acid metabolism in diabetes complications is emerging. Recent in vivo and cell culture studies including those from our group revealed that 12/15-lipoxygenase (12/15-LO) 1) contributes to impaired cell signaling and inflammatory response;and 2) is implicated in the pathogenesis of endothelial dysfunction, nephropathy and retinopathy, associated with diabetes. The objective of this proposal is to evaluate the role of 12/15-LO in peripheral diabetic neuropathy (PDN) using animal models of Type 1 and Type 2 diabetes and high glucose-exposed co-cultures of mouse Schwann cells and DRG neurons and cultures of human Schwann cells (HSC). Our preliminary data indicate that 1) 12/15-LO is abundantly expressed in the peripheral nerve and its expression and activity increase in diabetic conditions;2) 12/15-LO-/- mice develop less severe PDN than wild-type mice;3) some manifestations of PDN in STZ-diabetic mice are reversed by a short-term 12/15-LO inhibitor treatment;4) 12/15-LO overexpression is manifest after a short-term (24h) exposure of HSC to high glucose;and 5) a 12/15-LO inhibitor treatment counteracts high glucose-induced mitogen-activated protein kinase (MAPK) phosphorylation in HSC.
The SPECIFIC AIMS are 1) evaluate two structurally unrelated 12/15-LO inhibitors on functional, biochemical and structural indices of PDN in mouse models of Type 1 and Type 2 diabetes, i.e., STZ-diabetic and high-fat diet fed mice;2) compare severity of PDN in 12/15-LO-/- mice and wild-type mice with Type 1 and Type 2 diabetes;3) assess the role for the most important, """"""""upstream"""""""", mechanism of PDN, i.e. increased aldose reductase activity, in 12/15-LO upregulation, and 4) examine the contribution of 12/15-LO to MAPK activation, in peripheral nerve, spinal cord and DRG neurons in the afore-mentioned animal and cell culture models. The project will combine physiological, behavioral, biochemical, immunohistochemical and structural studies in animals with biochemical (HPLC, Western blotting, spectrofluorometric enzymatic assays) and molecular (real-time PCR, siRNA transfections) approaches in cell culture models. The findings will generate new information on the role for 12/15-LO in PDN of Type 1 and Type 2 diabetes, and may provide rationale for development of 12/15-LO inhibitors for its prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK074517-02S1
Application #
7777475
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jones, Teresa L Z
Project Start
2007-09-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$1,480
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Stavniichuk, Roman; Obrosov, Alexander A; Drel, Viktor R et al. (2013) 12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy. J Diabetes Mellitus 3:
Lupachyk, Sergey; Watcho, Pierre; Obrosov, Alexander A et al. (2013) Endoplasmic reticulum stress contributes to prediabetic peripheral neuropathy. Exp Neurol 247:342-8
Lupachyk, Sergey; Watcho, Pierre; Stavniichuk, Roman et al. (2013) Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy. Diabetes 62:944-52
Lupachyk, Sergey; Stavniichuk, Roman; Komissarenko, Julia I et al. (2012) Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis. Int J Mol Med 29:989-98
Shevalye, Hanna; Lupachyk, Sergey; Watcho, Pierre et al. (2012) Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology 153:1152-61
Stavniichuk, Roman; Shevalye, Hanna; Hirooka, Hiroko et al. (2012) Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy. Biochem Pharmacol 83:932-40
Shevalye, Hanna; Watcho, Pierre; Stavniichuk, Roman et al. (2012) Metanx alleviates multiple manifestations of peripheral neuropathy and increases intraepidermal nerve fiber density in Zucker diabetic fatty rats. Diabetes 61:2126-33
Lupachyk, Sergey; Watcho, Pierre; Hasanova, Nailia et al. (2012) Triglyceride, nonesterified fatty acids, and prediabetic neuropathy: role for oxidative-nitrosative stress. Free Radic Biol Med 52:1255-63
Lupachyk, Sergey; Shevalye, Hanna; Maksimchyk, Yury et al. (2011) PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function. Free Radic Biol Med 50:1400-9
Watcho, Pierre; Stavniichuk, Roman; Tane, Pierre et al. (2011) Evaluation of PMI-5011, an ethanolic extract of Artemisia dracunculus L., on peripheral neuropathy in streptozotocin-diabetic mice. Int J Mol Med 27:299-307

Showing the most recent 10 out of 19 publications