Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies.
This study evaluated the role of 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, in nitrosative stress in the peripheral nervous system and peripheral prediabetic and diabetic neuropathies. The experiments were performed in C57BL6/J mice made diabetic with streptozotocin or fed a high-fat diet and in human Schwann cells cultured in 5.5 or 30 mM glucose. 12/15-Lipoxygenase overexpression and activation were present in sciatic nerve and spinal cord of diabetic and high-fat diet-fed mice, as well as in human Schwann cells cultured in high concentrations of D-, but not L-glucose. 12/15-Lipoxygenase inhibition by cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (8 mg kg(-1) day(-1) sc, for 4 weeks after 12 weeks without treatment) alleviated the accumulation of nitrated proteins in the sciatic nerve and spinal cord, and large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss. 12/15-Lipoxygenase gene deficiency alleviated nitrosative stress and nerve conduction deficit, but not small sensory fiber neuropathy, in high-fat diet-fed mice. In conclusion, 12/15-lipoxygenase is implicated in nitrosative stress and peripheral neuropathy in mouse models of type 1 and early type 2 diabetes. Its presence in human Schwann cells and upregulation by high glucose suggest a potential involvement in human disease.
Stavniichuk
Roman
R
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Drel
Viktor R
VR
Shevalye
Hanna
H
Vareniuk
Igor
I
Stevens
Martin J
MJ
Nadler
Jerry L
JL
Obrosova
Irina G
IG
D000818:Animals; D002460:Cell Line; D003373:Coumaric Acids / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008084:Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D015538:Nitrosation / Q000187:drug effects; D011236:Prediabetic State / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013312:Stress, Physiological / Q000187:drug effects
D003373:Coumaric Acids; C007175:alpha-cyano-4-hydroxycinnamate; D008084:Lipoxygenase; D005947:Glucose