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Interactions between the 12/15‐lipoxygenase pathway and MAPK activation in diabetic peripheral neuropathy
Author(s) -
Stavniichuk Roman,
Drel Viktor R,
Shevalye Hanna,
Nadler Jerry L,
Obrosova Irina
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1094.3
Subject(s) - peripheral , peripheral neuropathy , lipoxygenase , medicine , mapk/erk pathway , diabetic neuropathy , chemistry , diabetes mellitus , endocrinology , enzyme , signal transduction , biochemistry
Both MAPK activation and, recently, the 12/15‐lipoxygenase (12/15‐LO) pathway, have been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). We evaluated the relationship between the two mechanisms using the 12/15‐LO inhibitor cinnamyl‐3,4‐dihydroxy‐á‐cyanocinnamate (CDC) and 12/15‐LO−/− mice. Male wild‐type (WT) and 12/15‐LO−/− mice were made diabetic with streptozotocin. Wild‐type mice with 12–14 wk duration of STZ diabetes displayed motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. They also displayed 12/15‐LO overexpression, 12(S)‐HETE accumulation (a sign of increased 12/15‐LO activity), and increased phosphorylation of p38, ERK, and SAP/JNK in the sciatic nerve. 12/15‐LO inhibition with CDC (8 mgkg‐1d‐1, s.c., for 4 wks after initial 12 wks without treatment) or 12/15‐LO gene deficiency alleviated peripheral nerve dysfunction and reduced p38 and ERK phosphorylation, without affecting SAP/JNK phosphorylation or intraepidermal nerve fiber loss, a sign of small sensory nerve fiber degeneration. In conclusion, the findings suggest interaction between the 12/15‐LO pathway and p38 and ERK, but not SAP/JNK, in the development of peripheral nerve dysfunction characteristic for DPN. Neither 12/15‐LO nor MAPK activation contribute to diabetes‐induced intraepidermal nerve fiber loss.