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12/15‐lipoxygenase and diabetic neuropathy
Author(s) -
Obrosova Irina G.,
Shin Jeho,
Lyzogubov Valeriy V.,
Nadler Jerry L,
Drel Viktor R.
Publication year - 2007
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.21.6.a1273-a
Subject(s) - dorsal root ganglion , hypoalgesia , medicine , endocrinology , diabetic neuropathy , streptozotocin , nerve conduction velocity , western blot , diabetes mellitus , peripheral neuropathy , chemistry , spinal cord , hyperalgesia , nociception , biochemistry , receptor , psychiatry , gene
Arachidonic acid metabolism plays an important role in diabetic complications. We evaluated the role for 12/15‐lipoxygenase (LO) in diabetic neuropathy (PDN). LO was localized in both endothelial and SC of murine peripheral nerve (double immunofluorescent histochemistry), spinal cord, and dorsal root ganglion neurons, and LO expression (Western blot analysis) was increased in three tissues in streptozotocin (STZ) diabetes of 10 wk duration. Diabetic LO−/− mice (C57Bl6/J background) had less severe PDN than diabetic wild‐type mice. In particular, sensory nerve conduction velocity deficit, tactile allodynia, and thermal hypoalgesia were less severe in diabetic LO−/− than in LO+/+ mice. Motor nerve conduction slowing and axonal atrophy developed in diabetic LO+/+ mice, but not in LO−/− mice. 10‐d treatment with the LO inhibitor cinnamyl‐3,4‐dihydroxy‐alpha‐cyanocinnamate (CDC, 8 mg kg −1 d −1 s.c., after 10 wks of untreated diabetes) partially reversed nerve conduction deficits and tactile allodynia, but not thermal hypoalgesia, in diabetic wild‐type mice. In in vitro study, increased LO mRNA (real‐time PCR) and protein expression was present early (~24 h) after exposure of human Schwann cells (HSC) to 30 mM vs. 5 mM glucose. CDC (10 μM) abolished high glucose‐induced phosphorylation of ERK1, SAPK/JNK and p38 MAPK in HSC. In conclusion, 12/15‐LO activation is a novel fundamental mechanism of PDN.