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12/15‐LIPOXYGENASE: ROLES IN LARGE AND SMALL FIBER PERIPHERAL DIABETIC NEUROPATHY
Author(s) -
Stavniichuk Roman,
Drel Viktor R,
Shevalye Hanna,
Vareniuk Igor,
Nadler Jerry L,
Obrosova Irina G
Publication year - 2010
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.24.1_supplement.1035.4
Subject(s) - sciatic nerve , atrophy , peripheral neuropathy , wallerian degeneration , medicine , endocrinology , nerve fiber , myelin , diabetic neuropathy , streptozotocin , sensory nerve , diabetes mellitus , anatomy , sensory system , neuroscience , central nervous system , biology
Upregulation of 12/15‐lipoxygenase (12/15‐LO), responsible for the formation of 12(S)‐HETE, 15(S)‐HETE and their derivatives from arachidonic acid, causes oxidative stress, MAPK activation, and inflammation. We evaluated the role for 12/15‐LO in peripheral diabetic neuropathy (PDN). Wild‐type (WT) and 12/15‐LO−/− mice were made diabetic with streptozotocin and maintained for 14 wks. 12/15‐LO deficiency did not affect glycemia. Diabetic WT mice displayed increased 12/15‐LO expressions and 12(S)‐HETE levels in sciatic nerve and spinal cord. Thermal hypoalgesia, tactile allodynia, and nerve conduction slowing were clearly manifest in diabetic WT mice, and were prevented or alleviated in diabetic 12/15‐LO−/− mice. Diabetic WT mice displayed reductions in myelinated fiber diameter and myelin thickness, indicative of axonal atrophy of large myelinated fibers, as well as in intraepidermal nerve fiber density (INFD), a sign of small sensory nerve fiber degeneration. 12/15‐LO deficiency prevented diabetes‐induced axonal atrophy, but not a reduction in INFD. In conclusion, the 12/15‐LO mechanism provides an important contribution to peripheral nerve dysfunction and axonal atrophy of large myelinated fibers, whereas its role in small sensory nerve fiber degeneration is minor. The latter should be considered in selection of endpoints for future clinical trials of 12/15‐LO inhibitors.