12/15-Lipoxygenase Inhibition and Gene Deficiency Counteract Peripheral Diabetic Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes
Abstract Number: 828-P
Authors: IRINA G. OBROSOVA, IGOR VARENIUK, ROMAN STAVNIICHUK, JERRY L. NADLER, VIKTOR R. DREL
Institutions: Baton Rouge, LA, Norfolk, VA
Results: This study evaluated the role for 12/15-lipoxygenase (LO), an enzyme catalyzing conversion of arachidonic acid to 12- and 15-hydroxyeicosatetraenoic acids and their derivatives, in peripheral diabetic neuropathy (PDN), using STZ-diabetic (Type 1) and high fat diet (HFD)-fed (Type 2) mouse models. Sciatic motor and hind-limb digital sensory nerve conduction velocities (MNCV and SNCV), thermal and mechanical algesia, tactile response threshold, intraepidermal nerve fiber density, myelinated nerve fiber diameter and myelin thickness were assessed for characterization of functional and structural manifestations of PDN. 12/15-lipoxygenase overexpression (Western blot analysis, immunohistochemistry) was present in peripheral nerve and DRG neurons in both animal models. The STZ-diabetic model study revealed: 1) reversal or alleviation of MNCV and SNCV deficits, thermal and mechanical hypoalgesia, and tactile allodynia by two structurally diverse LO inhibitors, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (8 mgkg-1d-1 s.c.) and baicalein (20 mgkg-1d-1 i.p.), administered for 4 wks after 12 wks of untreated diabetes; 2) presence of axonal atrophy (reduction of myelinated fiber diameter and myelin thickness) in wild-type, but not in LO-deficient, mice with 14-wk diabetes; and 3) intraepidermal nerve fiber loss similar in severity in diabetic wild-type and LO-deficient mice. In the HFD model study (16-wk HFD feeding), 1) HFD-fed LO-deficient mice did not develop MNCV and SNCV deficits that were clearly manifest in HFD-fed wild-type mice; 2) LO gene deficiency did not protect from development of HFD-induced thermal hypoalgesia and tactile allodynia; and 3) HFD feeding did not result in epidermal denervation or axonal atrophy in either wild-type or LO-deficient mice. The results suggest that LO plays an important, but different, role in the pathogenesis of PDN associated with Type 1 and Type 2 diabetes. Furthermore, this mechanism provides a major contribution to diabetes-associated large myelinated fiber atrophy, apparently being unimportant in unmyelinated sensory nerve fiber degeneration.