Stavniichuk R. Role of 12/15-lipoxygenase in metabolic and functional disorders of experimental diabetic neuropathy.

The dissertation is devoted to investigation of role 12/15-lipoxygenase (LO) plays in pathogenesis of peripheral diabetic neuropathy. 12-LO overexpression and activation had been found in sciatic nerve of diabetic mice. 12-LO inhibition with CDC alleviated diabetes-induced thermal hypoalgesia, tactile allodynia, motor and sensory nerve conduction velocity deficits, accumulation of nitrated proteins in sciatic nerve, as well as large and small nerve fiber dysfunction. 12-LO deficiency prevented or alleviated diabetes-induced reduction in tibial nerve myelinated fiber diameter, but not intraepidermal nerve fiber loss. The study also evaluates the interplay of aldose reductase, 12-lipoxygenase, and MAPKs in diabetic peripheral neuropathy.Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations as well as 12(S)HETE concentration, a measure of 12-LO activity, in the sciatic nerve. 12-LO expression was similarly elevated in untreated and fidarestat-treated diabetic mice. 12-LO gene deficiency prevented diabetes-associated p38 MAPK and ERK, but not SAPK/JNK activation in the sciatic nerve and all three MAPK activation in the dorsal root ganglia. 12/15-lipoxygenase expression and p38 MAPK, ERK, SAPK/JNK phosphorylation and nitrated proteins accumulation were increased in the high glucose-exposed human Schwann cells. CDC blunted excessive p38 MAPK and ERK, but not SAPK/JNK phosphorylation in high glucose exposed human Schwann cells, suggesting a potential involvement of 12/15-LO in the development of human PDN. In conclusion, LO overexpression and activation contribute to oxidative-nitrosative stress in peripheral nervous system and development of neuropathic changes associated with diabetes and prediabetes. The findings support the rationale for development and future studies of LO inhibitors and LO-inhibitor-containing combination therapies.