Hyperlipidemia: a new therapeutic target for diabetic neuropathy

Abstract

Emerging data establish dyslipidemia as a significant contributor to the development of diabetic neuropathy. In this review we discuss how separate metabolic imbalances, including hyperglycemia and hyperlipidemia, converge on mechanisms leading to oxidative stress in dorsal root ganglia sensory neurons. We conclude with suggestions for novel therapeutic strategies to prevent or reverse diabetes-induced nerve degeneration.

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Many excellent reviews have been published that 1) describe the various biochemical insults that contribute to the pathogenesis of DPN and 2) outline treatment strategies directed at blocking either causal mechanisms or treating neuropathic pain (Leinninger et al, 2004;Vincent et al, 2004Vincent et al, , 2009bPop-Busui et al, 2006;Calcutt and Backonja, 2007;Zochodne, 2007Zochodne, , 2008Calcutt et al, 2008Calcutt et al, , 2009Edwards et al, 2008;Tavakoli and Malik, 2008;Veves et al, 2008;Obrosova, 2009a;Fernyhough et al, 2010;Sivitz and Yorek, 2010;Malik et al, 2011). Thus, the intent of the current review is to briefly highlight and update many of these features and add to the discussion by proposing that both pharmaco-1 Abbreviations: AGE, advanced glycation end product; AR, aldose reductase; BDNF, brain-derived neurotrophic factor; COX, cyclooxygenase; DCCT, Diabetes Control and Complication Trial; DPN, diabetic peripheral neuropathy; DRG, dorsal root ganglia; F-6-P, fructose-6 phosphate; FDA, U.S. Food and Drug Administration; GDNF, glial cell-derived neurotrophic factor; GlcNAc, N-acetyl glucosamine; HETE, hydroxyeicosatetraenoic; HSF, heat-shock factor; Hsp, heat-shock protein; HSR, heat-shock response; 3R,4S,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide; LA, ␣-lipoic acid; MAPK, mitogen-activated protein kinase; MNCV, motor nerve conduction velocity; MnSOD, manganese superoxide dismutase; mtHsp70, mitochondrial paralog of Hsp70; NF-B, nuclear factor B; NGF, nerve growth factor; NT, neurotrophin; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; PKI-166, 4-phenethylamino-6-(yderoxyl)phenyl-7H-pyrrolo(2,3-d)pyrimidine; RAGE, receptor for AGE; RBX, ruboxistaurin; ROS, reactive oxygen species; SNCV, sensory nerve conduction velocity; sRAGE, soluble RAGE; STZ, streptozotocin; TCA, tricyclic antidepressant; TNF, tumor necrosis factor.…”

Neuroprotective and Anti-Inflammatory Activities of Atorvastatin in a Rat Chronic Constriction Injury Model

“…Abnormalities in low-density lipoprotein (LDL) profiles were more closely related to diabetic neuropathy than hyperglycemia. A higher prevalence of hyperlipidemia than impaired glucose tolerance or hypertension suggests that dyslipidemia is an essential factor underlying nerve injury (4)(5). The pathogenesis of damage to the pain mechanism is multifactorial and includes metabolic disturbances such as hyperglycemia, impaired glucose tolerance, dyslipidemia, oxidative stress, growth factor deficiencies, microvascular insufficiency, and autoimmune damage to nerve fibers (5).…”

Neuropathy-specific alterations in a Mexican population of diabetic patients

“…Patients with sensory neuropathies, especially those with hyperesthesia, showed a reduced HDL/LDL ratio. These factors may contribute to developing diabetic neuropathy by increasing the oxidative damage in neurons [29].…”