Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on neuropathy in a mouse model of type 2 diabetes

Abstract

The purpose of this study was to determine the effect of supplementing the diet of a mouse model of type 2 diabetes with menhaden (fish) oil or daily treatment with resolvin D1 on diabetic neuropathy. The end points evaluated included motor and sensory nerve conduction velocity, thermal sensitivity, innervation of sensory nerves in the cornea and skin, and the retinal ganglion cell complex thickness. Menhaden oil is a natural source for n-3 polyunsaturated fatty acids, which have been shown to have beneficial effects in other diseases. Resolvin D1 is a metabolite of docosahexaenoic acid and is known to have anti-inflammatory and neuroprotective properties. To model type 2 diabetes, mice were fed a high-fat diet for 8 wk followed by a low dosage of streptozotocin. After 8 wk of hyperglycemia, mice in experimental groups were treated for 6 wk with menhaden oil in the diet or daily injections of 1 ng/g body wt resolvin D1. Our findings show that menhaden oil or resolvin D1 did not improve elevated blood glucose, HbA1C, or glucose utilization. Untreated diabetic mice were thermal hypoalgesic, had reduced motor and sensory nerve conduction velocities, had decreased innervation of the cornea and skin, and had thinner retinal ganglion cell complex. These end points were significantly improved with menhaden oil or resolvin D1 treatment. Exogenously, resolvin D1 stimulated neurite outgrowth from primary cultures of dorsal root ganglion neurons from normal mice. These studies suggest that n-3 polyunsaturated fatty acids derived from fish oil could be an effective treatment for diabetic neuropathy.

Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints

“…We have previously shown that enalapril and α-lipoic acid reduce markers of oxidative stress in blood vessels and serum of diabetic rats (Coppey et al, 2001; 2006; Davidson et al, 2011; 2012b; Oltman et al, 2008; Yorek, 2008). We have also shown that enriching diets of diabetic rodents with menhaden oil reduces the n-6 to n-3 fatty acid ratio and increases production of the docosahexaenoic metabolite resolvin D1 (Coppey et al, 2012; 2015; Shevalye et al, 2015). Additionally, we have shown that direct treatment of a mouse model of type 2 diabetes with daily injections of resolvin D1 improved diabetic peripheral neuropathy including intraepidermal nerve fiber density and density of sub-epithelial corneal nerve fibers (Shevalye et al, 2015).…”

“…Images were collected using Zeiss 710 LSM confocal laser scanning microscope. Images were analyzed for % area fraction of lipid droplets using Image J software (Shevalye et al, 2015). Protein bound 3-nitrotyrosine concentration was measured in liver by indirect enzyme-linked immunosorbent assay as described (Weber et al, 2012) and modified by (Yorek et al, 2014).…”

“…In this regard we have focused on examining the use of a combination of dietary supplements and drugs (enalapril, α-lipoic acid and menhaden [fish] oil) for treatment of diabetic peripheral neuropathy in rodent models (Davidson et al, 2014). The reason for selecting these three compounds is that we have demonstrated that each of these treatments individually had beneficial effects on diabetic peripheral neuropathy and each have also been shown to be safe for use in humans (Coppey et al, 2001; 2006; 2012; 2015; Davidson et al, 2011; Gopinath et al, 2012; Mcllduff and Rutkove, 2011; Papanas and Ziegler, 2014; Rudkowska, 2010; Shevalye et al, 2015; Yee et al, 2010; Ziegler et al, 2011). The primary mechanism of action of these three compounds is oxidative and inflammatory stress.…”

Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy

“…It has been demonstrated in both human and animal subjects that diabetes alters the structure of corneal nerves, and this may be an early marker for diabetic PN. 2–6,12,18–25 We propose that a diabetes-induced loss in corneal nerve density will translate into a decrease in cornea sensitivity in response to corneal stimulation through hypertonicity that can be evaluated by capturing and measuring behavioral changes in facial and/or ocular movement. Quantifying these behavioral changes could provide an objective screening tool for detection of PN that can be easily performed during a routine eye examination.…”

Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

“…[1][2][3] As a result of these studies, the distribution and architecture of mouse corneal sensory innervation is reasonably well known, confirming that it follows the morphologic pattern of corneal nerve branching described in other mammalian species, 4,5 although remarkable differences exist in nerve density between mice strains. 4 Additionally, the corneal innervation of mice has been used to explore the origin and trophic dependence of peripheral sensory nerves during prenatal development 6 and postinjury nerve regeneration in adults, 3,7,8 as well as age-dependent changes in the architecture and function of corneal nerves. 2,9 Moreover, mice have been extensively employed to define the morphologic alterations of corneal nerves caused by a number of pathologic conditions such as diabetes, 10 surgical injury, 1,11,12 herpes virus infections, 13,14 and dry eye disease.…”