Effect of Fish oil Vs. Resolvin D1, E1, Methyl Esters of Resolvins D1 or D2 on Diabetic Peripheral Neuropathy

Abstract

ObjectiveFish oil is enriched in omega-3 polyunsaturated fatty acids primarily eicosapentaenoic and docosahexaenoic fatty acids. Metabolites of these two polyunsaturated fatty acids include the E and D series resolvins. Omega-3 polyunsaturated fatty acids and resolvins have been reported to have anti-inflammatory and neuroprotective properties. The objective of this study was to evaluate the efficacy of menhaden oil, a fish oil derived from the menhaden, resolvins D1 and E1 and the methyl esters of resolvins D1 and D2 on diabetic peripheral neuropathy. Hypothesis being examined was that the methyl esters of resolvins D1 and D2 would be move efficacious than resolvins D1 or E1 due to an extended half-life.MethodsA model of type 2 diabetes in C57BL/6J mice was created through a combination of a high fat diet followed 8 weeks later with treatment of low dosage of streptozotocin. After 8 weeks of untreated hyperglycemia type 2 diabetic mice were treated for 8 weeks with menhaden oil in the diet or daily injections of 1 ng/g body weight resolvins D1, E1 or methyl esters of resolvins D1 or D2. Afterwards, multiple neurological endpoints were examined.ResultsMenhaden oil or resolvins did not improve hyperglycemia. Untreated diabetic mice were thermal hypoalgesic, had mechanical allodynia, reduced motor and sensory nerve conduction velocities and decreased innervation of the cornea and skin. These endpoints were significantly improved with menhaden oil or resolvin treatment. However, the methyl esters of resolvins D1 or D2, contrary to our hypothesis, were generally less potent than menhaden oil or resolvins D1 or E1.ConclusionThese studies further support omega-3 polyunsaturated fatty acids derived from fish oil via in part due to their metabolites could be an effective treatment for diabetic neuropathy.

Omega‐3 polyunsaturated fatty acids exert anti‐oxidant effects through the nuclear factor (erythroid‐derived 2)‐related factor 2 pathway in immortalized mouse Schwann cells

“…ω‐3 PUFAs suppress inflammatory responses by inhibiting the arachidonate cascade in neutrophils, and the stimulation of the G protein‐coupled receptor 120 by DHA exerts anti‐inflammatory effects in macrophages. Recent studies report the anti‐oxidant effects of 4‐hydroxy‐2‐hexanal (4‐HHE), resolvin E1 and protectin D1, which are intracellular metabolites of ω‐3 PUFAs. We also examined the effects of 4‐HHE on the mRNA levels of anti‐oxidant enzymes and found that 4‐HHE increased the mRNA levels of Ho‐1 , Nqo‐1 and Cat (data not shown).…”

<p>Progressive Loss of Corneal Nerve Fibers and Sensitivity in Rats Modeling Obesity and Type 2 Diabetes Is Reversible with Omega-3 Fatty Acid Intervention: Supporting Cornea Analyses as a Marker for Peripheral Neuropathy and Treatment</p>

“…34,35,38,51 Furthermore, our studies have demonstrated that E and D series resolvins (resolutionphase interaction products), metabolites of eicosapentaenoic and docosahexaenoic acids, respectively, which are known to have anti-inflammatory and neuro-protective properties, may be the active mediators responsible for the effect of fish oil on peripheral neuropathy and nerve regeneration. [51][52][53] Zhang et al performed a systematic review and meta-analysis titled omega-3 polyunsaturated fatty acid oral supplements for improving peripheral nerve health. 54 Most of the randomized trials cited in this review focused on chemotherapy-induced peripheral neuropathy and the authors concluded that there was little support of a therapeutic benefit for omega-3 fatty acid oral supplementation in this patient cohort.…”

“…66 In our studies, we have shown that resolvin D1 increases neurite growth by primary cultures of dorsal ganglion neurons and improves corneal nerve density and neural function of diabetic mice. [51][52][53]…”

Effect of Dietary Content of Menhaden Oil with or without Salsalate on Neuropathic Endpoints in High-Fat-Fed/Low-Dose Streptozotocin-Treated Sprague Dawley Rats

“…To answer this question, it will be important to determine the combined levels of resolvins E1 and D1 as well as neuroprotectin D1 under the conditions used in this study. Previous studies have shown that treating diabetic mice with exogenous resolvin E1 or D1 improves peripheral neuropathy [ 5 – 7 ]. It has also been shown that resolvin D1 and neuroprotectin D1 can stimulate neurite outgrowth by dorsal root ganglion or trigeminal ganglion neurons in culture [ 6 , 37 ].…”

“…We have also shown that cotreatment of type 1 diabetic mice with menhaden (fish) oil and salsalate is more effective toward neuropathy than menhaden oil alone and that circulating resolvin D1 levels are increased when salsalate is combined with menhaden oil [ 5 ]. Lastly, we have demonstrated that treating either type 1 or type 2 diabetic mice with daily injections of resolvin E1 or D1, metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, most abundant omega-3 polyunsaturated fatty acids found in fish oil, improves peripheral neuropathy [ 6 , 7 ].…”