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      Eruca sativa Meal against Diabetic Neuropathic Pain: An H 2S-Mediated Effect of Glucoerucin

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          Abstract

          The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed meal, along with its main glucosinolate, glucoerucin (GER), on diabetic neuropathic pain induced in mice by streptozotocin (STZ). The mechanism of action was also investigated. Hypersensitivity was assessed by paw pressure and cold plate tests after the acute administration of the compounds. Once bio-activated by myrosinase, both E. sativa defatted meal (1 g kg −1 p.o.) and GER (100 µmol kg −1 p.o., equimolar to meal content) showed a dose-dependent pain-relieving effect in STZ-diabetic mice, but the meal was more effective than the glucosinolate. The co-administration with H 2S scavengers abolished the pain relief mediated by both E. sativa meal and GER. Their effect was also prevented by selectively blocking Kv7 potassium channels. Repeated treatments with E. sativa meal did not induce tolerance to the anti-hypersensitive effect. In conclusion, E. sativa meal can be suggested as a new nutraceutical tool for pain relief in patients with diabetic neuropathy.

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          Most cited references62

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          Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter.

          Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.
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            Oxidative stress in the pathogenesis of diabetic neuropathy.

            Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients.
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              Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep.

              Our goal was to evaluate pain severity, pain-related interference with function, sleep impairment, symptom levels of anxiety and depression, and quality of life among patients with painful diabetic peripheral neuropathy (DPN). Participants in a burden of illness survey (n = 255) completed the modified Brief Pain Inventory-DPN (BPI-DPN), MOS Sleep Scale, Hospital Anxiety and Depression Scale (HADS), Short Form Health Survey-12v2 (SF-12v2), and the EuroQoL (EQ-5D). Patients were 61 +/- 12.8 years old (51.4% female), had diabetes for 12 +/- 10.3 years and painful DPN for 6.4 +/- 6.4 years. Average and Worst Pain scores (BPI-DPN, 0-10 scales) were 5.0 +/- 2.5 and 5.6 +/- 2.8. Pain substantially interfered (>or=4 on 0-10 scales) with walking ability, normal work, sleep, enjoyment of life, mood, and general activity. Moderate to severe symptom levels of anxiety and depression (HADS-A and HADS-D scores >or=11 on 0-21 scales) occurred in 35% and 28% of patients, respectively. Patients reported greater sleep problems compared with the general U.S. population and significant impairment in both physical and mental functioning (SF-12v2) compared with subjects with diabetes. The mean EQ-5D utility score was 0.5 +/- 0.3. Greater pain levels in DPN (mild to moderate to severe) corresponded with higher symptom levels of anxiety and depression, more sleep problems, and lower utility ratings and physical and mental functioning, (all Ps < 0.01). Painful DPN is associated with decrements in many aspects of patients' lives: physical and emotional functioning, affective symptoms, and sleep problems. The negative impact is higher in patients with greater pain severity.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                19 August 2019
                August 2019
                : 24
                : 16
                : 3006
                Affiliations
                [1 ]Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
                [2 ]CREA-Council for Agricultural Research and Economics, Research Centre for Cereal and Industrial Crops, 40128 Bologna, Italy
                [3 ]Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
                [4 ]Interdepartmental Research Centre “Nutraceuticals and Food for Health (NUTRAFOOD)”, University of Pisa, 56126 Pisa, Italy
                [5 ]Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, 56126 Pisa, Italy
                Author notes
                Author information
                https://orcid.org/0000-0002-3459-2660
                https://orcid.org/0000-0002-9477-1724
                https://orcid.org/0000-0001-8374-4432
                Article
                molecules-24-03006
                10.3390/molecules24163006
                6721019
                31430978
                88b19bc9-964e-4f16-b6e2-38b3f4062be8
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 June 2019
                : 07 August 2019
                Categories
                Article

                diabetic neuropathy,neuropathic pain,glucosinolates,eruca sativa,glucoerucin,h2s,kv7 potassium channels

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