17
views
0
recommends
+1 Recommend
1 collections
    0
    shares

      Journal of Pain Research (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on reporting of high-quality laboratory and clinical findings in all fields of pain research and the prevention and management of pain. Sign up for email alerts here.

      52,235 Monthly downloads/views I 2.832 Impact Factor I 4.5 CiteScore I 1.2 Source Normalized Impact per Paper (SNIP) I 0.655 Scimago Journal & Country Rank (SJR)

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose

          Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.

          Patients and methods

          113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.

          Results

          Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as ≥50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG.

          Conclusion

          The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.

          Most cited references57

          • Record: found
          • Abstract: not found
          • Article: not found

          Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy

            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy☆

            Introduction Diabetes is one of the most debilitating conditions in patients affecting a substantial proportion of the world's population. Diabetes can predispose an individual to metabolic, cardiovascular disturbances and obesity, and these pathologies are accompanied by vascular complications [1]. Hyperglycaemia-induced damage to the endothelial cells results in micro-vascular complications of the diabetes such as diabetic neuropathy, nephropathy and retinopathy and macro-vascular complications such as cardiomyopathy [2]. Diabetic neuropathy remains the most severe form of complication affecting 40–50% of people with both types of diabetes. The clinical features of diabetic neuropathy range from sensory deficit to allodynia and hyperalgesia. Diabetic neuropathy arises from the long term effects of hyperglycaemia induced damage to peripheral nervous tissue as well as the vasa nervorum [3]. The current knowledge of pathophysiological mechanisms of hyperglycaemia-induced diabetic neuropathy is substantial and recent advances made in field could lead to the development of some novel therapeutic strategies targeted at advance glycation end products (AGE), sorbitol accumulation, protein kinase C (PKC) activation and hexosamine pathway. The axis of pathophysiological factors responsible for diabetes and diabetic neuropathy converge at two of the most extensively studied pathways, oxidative–nitrosative stress and neuroinflammation (Fig. 1). Molecular studies have revealed the involvement of transcriptional regulators such as Nrf2-Keap1 and the NF-κB inflammatory cascade in the pathophysiology of many diseases [4]. NF-κB has been shown to respond to the cellular redox status since a reducing environment prevents its activation whereas oxidative/nitrosative stress promotes phosphorylation and degradation of IκB [5]. Nrf2 increases intracellular GSH levels and GSH-dependent enzymes favouring a reducing environment thereby inhibiting NF-κB. Li et al. demonstrated that Nrf2-deficient mice exhibit greater induction of pro-inflammatory genes regulated by NF-κB such as interleukins, TNF-α, iNOS and COX-2 pointing towards the fact that Nrf2 deficiency enhances NF-κB-mediated pro-inflammatory reactions [6]. Soares et al. showed that HO-1 inhibited the TNF-α dependent activation of NF-κB in endothelial cells. It has been postulated that HO-1 induced by the Nrf2-EpRE interaction inhibits the NF-κB dependent transcriptional apparatus. Inhibition of NF-κB downstream of IκB phosphorylation/degradation and nuclear translocation has been hypothesized to be the site of action of HO-1 [11]. These data further support the concept that the Nrf2 directed increase in the expression of HO-1 is one of the hubs for cross-talk between Nrf2 and NF-κB (Figs. 2 and 3). Recent studies have shown that NF-κB suppresses the transcriptional activity of Nrf2. Liu et al. demonstrated that NF-κB p65 subunit repressed the beneficial effects of Nrf2 by promoting the localisation of transcription repressors, histone deacetylases with Nrf2/ARE and sequestering coactivators like CREB binding protein (CBP) [12]. Cells over-expressing NF-κB showed lesser expression of HO-1 which further confirms that NF-κB activation can act as a repressor of Nrf2 transcriptional activity. In a recent study, Yu et al. found that the N-terminal region of p65 subunit of NF-κB was physically associated with Keap1, and thus provide an additional mechanism for Nrf2–ARE inhibition. It was also suggested that NF-κB not only interacted with cytosolic Keap1 but also promoted nuclear translocation of Keap1 [13]. Previous studies with agents like curcumin [17], melatonin [18], resveratrol [19] and sulphoraphane [20] have reported beneficial effects in ameliorating various functional (motor nerve conduction velocity and nerve blood flow), sensorimotor (thermal and mechanical hyperalgesia) and biochemical deficits in experimental diabetic neuropathy (Fig. 4). These agents also suppressed the increased activity and levels of NF-κB and associated proteins and hence protected against neuroinflammation in diabetic neuropathy. As expected, treatment with these agents increased the levels of Nrf2 and HO-1 which further modulating the redox regulation of pro-inflammatory signalling pathways. Additional studies to find any common co-activators or co-repressors shared by these transcription factors and co-regulation by upstream and downstream signalling in these cascades will enable a better appreciation of the crosstalk between these two transcription factors in diabetic neuropathy. In summary, Nrf2 and NF-κB individually affect many signalling cascades to maintain a redox homeostasis; additionally they interact with each other to further modulate level of key redox modulators in health and disease. Studies with specific agents that might regulate the crosstalk between the two central pleiotropic transcription factors, Nrf2 and NF-κB, may be one of the prospective strategies that might aid in finding newer therapeutic choices for prevention and treatment of diabetic neuropathy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Total antioxidant capacity of teas by the ferric reducing/antioxidant power assay.

              This study aimed to compare in vitro antioxidant power of different types of tea (Camellia sinensis). The ferric reducing/antioxidant power (FRAP) assay was used to measure the total antioxidant power of freshly prepared infusions of 25 types of teas. Results showed that different teas had widely different in vitro antioxidant power and that the antioxidant capacity was strongly correlated (r = 0. 956) with the total phenolics content of the tea. Expressed as micromol of antioxidant power/g of dried tea leaves, values ranged as 132-654 micromol/g for black ("fermented") teas, 233-532 micromol/g for Oolong ("semifermented") teas, and 272-1144 micromol/g for green ("nonfermented") teas. One cup of tea of usual strength (1-2%), therefore, can provide the same potential for improving antioxidant status as around 150 mg of pure ascorbic acid (vitamin C).
                Bookmark

                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                19 November 2019
                2019
                : 12
                : 3147-3159
                Affiliations
                [1 ]Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences , Hamadan, Iran
                [2 ]Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences , Hamadan, Iran
                [3 ]Modeling of Noncommunicable Diseases Research Center, School of Public Health, Hamadan University of Medical Sciences , Hamadan, Iran
                [4 ]Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences , Shiraz, Iran
                Author notes
                Correspondence: Maryam Mehrpooya Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences , Shahid Fahmideh Ave, Hamadan6517838678, IranTel +98813821868Fax +988138381591 Email m_mehrpooya2003@yahoo.com
                Author information
                http://orcid.org/0000-0002-1232-6003
                http://orcid.org/0000-0001-7521-4909
                http://orcid.org/0000-0002-0038-1494
                http://orcid.org/0000-0003-4119-1600
                Article
                228255
                10.2147/JPR.S228255
                6875491
                32146360-0594-431d-9ebe-eddd9dd2da1a
                © 2019 Heidari et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 22 August 2019
                : 01 November 2019
                Page count
                Figures: 3, Tables: 4, References: 73, Pages: 13
                Categories
                Original Research

                Anesthesiology & Pain management
                painful diabetic neuropathy,oxidative stress,n-acetylcysteine,pregabalin

                Comments

                Comment on this article