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Bonetti M, Frigerio M, Ottaviani GM, Pellicanò G, Zambello A, Muto M, Carinci F, Maffezzoni F. Effective Management of Chronic Low Back Pain in the Elderly: A One-Year Cohort Study of Oxygen-Ozone Therapy Under CT Guidance Combined with Alpha Lipoic Acid, Palmitoylethanolamide, and Myrrh. Biomedicines 2025; 13:1250. [PMID: 40427076 PMCID: PMC12109079 DOI: 10.3390/biomedicines13051250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/15/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
Background and Objective: This observational study aimed to evaluate the clinical efficacy of combined oxygen-ozone (O2-O3) therapy under CT guidance with the oral administration of alpha-lipoic acid (ALA), palmitoylethanolamine (PEA), and myrrh in elderly patients suffering from chronic low back pain (LBP). Given the rising prevalence of degenerative spinal diseases in older adults, this study addresses the need for effective, minimally invasive treatment options. Methods: A total of 276 patients aged 65 to 92 years, with chronic unilateral or bilateral LBP, underwent CT-guided paravertebral infiltrations with an O2-O3 gas mixture. This treatment was complemented with a 30-day regimen of ALA (800 mg/day), PEA (600 mg/day), and myrrh (200 mg/day). Clinical outcomes were assessed at one month and one year post-treatment using the Visual Analog Scale (VAS) and the modified McNab method. Results: At one month, 32.94% of patients reported an excellent improvement, with the mean VAS score dropping from 8.17 to 2.81. At the one-year follow-up, 68.15% cumulatively experienced positive outcomes, with 17.78% reporting the complete resolution of pain. In this occasion, the mean VAS score was 3.57. Conclusions: The study demonstrates that the combination of oxygen-ozone therapy and oral ALA, PEA, and myrrh is a promising alternative for managing chronic low back pain in the elderly, leading to significant pain reduction and improved quality of life. Findings emphasize the need for further research to validate these results and explore the long-term benefits.
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Affiliation(s)
- Matteo Bonetti
- Department of Neuroradiology, Istituto Clinico Città di Brescia Hospital, Via Bartolomeo Gualla 15, 25128 Brescia, Italy
| | - Michele Frigerio
- Department of Neuroradiology, Istituto Clinico Città di Brescia Hospital, Via Bartolomeo Gualla 15, 25128 Brescia, Italy
| | - Gian Maria Ottaviani
- Department of Emergency, Spedali Civili di Brescia Hospital, Piazzale Spedali Civili 1, 25123 Brescia, Italy
| | - Giannantonio Pellicanò
- Department of Neuroradiology, Careggi University Hospital—Azienda Ospedaliera Universitaria Careggi, Largo Giovanni Alessandro Brambilla 3, 50134 Florence, Italy
| | - Alessio Zambello
- Department of Anesthesia and Pain Therapy, Casa di Cura Borghi Hospital, Via Francesco Petrarca 33, 21020 Brebbia, Italy
| | - Mario Muto
- Department of Neuroradiology, Cardarelli Hospital, Via Antonio Cardarelli 9, 80131 Naples, Italy
| | - Francesco Carinci
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Federico Maffezzoni
- Poliambulatorio Specialistico Oberdan, Via Guglielmo Oberdan 126, 25128 Brescia, Italy;
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Arthur P, Kalvala AK, Surapaneni SK, Singh MS. Applications of Cannabinoids in Neuropathic Pain: An Updated Review. Crit Rev Ther Drug Carrier Syst 2024; 41:1-33. [PMID: 37824417 PMCID: PMC11228808 DOI: 10.1615/critrevtherdrugcarriersyst.2022038592] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.
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Affiliation(s)
- Peggy Arthur
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA
| | - Anil Kumar Kalvala
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA
| | - Sunil Kumar Surapaneni
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA
| | - Mandip Sachdeva Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA
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Jang HN, Oh TJ. Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy. Diabetes Metab J 2023; 47:743-756. [PMID: 37670573 PMCID: PMC10695723 DOI: 10.4093/dmj.2023.0018] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/28/2023] [Indexed: 09/07/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%-25% of patients with diabetes experience neuropathic pain, referred to as "painful DPN." Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.
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Affiliation(s)
- Han Na Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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Gilron I, Robb S, Tu D, Holden RR, Milev R, Towheed T. Combination analgesic development for enhanced clinical efficacy (the CADENCE trial): a double-blind, controlled trial of an alpha-lipoic acid-pregabalin combination for fibromyalgia pain. Pain 2023; 164:1783-1792. [PMID: 36877492 DOI: 10.1097/j.pain.0000000000002875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/13/2023] [Indexed: 03/07/2023]
Abstract
ABSTRACT Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different ( P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.
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Affiliation(s)
- Ian Gilron
- Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
- School of Policy Studies, Queen's University, Kingston, ON, Canada
- Providence Care Hospital, Queen's University, Kingston, ON, Canada
| | - Sylvia Robb
- Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada
| | - Dongsheng Tu
- Departments of Public Health Sciences and Mathematics & Statistics, Queen's University, Kingston, ON, Canada
| | - Ronald R Holden
- Departments of Psychology, Queen's University, Kingston, ON, Canada
| | - Roumen Milev
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
- Departments of Psychology, Queen's University, Kingston, ON, Canada
- Departments of Psychiatry, Queen's University, Kingston, ON, Canada
- Providence Care Hospital, Queen's University, Kingston, ON, Canada
| | - Tanveer Towheed
- Division of Rheumatology, Department of Medicine, Queen's University, Kingston, ON, Canada
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Sharma A, Behl T, Sharma L, Shah OP, Yadav S, Sachdeva M, Rashid S, Bungau SG, Bustea C. Exploring the molecular pathways and therapeutic implications of angiogenesis in neuropathic pain. Biomed Pharmacother 2023; 162:114693. [PMID: 37062217 DOI: 10.1016/j.biopha.2023.114693] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/26/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023] Open
Abstract
Recently, much attention has been paid to chronic neuro-inflammatory condition underlying neuropathic pain. It is generally linked with thermal hyperalgesia and tactile allodynia. It results due to injury or infection in the nervous system. The neuropathic pain spectrum covers a variety of pathophysiological states, mostly involved are ischemic injury viral infections associated neuropathies, chemotherapy-induced peripheral neuropathies, autoimmune disorders, traumatic origin, hereditary neuropathies, inflammatory disorders, and channelopathies. In CNS, angiogenesis is evident in inflammation of neurons and pain in bone cancer. The role of chemokines and cytokines is dualistic; their aggressive secretion produces detrimental effects, leading to neuropathic pain. However, whether the angiogenesis contributes and exists in neuropathic pain remains doubtful. In the present review, we elucidated summary of diverse mechanisms of neuropathic pain associated with angiogenesis. Moreover, an overview of multiple targets that have provided insights on the VEGF signaling, signaling through Tie-1 and Tie-2 receptor, erythropoietin pathway promoting axonal growth are also discussed. Because angiogenesis as a result of these signaling, results in inflammation, we focused on the mechanisms of neuropathic pain. These factors are mainly responsible for the activation of post-traumatic regeneration of the PNS and CNS. Furthermore, we also reviewed synthetic and herbal treatments targeting angiogenesis in neuropathic pain.
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Affiliation(s)
- Aditi Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Tapan Behl
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, 248007 Dehradun, Uttarakhand, India.
| | - Lalit Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Om Prakash Shah
- School of Pharmaceutical Sciences, Shoolini University, Solan 173211, Himachal Pradesh, India
| | - Shivam Yadav
- Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Chhatrapati Shahu ji Maharaj University, Kanpur 208024, Uttar Pradesh, India
| | - Monika Sachdeva
- Fatima College of Health Sciences, Al Ain 00000, United Arab Emirates
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410028, Romania; Doctoral School of Biomedical Sciences, University of Oradea, Oradea 410028, Romania.
| | - Cristiana Bustea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410073, Romania
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Yuan M, Sano H, Nishino T, Chen H, Li RS, Matsuo Y, Nishida K, Koga T, Takeda T, Tanaka Y, Ishii Y. α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism. Biochem Pharmacol 2023; 210:115490. [PMID: 36893816 DOI: 10.1016/j.bcp.2023.115490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023]
Abstract
Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.
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Affiliation(s)
- Ming Yuan
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hiroe Sano
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Takaaki Nishino
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hongbin Chen
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Ren-Shi Li
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, PR China
| | - Yuki Matsuo
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kyoko Nishida
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Takayuki Koga
- Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan
| | - Tomoki Takeda
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan
| | - Yoshitaka Tanaka
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yuji Ishii
- Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Cross W, Srivastava S. A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus. J Pain Res 2023; 16:1115-1126. [PMID: 37020664 PMCID: PMC10069439 DOI: 10.2147/jpr.s397777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/01/2023] [Indexed: 03/31/2023] Open
Abstract
Background The primary objective of the present study was to evaluate the effects of a Nerve Support Formula NeuropAWAY® on diabetic neuropathic pain. Methods This double-blind, placebo-controlled, randomized trial was conducted between August 2020 and February 2021. Patients aged ≥40 and ≤65 years with a history of type 2 diabetes (T2D) with a confirmed diagnosis of diabetic neuropathic pain were included in the study. The primary efficacy endpoint was to assess the effect of the 42 days administration of the Nerve Support Formula on the neuropathic pain as assessed by the 11 point Pain Intensity Numeric Rating Scale (PI-NRS). The secondary objectives were to assess the effect on plasma vitamin B12 levels, nerve conduction velocity, blood flow velocity, Brief Pain Inventory, Neuropathy Total Symptom Score, and Insomnia Severity Index. Results The enrolled study population (n=59) was randomized in two study groups; the Investigational Product (IP) group - Nerve Support Formula (n=27) and placebo group (n=32). The mean age of these participants was 52.63 and 53.72 for IP and placebo group, respectively. The mean (SD) HbA1c levels for IP and placebo group were 8.37 (0.85) and 8.16 (0.86), respectively. By the end of the study (Day 42) the decrease in PI-NRS scores for the IP group was maximal (↓61.32%) and highly significant (p<0.001) in comparison to the placebo group (↑2.47%). Significant improvements (p<0.05) were also noted in the secondary efficacy variables after 42 days of IP intake. Conclusion The formula was found to be significantly effective as compared to placebo in reducing pain and other sensory symptoms related to the diabetic peripheral neuropathy.
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New Approach to Chronic Back Pain Treatment: A Case Control Study. Biomedicines 2022; 11:biomedicines11010073. [PMID: 36672581 PMCID: PMC9855610 DOI: 10.3390/biomedicines11010073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/01/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Our study compares the clinical outcome of chronic low back pain present for over six months treated with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh and periradicular infiltrations of oxygen-ozone under CT guide to periradicular steroidal infiltrations in a short (one week), medium (three months) and long-term period (six months). METHODS We enrolled 246 patients (Group A) with low back pain treated with periradicular infiltrations of oxygen-ozone under CT guide combined with 800 mg/day of ALA + 600 mg/day of PEA + 200 mg/day of myrrh orally. Group B consisted of 176 patients with low back pain treated with periradicular infiltrations of steroids. Patients were clinically monitored one week after the end of treatment, at three months, and at six months using a modified version of McNab's method. RESULTS In Group A, the one-week clinical follow-up registered a complete remission of painful symptoms in 206 patients (83.7%), and this manifestation remained optimal in 191 patients at the three-month follow-up (77.6%) and in 178 at six months (72.3%). While the results were satisfactory in 28 patients (10.9%) at one week, 32 (13%) in the medium term, and 41 (16.6%) in the long term, non-significant results were found in 12 patients in the control at one week (4.6%), in 23 at three months (9.3%) and in 27 at six months (10.9%). In Group B, at the short-term follow-up we obtained an excellent clinical result in 103 patients (80.5%), while at three months 85 patients reported the persistence of clinical benefit (66.4%) and at six months, 72 (56.2%) reported the same result. The result was rated satisfactory in 11 (8.5%) and poor in 4 (3%). At the three-month follow-up, 23 (18%) reported a satisfactory result, and 20 (15.6%) had a poor result. At six months, 24 (18.8%) reported the persistence of a satisfactory result while for 32 the result was poor (25%). CONCLUSION The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh can be considered a valid alternative to common therapeutic approaches in the treatment of chronic low back pain.
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Capece U, Moffa S, Improta I, Di Giuseppe G, Nista EC, Cefalo CMA, Cinti F, Pontecorvi A, Gasbarrini A, Giaccari A, Mezza T. Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features. Nutrients 2022; 15:nu15010018. [PMID: 36615676 PMCID: PMC9824456 DOI: 10.3390/nu15010018] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.
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Affiliation(s)
- Umberto Capece
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Simona Moffa
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ilaria Improta
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Enrico Celestino Nista
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Chiara M. A. Cefalo
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Cinti
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Andrea Giaccari
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
| | - Teresa Mezza
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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Jadhav VB, Vaghela JS. Sphaeranthus indicus Linn ameliorates streptozotocin-induced experimental diabetic neuropathy by targeting oxidative stress-mediated alterations. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00444-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Abstract
Background
Diabetes-induced neuropathic pain is manifested as a lowering of nerve transmission rate, increased discomfort, sensual loss, and axonal degradation, and is the most prevalent secondary consequence of diabetes. Diabetes is a devitalizing disease affecting people from diverse groups in both developing and industrialized countries. The inflammation pathway and oxidative stress both contribute considerably to diabetic peripheral neuropathy via the activation of inflammatory cytokines. Hyperglycemia-mediated neural oxidative stress and damage activates a number of metabolic pathways, causing diabetic neuropathy. The current study investigated the neuroprotective potential of methanolic extract of Sphaeranthus indicus Linn (MESI) in ameliorating diabetic neuropathic pain induced by administration of streptozotocin in rats.
Results
Four weeks after intraperitoneal treatment of streptozotocin (STZ), there was a significant decrease in mechano-tactile allodynia and mechanical and thermal hyperalgesia. Furthermore, STZ-induced oxidative stress increases the extent of neural lipid peroxidation (LPO), as evidenced by increased MDA levels, decreases the activities of endogenous antioxidants such as superoxide dismutase (SOD) and glutathione (GSH), and alters sciatic neural histoarchitecture. Chronic administration of methanolic extract of Sphaeranthus indicus Linn (MESI) for 4 weeks significantly and dose-dependently attenuated the decrease in levels of nociceptive thresholds, endogenous antioxidants (SOD and GSH), and increase in LPO. Furthermore, MESI significantly restored sciatic neural histoarchitecture.
Conclusion
The amelioration of streptozotocin-induced diabetic neuropathy by methanolic extract of Sphaeranthus indicus Linn (MESI) could be attributed to its antinociceptive, antioxidant, and neuroprotective properties.
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Managing Chronic Neuropathic Pain: Recent Advances and New Challenges. Neurol Res Int 2022; 2022:8336561. [PMID: 36277331 PMCID: PMC9581623 DOI: 10.1155/2022/8336561] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/03/2022] [Accepted: 08/07/2022] [Indexed: 11/17/2022] Open
Abstract
Aim. Neuropathic pain affects 7–10% of the population, with most of the patients receiving inadequate and incomplete treatment. Owing to the high financial burden and the poor quality of life of the patients and their caretakers, there is a dire need to address the challenges in diagnosing and treating chronic neuropathic pain. Methods. This literature review was conducted to review novel treatments and related challenges through a systematic search from sources such as PubMed, Google Scholar with the combination of MESH words such as neuropathic pain, management of neuropathic pain. Articles from non-English literature, reports without human subjects, animal studies, and abstracts/posters were excluded. However, human studies and studies published in English were included. Result. This review article discusses novel treatment modalities while acknowledging the challenges medical workers face while encountering neuropathic pain. Despite the recent advances in diagnosis and treatment modalities, several challenges still exist. Hence, there is still a need to explore the various treatment modalities, emphasizing the cause and underlying pathophysiology of neuropathic pain. Conclusion. We recommend integrated multimodal treatment with the current treatment facility, including various medical disciplines. However, a personalized approach would work the best depending on the ’patient’s medical history. Therefore, this article recommends an integrated, cause-specific, cost-effective approach to address this problem of chronic neuropathic pain.
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12
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Oxygen-Ozone Therapy Associated with Alpha Lipoic Acid Plus Palmitoylethanolamide and Myrrh versus Ozone Therapy in the Combined Treatment of Sciatic Pain Due to Herniated Discs: Observational Study on 318 Patients. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19095716. [PMID: 35565111 PMCID: PMC9100908 DOI: 10.3390/ijerph19095716] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/05/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND The aim of our observational study is to compare the therapeutic efficacy of combined treatment of oxygen-ozone therapy and oral treatment with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh in patients with peripheral neuropathic pain (sciatica) on radicular disc conflict from disc herniation and the results obtained with oxygen-ozone treatment alone. METHODS We enrolled 318 patients with the neuroradiological diagnosis of disc herniation performed with computed tomography (CT) or magnetic resonance imaging (MRI) and symptoms characterized by low back pain complicated by sciatica, which we divided into two groups. Group A was composed of 165 patients who were treated only with oxygen-ozone therapy with CT-guided intraforaminal technique, while the remaining 153 (Group B) have undergone combined oral treatment with ALA + PEA and myrrh. Follow-up visits for the evaluation of the clinical outcome of the treatment were conducted after 60 ± 8 days using a modified version of McNab's method. RESULTS At the clinical check-up, 126/165 patients included in Group A had a complete remission of pain (76.4%), while in Group B, 119/153 (77.8%) had a complete remission of pain. CONCLUSION The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh is preferred over the simple treatment with only ozone in such patients in the phase of greatest acuity of the disease, where the pain appears to be better controlled.
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13
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Córdova-Martínez A, Caballero-García A, Pérez-Valdecantos D, Roche E, Noriega-González DC. Peripheral Neuropathies Derived from COVID-19: New Perspectives for Treatment. Biomedicines 2022; 10:1051. [PMID: 35625788 PMCID: PMC9138404 DOI: 10.3390/biomedicines10051051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/26/2022] [Accepted: 04/30/2022] [Indexed: 12/15/2022] Open
Abstract
Peripheral neuropathies constitute a group of disorders affecting the peripheral nervous system. Neuropathies have multiple causes such as infections (i.e., COVID-19), diabetes, and nutritional (low vitamin levels), among others. Many micronutrients, such as vitamins (A, C, D, E, B6, B12, and folate), certain minerals (Fe, Mg, Zn, Se, and Cu), and ω-3 fatty acids have immunomodulatory effects. Therefore, they may play an instrumental role in the treatment of COVID-19 infection. However, many COVID-19 patients can undergo neuropathy. In this context, there is a wealth of information on a variety of first-, second-, and third-line treatment options. This review focuses on the application of nutraceutical strategies in order to improve the symptomatology of neuropathy and neuropathic pain in patients that suffered from COVID-19. Our aim is to provide an alternative vision to traditional medical-pharmacological treatment through nutraceuticals.
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Affiliation(s)
- Alfredo Córdova-Martínez
- Department of Biochemistry, Molecular Biology and Physiology, Faculty of Health Sciences, GIR Physical Exercise and Aging, University of Valladolid, Campus Duques de Soria, 42004 Soria, Spain;
| | - Alberto Caballero-García
- Department of Anatomy and Radiology, Faculty of Health Sciences, GIR Physical Exercise and Aging, University of Valladolid, Campus Duques de Soria, 42004 Soria, Spain;
| | - Daniel Pérez-Valdecantos
- Department of Biochemistry, Molecular Biology and Physiology, Faculty of Health Sciences, GIR Physical Exercise and Aging, University of Valladolid, Campus Duques de Soria, 42004 Soria, Spain;
| | - Enrique Roche
- Department of Applied Biology-Nutrition, Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain;
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - David César Noriega-González
- Department of Surgery, Ophthalmology, Otorhinolaryngology and Physiotherapy, Faculty of Medicine, Hospital Clínico Universitario de Valladolid, 47005 Valladolid, Spain;
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14
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Derosa G, D’Angelo A, Preti PS, Maffioli P. Evaluation of the Effect on Sexual Performance of a Nutraceutical Combination Containing Alpha Lipoic Acid, Vitis vinifera L. and Ginkgo biloba, Compared to Placebo, Avanafil or a Combination of Nutraceutical Plus Avanafil in Males With Type 2 Diabetes Mellitus With Erectile Dysfunction. Front Endocrinol (Lausanne) 2022; 13:847240. [PMID: 35464055 PMCID: PMC9022207 DOI: 10.3389/fendo.2022.847240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 02/25/2022] [Indexed: 01/28/2023] Open
Abstract
AIM To evaluate if therapy with a nutraceutical combination of alpha lipoic acid, Vitis vinifera L. and Ginkgo biloba (Blunorm forte®) can be helpful and be synergic with Avanafil. METHODS The trial included 123 males with type 2 diabetic mellitus and with erectile dysfunction (ED), aged ≥18 years. Patients were divided in four different arms: 1st arm: placebo during the three months of treatment and before sexual act; 2nd arm: placebo for three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 3rd arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast) during the three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 4th arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast and dinner) during the three months and placebo 15-30 minutes before sexual act. RESULTS A significant reduction of fasting plasma glucose, and homeostasis model assessment-insulin resistance index were recorded both in Avanafil + Blunorm forte and with Blunorm forte. Metalloproteinases-2, and -9 were reduced in the Avanafil + Blunorm forte group. High sensitivity-C-reactive protein was decreased by both Avanafil, and Avanafil + Blunorm forte group. No variations were recorded with the other treatments. The group treated with Blunorm forte and Avanafil reached a higher International Index of Erectile Function (IIEF) score after 3 months of therapy compared to baseline and placebo and compared to Avanafil and Blunorm forte taken alone. CONCLUSION Blunorm forte® can be helpful and synergic with Avanafil in increasing sexual performance compared to placebo.
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Affiliation(s)
- Giuseppe Derosa
- Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- *Correspondence: Giuseppe Derosa,
| | - Angela D’Angelo
- Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Paola Stefania Preti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Pamela Maffioli
- Centre of Diabetes and Metabolic Diseases, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
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15
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Vakali E, Rigopoulos D, Carrillo AE, Flouris AD, Dinas PC. Effects of Alpha-lipoic Acid Supplementation on Human Diabetic Nephropathy: A Systematic Review and Meta-analysis. Curr Diabetes Rev 2022; 18:e140921196457. [PMID: 34521329 DOI: 10.2174/1573399817666210914103329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is kidney dysfunction, which occurs due to elevated urine albumin excretion rate and reduced glomerular filtration rate. Studies on animals have shown that alpha-lipoic acid (ALA) supplementation can reduce the development of DN. OBJECTIVES We performed a systematic review and meta-analysis to examine the effects of ALA supplementation on biological indices (albumin, creatinine, etc.) indicative of human DN. METHODS The search procedure included PubMed Central, Embase, Cochrane Library (trials), and Web of Science (protocol registration: INPLASY202060095). RESULTS We found that ALA supplementation decreased 24h urine albumin excretion rate in patients with diabetes (standardized mean difference=-2.27; confidence interval (CI)=(-4.09)-(-0.45); I2=98%; Z=2.44; p=0.01). A subgroup analysis revealed that the results of studies examining only ALA did not differ from those examined ALA in combination with additional medicines (Chisquared= 0.19; p=0.66; I2=0%), while neither ALA nor ALA plus medication had an effect on 24h urine albumin excretion rate (p>0.05). Also, ALA supplementation decreased urine albumin mg/l (mean difference (MD)=-12.95; CI=(-23.88)-(-2.02); I2=44%; Z=2.32; p=0.02) and urine albumin to creatinine ratio (MD=-26.96; CI=(-35.25)-(-18.67); I2=0%; Z=6.37; p<0.01) in patients with diabetes. When the studies examining ALA plus medication were excluded, it was found that ALA supplementation had no effect on urine albumin mg/l (p>0.05) but did significantly decrease urine albumin to creatinine ratio (MD=-25.88, CI=(34.40-(-17.36), I2=0%, Z=5.95, p<0.00001). CONCLUSION The available evidence suggests that ALA supplementation does not improve biological indices that reflect DN in humans. Overall, we identified limited evidence, and therefore, the outcomes should be considered with caution.
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Affiliation(s)
- Elena Vakali
- Medical School, National and Kapodistrian University of Athens, Athens, GR11527, Greece
| | - Dimitrios Rigopoulos
- FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, GR42100, Greece
| | - Andres E Carrillo
- FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, GR42100, Greece
- Department of Exercise Science, Chatham University, Pittsburgh, PA15232, USA
| | - Andreas D Flouris
- FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, GR42100, Greece
| | - Petros C Dinas
- FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, GR42100, Greece
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16
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Neerati P, Prathapagiri H. Alpha lipoic acid attenuated neuropathic pain induced by chronic constriction Injury of sciatic nerve in rats. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-021-00263-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Abstract
Background
Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard.
Methodology
The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies.
Results
ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect.
Conclusion
Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.
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17
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Dragomanova S, Miteva S, Nicoletti F, Mangano K, Fagone P, Pricoco S, Staykov H, Tancheva L. Therapeutic Potential of Alpha-Lipoic Acid in Viral Infections, including COVID-19. Antioxidants (Basel) 2021; 10:1294. [PMID: 34439542 PMCID: PMC8389191 DOI: 10.3390/antiox10081294] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/20/2022] Open
Abstract
Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, is thought to play an important pathogenetic role in several diseases, including viral infections. Alpha-lipoic acid (LA) is one of the most-studied and used natural compounds, as it is endowed with a well-defined antioxidant and immunomodulatory profile. Owing to these properties, LA has been tested in several chronic immunoinflammatory conditions, such as diabetic neuropathy and metabolic syndrome. In addition, a pharmacological antiviral profile of LA is emerging, that has attracted attention on the possible use of this compound for the cotreatment of several viral infections. Here, we will review the emerging literature on the potential use of LA in viral infections, including COVID-19.
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Affiliation(s)
- Stela Dragomanova
- Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University, 9002 Varna, Bulgaria;
| | - Simona Miteva
- Department of Behavior Neurobiology, Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (S.M.); (L.T.)
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy; (K.M.); (P.F.); (S.P.)
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy; (K.M.); (P.F.); (S.P.)
| | - Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy; (K.M.); (P.F.); (S.P.)
| | - Salvatore Pricoco
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy; (K.M.); (P.F.); (S.P.)
| | - Hristian Staykov
- Department of Pharmacology and toxicology, Medical University, Sofia, 2, Zdrave Str., 1431 Sofia, Bulgaria;
| | - Lyubka Tancheva
- Department of Behavior Neurobiology, Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (S.M.); (L.T.)
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18
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Agnes JP, Santos VWD, das Neves RN, Gonçalves RM, Delgobo M, Girardi CS, Lückemeyer DD, Ferreira MDA, Macedo-Júnior SJ, Lopes SC, Spiller F, Gelain DP, Moreira JCF, Prediger RD, Ferreira J, Zanotto-Filho A. Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation. THE JOURNAL OF PAIN 2021; 22:996-1013. [PMID: 33774154 DOI: 10.1016/j.jpain.2021.03.142] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/25/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022]
Abstract
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.
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Affiliation(s)
- Jonathan Paulo Agnes
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Vitória Wibbelt Dos Santos
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Raquel Nascimento das Neves
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Rosângela Mayer Gonçalves
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Marina Delgobo
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Carolina Saibro Girardi
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Débora Denardin Lückemeyer
- Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Marcella de Amorim Ferreira
- Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Sérgio José Macedo-Júnior
- Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Samantha Cristiane Lopes
- Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Fernando Spiller
- Laboratório de Imunobiologia (Lidi), Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Daniel Pens Gelain
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - José Cláudio Fonseca Moreira
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Rui Daniel Prediger
- Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Juliano Ferreira
- Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
| | - Alfeu Zanotto-Filho
- Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.
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19
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Bondar A, Popa AR, Papanas N, Popoviciu M, Vesa CM, Sabau M, Daina C, Stoica RA, Katsiki N, Stoian AP. Diabetic neuropathy: A narrative review of risk factors, classification, screening and current pathogenic treatment options (Review). Exp Ther Med 2021; 22:690. [PMID: 33986855 PMCID: PMC8111877 DOI: 10.3892/etm.2021.10122] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetic neuropathy (DN) is a frequent complication of diabetes mellitus (DM) with severe consequences as it progresses and influences all human body systems. This review discusses the risk factors for DN, the main characteristics of the clinical forms of DN, the screening methods and the current therapeutic options. Distal symmetric DN is the primary clinical form, and DM patients should be screened for this complication. The most important treatment of DN remains good glucose control, generally defined as HbA1c ≤7%. Symptomatic treatment improves life quality in diabetic patients. Pharmacological agents such as alpha (α)-lipoic acid and benfotiamine have been validated in several studies since they act on specific pathways such as increased oxidative stress (α-lipoic acid exerts antioxidant effects) and the excessive production of advanced glycosylation products (benfotiamine may inhibit their production via the normalization of glucose). Timely diagnosis of DN is significant to avoid several complications, including lower limb amputations and cardiac arrhythmias.
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Affiliation(s)
- Andrei Bondar
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Amorin Remus Popa
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Nikolaos Papanas
- Second Department of Internal Medicine, ‘Democritus’ University of Thrace Diabetes Centre, 68100 Alexandroupolis, Greece
| | - Mihaela Popoviciu
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Cosmin Mihai Vesa
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Monica Sabau
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Cristian Daina
- Department of Psychiatry, Clinical County Emergency Hospital of Oradea, 410169 Oradea, Romania
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Roxana Adriana Stoica
- Department of Diabetes, Nutrition and Metabolic Diseases, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Niki Katsiki
- Second Propaedeutic Department of Internal Medicine, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
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20
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Kale MB, Bajaj K, Umare M, Wankhede NL, Taksande BG, Umekar MJ, Upaganlawar A. Exercise and Nutraceuticals: Eminent approach for Diabetic Neuropathy. Curr Mol Pharmacol 2021; 15:108-128. [PMID: 34191703 DOI: 10.2174/1874467214666210629123010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal-based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, use of herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health and has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including herbal and nutraceuticals therapy is also beneficial for the condition. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.
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Affiliation(s)
- Mayur Bhimrao Kale
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Komal Bajaj
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Mohit Umare
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Nitu L Wankhede
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | | | - Milind Janrao Umekar
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Aman Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad-42310, Nasik, Maharashtra, India
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Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9940169. [PMID: 34093722 PMCID: PMC8137294 DOI: 10.1155/2021/9940169] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.
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Elbadawy AM, Abd Elmoniem RO, Elsayed AM. Alpha lipoic acid and diabetes mellitus: potential effects on peripheral neuropathy and different metabolic parameters. ALEXANDRIA JOURNAL OF MEDICINE 2021. [DOI: 10.1080/20905068.2021.1907961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Ben Y, Hao J, Zhang Z, Xiong Y, Zhang C, Chang Y, Yang F, Li H, Zhang T, Wang X, Xu Q. Astragaloside IV Inhibits Mitochondrial-Dependent Apoptosis of the Dorsal Root Ganglion in Diabetic Peripheral Neuropathy Rats Through Modulation of the SIRT1/p53 Signaling Pathway. Diabetes Metab Syndr Obes 2021; 14:1647-1661. [PMID: 33883914 PMCID: PMC8055373 DOI: 10.2147/dmso.s301068] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/12/2021] [Indexed: 12/21/2022] Open
Abstract
PURPOSE To investigate the effect of astragaloside IV (AS-IV) on mitochondrial-dependent apoptosis in the dorsal root ganglion of diabetic peripheral neuropathy (DPN) rats through the SIRT1/p53 pathway. METHODS Diabetic rat model was induced by high-carbohydrate/high-fat diet and intraperitoneal injection of STZ. Diabetic rats were divided into three groups (n =16 per group): DPN group, AS-IV group (60mg/kg/d) and α-lipoic acid (ALA) group (60mg/kg/d). Weight and blood glucose levels were monitored every 4 weeks for 12 weeks. DPN was evaluated using the Von Frey Filaments Test and nerve conduction velocity. The dorsal root ganglia of rats were isolated and the pathological changes of mitochondria were observed by electron microscopy. The activity of mitochondrial electron transport chain complex, mitochondrial membrane potential, malonaldehyde (MDA) and glutathione (GSH) levels were measured. Neural apoptosis was detected using the Terminal Deoxynucleotidyl Nick-End Labeling (TUNEL) assay kit. The cleaved caspase-3, major proteins in the SIRT1/p53 pathway, including SIRT1, acetyl p53, Drp1, BAX, and BCL-2, were detected using immunohistochemistry and Western blot. Gene expression of major proteins in the SIRT1/p53 pathway was also detected. RESULTS After 12 weeks of treatment, AS-IV and ALA did not significantly affect body weight or fasting glucose levels, but reduced mechanical abnormal pain in DPN and improved nerve conduction velocity. AS-IV and ALA increased the level of GSH and decreased the level of MDA. Both AS-IV and ALA can reduce mitochondrial damage, improve mitochondrial electron transport chain complex activity and mitochondrial membrane potential, and reduce the percentages of positive cells with DNA fragmentation and the expression of cleaved caspase-3 protein. AS-IV and ALA up-regulated the expression of SIRT1 and down-regulated the expression of acetyl-p53, Drp1 and the ratio of BAX to BCL-2. Changes in gene expression were similar. CONCLUSION AS-IV can reduce the occurrence of mitochondrial-dependent apoptosis by regulating the SIRT1/p53 pathway. It has a similar therapeutic effect as ALA and is therefore a promising drug for the potential treatment of DPN.
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Affiliation(s)
- Ying Ben
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Juan Hao
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Zhihong Zhang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Yunzhao Xiong
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Cuijuan Zhang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Yi Chang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Fan Yang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Hui Li
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Tianya Zhang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Xiangting Wang
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
| | - Qingyou Xu
- Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China
- Correspondence: Qingyou Xu Hebei University of Chinese Medicine, No. 326 Xinshinan Road, Qiaoxi District, Shijiazhuang, Hebei Province, 050090, People’s Republic of ChinaTel +86 13832368865Fax +86 311 89926000 Email
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Cai J, Chen J, Zeng Q, Liu J, Zhang Y, Cheng H, Yao S, Chen Q. Assessment of the efficacy of α-lipoic acid in treatment of diabetes mellitus patients with erectile dysfunction: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e22161. [PMID: 32899103 PMCID: PMC7478782 DOI: 10.1097/md.0000000000022161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Diabetes mellitus with erectile dysfunction (DMED) is one of the most common causes of disability in diabetic population, and its pathogenesis is related to a variety of factors. Because its pathogenesis is complex and the existing treatment methods have limitations, DMED is difficult to treat in clinical. Recently, some studies have shown that α-lipoic acid (ALA) is associated with DMED, but there is no systematic review and meta-analysis on the relationship between ALA and DMED. METHODS We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library, PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Simultaneously we will retrieve clinical registration tests and grey literatures. This study only screen the clinical randomized controlled trials (RCTs) about ALA for DMED to assess its efficacy. The 2 researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on whether or not heterogeneity exists. Erectile dysfunction (ED) will be diagnosed by the International Index of Erectile Function 5 (IIEF-5) score. Finally, meta-analysis was conducted by RevMan software version 5.3. RESULTS This study will synthesize and provide high quality to evaluate the effectiveness of ALA supplementation for the treatment of DMED. CONCLUSION This systematic review aims to provide new options for ALA supplementation treatment of DMED in terms of its efficacy and safety. PROSPERO REGISTRATION NUMBER INPLASY202070130.
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The Neuroprotective Role of Alpha Thioctic Acid and Vitamin B Complex in Diabetic Neuropathy - an Experimental Study. CURRENT HEALTH SCIENCES JOURNAL 2020; 46:150-155. [PMID: 32874687 PMCID: PMC7445648 DOI: 10.12865/chsj.46.02.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 05/26/2020] [Indexed: 11/18/2022]
Abstract
Worldwide, approximately 463 million people are estimated to suffer from a form of diabetes mellitus, with diabetic neuropathy being one of its most common complication. Using streptozotocin to induce diabetes in C57BL/6J mice, we assess the neuroprotective role of alpha thioctic acid and vitamin B complex in diabetic neuropathy. In order to highlight the peripheral nerve changes produced by diabetes, we performed an electroneurographic recording of the animals and compared the amplitude of the compound muscle action potential (CMAP). Treatment with alpha thioctic acid (A), or vitamin B complex (B), or A+B caused a smaller decrease in CMAP amplitude than if these therapies had not been applied. On the other hand, we found that in group A+B a smaller decrease of CMAP amplitude was observed compared to the control group (6 weeks after the onset of diabetes p<0.0001). Also, separate treatment with alpha thioctic acid alone caused a smaller decrease in CMAP amplitude compared to the control group (6 weeks after the onset of diabetes mellitus p<0.0436), but also separate treatment with vitamin B complex alone resulted in a smaller decrease of CMAP amplitude compared to the Control group (6 weeks after the onset of diabetes p<0.0070). The combined therapy with alpha thioctic acid and vitamin B complex has a greater effect in preventing axonal degeneration in diabetic neuropathy than the single therapy only with alpha thioctic acid or only with vitamin B complex.
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Won JC, Kwon HS, Moon SS, Chun SW, Kim CH, Park IB, Kim IJ, Lee J, Cha BY, Park TS. γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial. Diabetes Metab J 2020; 44:542-554. [PMID: 31701699 PMCID: PMC7453980 DOI: 10.4093/dmj.2019.0099] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/13/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN). METHODS This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS). RESULTS Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ₁=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ₂=0.054). There were no serious adverse events associated with the treatments. CONCLUSION GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.
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Affiliation(s)
- Jong Chul Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Cardiovascular and Metabolic Disease Center, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Hyuk Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seong Su Moon
- Department of Internal Medicine, Dongguk University College of Medicine, Gyeongju, Korea
| | - Sung Wan Chun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Chong Hwa Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Ie Byung Park
- Division of Endocrinology and Metabolism, Department of Internal Medicien, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - In Joo Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Jihyun Lee
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Bong Yun Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Tae Sun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.
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Naseri R, Farzaei F, Fakhri S, El-Senduny FF, Altouhamy M, Bahramsoltani R, Ebrahimi F, Rahimi R, Farzaei MH. Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective. Daru 2019; 27:781-798. [PMID: 31352568 PMCID: PMC6895369 DOI: 10.1007/s40199-019-00289-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/01/2019] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP. EVIDENCE ACQUISITION A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019. RESULTS DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP. CONCLUSION The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
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Affiliation(s)
- Rozita Naseri
- Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fardous F El-Senduny
- Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | - Miram Altouhamy
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Roodabeh Bahramsoltani
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Farnaz Ebrahimi
- Pharmacy students` research committee, School of pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roja Rahimi
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Effect of 3-month α-lipoic acid treatment on sural nerve conduction velocity and amplitude in patients with diabetic neuropathy: a pilot study. ACTA ACUST UNITED AC 2019; 4:e141-e143. [PMID: 31448345 PMCID: PMC6704764 DOI: 10.5114/amsad.2019.86750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 06/22/2019] [Indexed: 11/24/2022]
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Rowin J. Integrative neuromuscular medicine: Neuropathy and neuropathic pain: Consider the alternatives. Muscle Nerve 2019; 60:124-136. [DOI: 10.1002/mus.26510] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Julie Rowin
- Wellness and Integrative Neurology, Advanced Pain and Anesthesia ConsultantsCenters for Pain Management Westchester Illinois USA
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Polyphenols of marine red macroalga Symphyocladia latiuscula ameliorate diabetic peripheral neuropathy in experimental animals. Heliyon 2019; 5:e01781. [PMID: 31193485 PMCID: PMC6529741 DOI: 10.1016/j.heliyon.2019.e01781] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/24/2019] [Accepted: 05/17/2019] [Indexed: 12/29/2022] Open
Abstract
Aims Chronic hyperglycaemia activates the polyol pathway of glucose metabolism thereby stimulating the activation aldose reductase enzyme that in turn initiates a cascade of deleterious events, eventually, leading to nerve damage or neuropathy. Marine macroalgae and their isolated chemical constituents have been found to possess potential antidiabetic activity and have proved beneficial in the treatment of diabetes. In this study the neuroprotective effect of polyphenols isolated from the red macroalga Symphyocladia latiuscula was evaluated in experimental diabetic peripheral neuropathy. Main methods The polyphenolic fraction from Symphyocladia latiuscula was isolated. Diabetic peripheral neuropathy (DPN) was induced in animals by intraperitoneal injection of streptozotocin (45 mg/kg, b. w) and maintained for 6 weeks followed by treatment with SLPP or epalrestat. Nerve Conduction Velocity (NCV) and Compound Muscle Action Potential (CMAP) were measured using a non-invasive method followed by muscular grip strength test. Sciatic nerve aldose reductase activity, sorbitol accumulation, Na+K+-ATPase activity, production of pro-inflammatory cytokines and expression of AR and PKC were assessed. Key findings The Symphyocladia latiuscula polyphenols (SLPP) were found to inhibit aldose reductase activity as well as their expression in diabetic animals thereby improving the NCV, CMAP and muscle grip strength. Improvements in the sciatic nerve Na+K+-ATPase activity and intraneural accumulation of sorbitol, an index of aldose reductase overactivity, were evident with SLPP treatment. The production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and expression of protein kinase C (PKC) were also diminished. Significance The data suggest that the polyphenols of Symphyocladia latiuscula have neuroprotective potential against experimental DPN.
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Wang G, Yang B, Fu Z, Wang X, Zhang Z. Efficacy and safety of oxaliplatin-based regimen versus cisplatin-based regimen in the treatment of gastric cancer: a meta-analysis of randomized controlled trials. Int J Clin Oncol 2019; 24:614-623. [PMID: 30919257 DOI: 10.1007/s10147-019-01425-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 03/01/2019] [Indexed: 01/14/2023]
Abstract
BACKGROUND Cisplatin played an important role in the treatment of gastric cancer (GC). Oxaliplatin has been shown to be at least as effective as cisplatin for GC, with less toxicity and a better tolerability profile. We performed a meta-analysis to compare the efficacy and safety of oxaliplatin-based regimen versus cisplatin-based regimen in the treatment of GC. METHODS Databases of CNKI, CBM, VIP, Wanfang, PubMed, Embase, Cochrane Library were searched for eligible literatures from their establishments to November 2018. Randomized controlled trials that compared the efficacy and safety of oxaliplatin-based regimen with that of cisplatin-based regimen in the treatment of GC were included. Statistical analyses were calculated using RevMan 5.3 software. RESULTS Seven randomized controlled trials including 2297 patients were included. Compared with cisplatin-based regimen intervention in GC, oxaliplatin-based regimen treatment was able to significantly improve the partial response rate (OR = 1.26, 95% CI 1.07-1.49; p = 0.007), disease progression rate (OR = 0.41, 95% CI 0.25-0.66; p = 0.0002) and 1-year survival (OR = 1.25, 95% CI 1.00-1.56; p = 0.05). The toxicities of hematopoietic system were significantly higher in cisplatin-based regimen group (OR = 0.6, 95% CI 0.46-0.79; p = 0.0002), while oxaliplatin-based regimen group had higher neurosensory toxicity (OR = 2.21, 95% CI 1.52-3.21; p < 0.0001), In addition, gastrointestinal toxicity was similar between the two groups (OR = 1.01, 95% CI 0.5-2.01; p = 0.27). CONCLUSIONS Compared with cisplatin-based regimen, oxaliplatin-based regimen treatment has an obvious advantage in patients with GC with acceptable tolerance.
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Affiliation(s)
- Gongchen Wang
- Affiliated Hospital of Gansu University of Chinese Medicine, 732 West Jiayuguan Road, Chengguan District, Lanzhou, 730000, Gansu, China
| | - Binfeng Yang
- Affiliated Hospital of Gansu University of Chinese Medicine, 732 West Jiayuguan Road, Chengguan District, Lanzhou, 730000, Gansu, China
| | - Zhaoyuan Fu
- Affiliated Hospital of Gansu University of Chinese Medicine, 732 West Jiayuguan Road, Chengguan District, Lanzhou, 730000, Gansu, China
| | - Xin Wang
- Affiliated Hospital of Gansu University of Chinese Medicine, 732 West Jiayuguan Road, Chengguan District, Lanzhou, 730000, Gansu, China
| | - Zhiming Zhang
- Affiliated Hospital of Gansu University of Chinese Medicine, 732 West Jiayuguan Road, Chengguan District, Lanzhou, 730000, Gansu, China.
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Abstract
The hyperglycemia-induced enhanced oxidative stress is a key factor of diabetic peripheral neuropathy implicated in the pathogenesis of diabetic neuropathy, and microRNA may be involved, playing promotion or protection roles. In this study, we aimed to investigate the function of miR-25 during the development of oxidative/nitrative stress and in subsequent neurological problems. We detected the oxidative stress effects and expression of miR-25 on sciatic nerves from db/db diabetic model mice and analyzed the expression of related genes by qPCR and Western blotting. Interestingly, we observed increased reactive oxygen species (ROS) and Nox4 expression in db/db mice accompanied with reduced miR-25. MiR-25 inhibitor treatment increased nicotinamide adenine dinucleotide phosphate activity in Schwann cells, whereas miR-25 precursor overexpression led to opposite results. MiR-25 precursor reduced the activation of protein kinase C and decreased Nox4 expression at both mRNA and protein levels. Advanced glycation endproducts (AGEs) and the receptor for advanced glycation endproducts (RAGE) were increased in the serum and in the peripheral nerves obtained from diabetic mice, and miR-25 inhibitor treatment in Schwann cells from wt mice led to the same effect. However, miR-25 precursor transfection reduced AGEs and RAGE, and further reduced inflammatory factors that contribute to the pathological process of peripheral nerves. These findings, for the first time, indicate that miR-25 acts as a protection factor in diabetic neuropathy by downregulating AGE-RAGE and reducing nicotinamide adenine dinucleotide phosphate oxidase. miR-25 reduced protein kinase C-α phosphorylation to produce less reactive oxygen species in diabetic peripheral nerves, and therefore it played an important role in the regulation of oxidative/nitrative stress and in consequent neurological dysfunction.
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Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3142732. [PMID: 30881589 PMCID: PMC6387730 DOI: 10.1155/2019/3142732] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 01/13/2023]
Abstract
Peripheral neuropathy is the major dose-limiting side effect of paclitaxel (PTX), affecting both the quality of life and the survival of cancer patients. Nab-paclitaxel (nab-PTX) was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based PTX. However, the prevalence of peripheral neuropathy induced by nab-PTX was reported higher than that induced by solvent-based PTX. Upon investigation, oxidative stress plays a major role in the toxicity of nab-PTX. In order to assess if the antioxidant alphalipoic acid (α-LA) could prevent the nab-PTX-induced peripheral neuropathy, Sprague-Dawley (SD) rats were treated with three doses of α-LA (15, 30, and 60 mg/kg in normal saline, i.p., q.d. (days 1-30)) and/or nab-PTX (7.4 mg/kg in normal saline, i.v., q.w. (days 8, 15, and 22)). Body weight and peripheral neuropathy were measured and assessed regularly during the study. The assessment of peripheral neuropathy was performed by the von Frey and acetone tests. A tumor xenograft model of pancreatic cancer was used to assess the impact of α-LA on the antitumor effect of nab-PTX. Results showed that α-LA significantly ameliorated the peripheral neuropathy induced by nab-PTX (p < 0.05) without promoting tumor growth or reducing the chemotherapeutic effect of nab-PTX in a tumor xenograft model. Moreover, α-LA might significantly reverse the superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels altered by nab-PTX in the serum and the spinal cord of rats. Furthermore, α-LA could reverse the mRNA and protein expressions of Nrf2 (nuclear factor erythroid 2-related factor 2) and three Nrf2-responsive genes (HO-1, γ-GCLC, and NQO1) altered by nab-PTX in the dorsal root ganglion (DRG) of rats. In conclusion, our study suggests that α-LA could prevent oxidative stress and peripheral neuropathy in nab-PTX-treated rats through the Nrf2 signalling pathway without diminishing chemotherapeutic effect.
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Sibiya N, Mabandla M. The pectin-insulin patch application prevents the onset of peripheral neuropathy-like symptoms in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol 2018; 96:1286-1292. [PMID: 30326192 DOI: 10.1139/cjpp-2018-0415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Peripheral neuropathic condition is amongst the classical symptoms of progressed diabetes. An intensive glycemic control with insulin injections has been shown to delay the onset and the progression of this condition in diabetes. In this study, we investigated the effect of pectin-insulin patch application on peripheral neuropathic symptoms in streptozotocin-induced diabetic rats. Pectin-insulin patches (20.0, 40.8, and 82.9 μg/kg) were daily applied thrice in streptozotocin-induced diabetic rats for 45 days. The diabetic animals sham treated with insulin-free patch served as negative control, while diabetic animals receiving subcutaneous insulin served as positive controls. The locomotor activity, gripping strength, and thermal perception were assessed at day 36, day 40, and day 44, respectively. On the 45th day, the animals were sacrificed, after which the plasma insulin, nitric oxide, C-reactive protein, tumor necrosis factor alpha, and malondialdehyde were measured. The patch application attenuated hyperglycemia with an improvement in the locomotor activity, thermal perception, and gripping strength in diabetic animals. Furthermore, the application of the patch augmented plasma nitric oxide while attenuating plasma malondialdehyde and tumor necrosis factor alpha. The application of pectin-insulin patch delays the onset of peripheral neuropathic-like symptoms in diabetic animals.
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Affiliation(s)
| | - Musa Mabandla
- b School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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Akbari M, Ostadmohammadi V, Lankarani KB, Tabrizi R, Kolahdooz F, Khatibi SR, Asemi Z. The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials. Metabolism 2018; 87:56-69. [PMID: 29990473 DOI: 10.1016/j.metabol.2018.07.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 06/24/2018] [Accepted: 07/05/2018] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effect of alpha-lipoic acid (ALA) supplementation on glycemic control and lipid profiles among patients with metabolic diseases. METHODS We searched the following databases till October 2017: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. The relevant data were extracted and assessed for quality of the studies according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I-squared tests (I2). Twenty-four studies were included in the meta-analyses. RESULTS The findings of this meta-analysis showed that ALA supplementation among patients with metabolic diseases significantly decreased fasting glucose (SMD -0.54; 95% CI, -0.89, -0.19; P = 0.003), insulin (SMD -1.01; 95% CI, -1.70, -0.31; P = 0.006), homeostasis model assessment of insulin resistance (SMD -0.76; 95% CI, -1.15, -0.36; P < 0.001) and hemoglobin A1c (SMD -1.22; 95% CI, -2.01, -0.44; P = 0.002), triglycerides (SMD -0.58; 95% CI, -1.00, -0.16; P = 0.006), total- (SMD -0.64; 95% CI, -1.01, -0.27; P = 0.001), low density lipoprotein-cholesterol (SMD -0.44; 95% CI, -0.76, -0.11; P = 0.008). We found no detrimental effect of ALA supplementation on high density lipoprotein-cholesterol (HDL-cholesterol) levels (SMD 0.57; 95% CI, -0.14, 1.29; P = 0.11). CONCLUSIONS Overall, the current meta-analysis demonstrated that ALA administration may lead to an improvement in glucose homeostasis parameters and lipid profiles except HDL-cholesterol levels.
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Affiliation(s)
- Maryam Akbari
- Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahidreza Ostadmohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R., Iran
| | - Kamran B Lankarani
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Tabrizi
- Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fariba Kolahdooz
- Indigenous and Global Health Research, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Seyed Reza Khatibi
- Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R., Iran.
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Wang X, Lin H, Xu S, Jin Y, Zhang R. Alpha lipoic acid combined with epalrestat: a therapeutic option for patients with diabetic peripheral neuropathy. Drug Des Devel Ther 2018; 12:2827-2840. [PMID: 30233145 PMCID: PMC6135078 DOI: 10.2147/dddt.s168878] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Alpha lipoic acid (ALA), a type of antioxidant, is used in combination with epalrestat in the treatment of diabetic peripheral neuropathy (DPN). However, whether combined treatment is superior to epalrestat monotherapy is controversial. METHODS We conducted a systematic search of PubMed, Cochrane Library and Chinese databases to identify all randomized controlled trials (RCTs) up to October 31, 2017. Data were extracted to evaluate methodological quality and analyzed using Review Manager 5.3.0 software. RESULTS Twelve studies were included. Compared to epalrestat monotherapy, ALA 600 mg/d once a day (qd) combined with epalrestat 50 mg three times a day (tid) augmented the total effectiveness rate (14 days - risk ratio [RR]: 1.40, 95% CI: 1.16-1.69, P=0.0005; 28 days - RR: 1.48, 95% CI: 1.27-1.72, P<0.00001); at the same, it could improve the median motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), peroneal MNCV, and SNCV after 14, 21, and 28 days of treatment and could reduce the Toronto Clinical Scoring System (TCSS) (weighted mean difference [WMD]: -1.60, 95% CI: (-2.91, -0.29), P=0.02) and Total Symptom Score (TSS) (WMD: -0.93, 95% CI: -1.27, -0.60, P<0.00001) after 21 days of treatment. The treatment strategy of ALA 300 mg/d qd combined with epalrestat 50 mg tid had the same effects in regard to the total effectiveness rate (RR: 1.37, 95% CI: 1.18-1.59, P<0.0001), median MNCV (WMD: 6.12, 95% CI: 5.04, 7.20, P=0.00001), median SNCV (WMD: 6.70, 95% CI: 5.75, 7.65, P=0.00001), peroneal MNCV (WMD: 6.68, 95% CI: 5.82, 7.55, P=0.00001), and peroneal SNCV (WMD: 4.27, 95% CI: 3.34, 5.20, P=0.00001) after 28 days of treatment. CONCLUSION ALA combined with epalrestat is an effective option for DPN patients. Future large-sample RCTs should be conducted to further confirm this finding.
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Affiliation(s)
- Xiaotong Wang
- Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, Guangzhou University of Chinese Medicine, Shenzhen 518133, People's Republic of China,
| | - Haixiong Lin
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People's Republic of China
| | - Shuai Xu
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Yuanlin Jin
- Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, Guangzhou University of Chinese Medicine, Shenzhen 518133, People's Republic of China,
| | - Ren Zhang
- The College of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China,
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Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
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Jiang DQ, Xu LC, Jiang LL, Li MX, Wang Y. Fasudil combined with methylcobalamin or lipoic acid can improve the nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis. Medicine (Baltimore) 2018; 97:e11390. [PMID: 29979431 PMCID: PMC6076121 DOI: 10.1097/md.0000000000011390] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Fasudil (F) plus methylcobalamin (M) or lipoic acid (L) treatment has been suggested as a therapeutic approach for diabetic peripheral neuropathy (DPN) in numerous studies. However, the effect of the combined use still remains dubious. OBJECTIVE The aim of this report was to evaluate the efficacy of F plus M or L (F + M or F + L) for the treatment of DPN compared with that of M or L monotherapy, respectively, in order to provide the basis and reference for clinical rational drug use. METHODS Randomized controlled trials (RCTs) of F for DPN published up to September 2017 were searched. Relative risk (RR), mean difference (MD), and 95% confidence interval (CI) were calculated and heterogeneity was assessed with the I test. Sensitivity analyses were also performed. The outcomes measured were as follows: the clinical efficacy, median motor nerve conduction velocities (NCVs) (MNCVs), median sensory NCV (SNCV), peroneal MNCV, peroneal SNCV, and adverse effects. RESULTS Thirteen RCTs with 1148 participants were included. Clinical efficacy of F + M combination therapy was significantly better than M monotherapy (8 trials; RR 1.26, 95% CI 1.17-1.35, P < .00001, I = 0%), the efficacy of F + L combination therapy was also obviously better than L monotherapy (4 trials; RR 1.27, 95% CI 1.16-1.39, P < .00001, I = 0%). Compared with monotherapy, the pooled effects of combination therapy on NCV were (MD 6.69, 95% CI 4.74-8.64, P < .00001, I = 92%) for median MNCV, (MD 6.71, 95% CI 1.77-11.65, P = .008, I = 99%) for median SNCV, (MD 4.18, 95% CI 2.37-5.99, P < .00001, I = 94%) for peroneal MNCV, (MD 5.89, 95% CI 3.57-8.20, P < .00001, I = 95%) for peroneal SNCV. Furthermore, there were no serious adverse events associated with drug intervention. CONCLUSION Combination therapy with F plus M or L was superior to M or L monotherapy for improvement of neuropathic symptoms and NCVs in DPN patients, respectively. Moreover, no serious adverse events occur in combination therapy.
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Affiliation(s)
- De-Qi Jiang
- College of Biology and Pharmacy, Yulin Normal University
- Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology, Yulin
| | - Lan-Cheng Xu
- College of Biology and Pharmacy, Yulin Normal University
| | - Li-Lin Jiang
- College of Biology and Pharmacy, Yulin Normal University
| | - Ming-Xing Li
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Yong Wang
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, China
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Lee KA, Lee NY, Park TS, Jin HY. Comparison of peripheral nerve protection between insulin-based glucose control and alpha lipoic acid (ALA) in the streptozotocin (STZ)-induced diabetic rat. Endocrine 2018; 61:58-67. [PMID: 29736880 DOI: 10.1007/s12020-018-1613-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 04/17/2018] [Indexed: 01/29/2023]
Abstract
Strict glucose control is a well-proven therapeutic approach for peripheral neuropathies in patients with diabetes. Alpha lipoic acid (ALA) has also been accepted as a therapeutic agent for diabetic peripheral neuropathy (DPN) in the respect of pathogenesis. However, the potential of ALA as a treatment for DPN in comparison to that of glucose control is unclear. In this study, we compared the neuroprotective potential of glucose control and ALA. Animals were divided into 6 groups based on the intervention used, as follows: normal, diabetes (DM), DM+racemic form of ALA, DM+R form of ALA, DM+once daily insulin glargine, and DM+once daily insulin glargine with twice daily insulin glulisine. Various sensory tests were performed after 12 weeks of treatment, and immunohistochemistry of nerve fibers obtained from the sciatic and cutaneous nerves was performed after 24 weeks of treatment. There were no significant differences between the ALA-treated and insulin-treated DM groups in the sensory tests or in antioxidant activity. The axonal diameters and myelin sheath area of the sciatic nerves and the cutaneous small nerves, as assessed based on intraepidermal nerve fiber density, were similar in the ALA-treated and insulin-treated animals, although there was a non-significant trend for a mild increase in the both basal and rapid-acting insulin group compared with non-treated DM group. In conclusion, our results suggest that the neuroprotective benefits of ALA and insulin-based glucose control may be similar, although glucose control may have had slightly more beneficial effects in this animal model of diabetes. Of note, glucose levels should be strictly controlled, including corrections for fluctuations in the glucose level, to obtain therapeutic benefits in DPN.
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Affiliation(s)
- Kyung Ae Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea
| | - Na Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea
| | - Tae Sun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea
| | - Heung Yong Jin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
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Agathos E, Tentolouris A, Eleftheriadou I, Katsaouni P, Nemtzas I, Petrou A, Papanikolaou C, Tentolouris N. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res 2018; 46:1779-1790. [PMID: 29517942 PMCID: PMC5991249 DOI: 10.1177/0300060518756540] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 01/09/2018] [Indexed: 12/16/2022] Open
Abstract
Objective To examine the effect of α-lipoic acid on neuropathic symptoms in patients with diabetic neuropathy (DN). Methods Patients with painful DN were treated with 600 mg/day α-lipoic acid, orally, for 40 days. Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ) and douleur neuropathique (DN)4 questionnaire scores were assessed at baseline and day 40. Quality-of-life treatment effects were assessed by Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI) and Sheehan Disability Scale (SDS). Changes in body weight, arterial blood pressure, fasting serum glucose and lipids were also assessed. Results Out of 72 patients included, significant reductions in neuropathic symptoms were shown by reduced NSS, SPNSQ and DN4 scores at day 40 versus baseline. BPI, NPSI, and SDS in terms of work disability, social life disability, and family life disability scores were also significantly reduced. Moreover, 50% of patients rated their health condition as 'very much better' or 'much better' following α-lipoic acid administration. Fasting triglyceride levels were reduced, but no difference was found in body weight, blood pressure, fasting glucose, or other lipids at day 40 versus baseline. Conclusions A-lipoic acid administration was associated with reduced neuropathic symptoms and triglycerides, and improved quality of life.
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Affiliation(s)
- Evangelos Agathos
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Anastasios Tentolouris
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Panagiota Katsaouni
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Ioannis Nemtzas
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Alexandra Petrou
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Christina Papanikolaou
- Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Part of this work was orally presented at the 5th Hellenic Congress of the Hellenic Association for the Study of the Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens, Greece
| | - Nikolaos Tentolouris
- Nikolaos Tentolouris, Diabetes Centre, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, 11527, Athens, Greece.
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Etchegoyen M, Nobile MH, Baez F, Posesorski B, González J, Lago N, Milei J, Otero-Losada M. Metabolic Syndrome and Neuroprotection. Front Neurosci 2018; 12:196. [PMID: 29731703 PMCID: PMC5919958 DOI: 10.3389/fnins.2018.00196] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/12/2018] [Indexed: 12/17/2022] Open
Abstract
Introduction: Over the years the prevalence of metabolic syndrome (MetS) has drastically increased in developing countries as a major byproduct of industrialization. Many factors, such as the consumption of high-calorie diets and a sedentary lifestyle, bolster the spread of this disorder. Undoubtedly, the massive and still increasing incidence of MetS places this epidemic as an important public health issue. Hereon we revisit another outlook of MetS beyond its classical association with cardiovascular disease (CVD) and Diabetes Mellitus Type 2 (DM2), for MetS also poses a risk factor for the nervous tissue and threatens neuronal function. First, we revise a few essential concepts of MetS pathophysiology. Second, we explore some neuroprotective approaches in MetS pertaining brain hypoxia. The articles chosen for this review range from the years 1989 until 2017; the selection criteria was based on those providing data and exploratory information on MetS as well as those that studied innovative therapeutic approaches. Pathophysiology: The characteristically impaired metabolic pathways of MetS lead to hyperglycemia, insulin resistance (IR), inflammation, and hypoxia, all closely associated with an overall pro-oxidative status. Oxidative stress is well-known to cause the wreckage of cellular structures and tissue architecture. Alteration of the redox homeostasis and oxidative stress alter the macromolecular array of DNA, lipids, and proteins, in turn disrupting the biochemical pathways necessary for normal cell function. Neuroprotection: Different neuroprotective strategies are discussed involving lifestyle changes, medication aimed to mitigate MetS cardinal symptoms, and treatments targeted toward reducing oxidative stress. It is well-known that the routine practice of physical exercise, aerobic activity in particular, and a complete and well-balanced nutrition are key factors to prevent MetS. Nevertheless, pharmacological control of MetS as a whole and pertaining hypertension, dyslipidemia, and endothelial injury contribute to neuronal health improvement. Conclusion: The development of MetS has risen as a risk factor for neurological disorders. The therapeutic strategies include multidisciplinary approaches directed to address different pathological pathways all in concert.
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Affiliation(s)
- Melisa Etchegoyen
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Mariana H Nobile
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Francisco Baez
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Barbara Posesorski
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Julian González
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Néstor Lago
- Institute of Cardiovascular Pathophysiology, School of Medicine, University of Buenos Aires, UBA-CONICET, Buenos Aires, Argentina
| | - José Milei
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Matilde Otero-Losada
- Institute of Cardiological Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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R(+)-Thioctic Acid Effects on Oxidative Stress and Peripheral Neuropathy in Type II Diabetic Patients: Preliminary Results by Electron Paramagnetic Resonance and Electroneurography. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1767265. [PMID: 29849866 PMCID: PMC5914101 DOI: 10.1155/2018/1767265] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 11/02/2017] [Accepted: 12/27/2017] [Indexed: 12/15/2022]
Abstract
Objectives Diabetic neuropathy is the most common complication of diabetes. The idea of alterations in energy metabolism in diabetes is emerging. The biogenic antioxidant R(+)-thioctic acid has been successfully used in the treatment of diabetic polyneuropathic (DPN) patients. Methods The effects of R(+)-thioctic acid (1 tablet, 1.6 g) administration were evaluated in 12 DPN patients at baseline and at 15, 30, 60, and 120 administration days throughout the assessment of oxidative stress (OxS); ROS production rate by electron paramagnetic resonance (EPR) technique; and oxidative damage biomarkers (thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC)), electroneurography (ENG) and visual analogue scale. Results Supplementation induced significant changes (p < 0.05) at 30 and 60 days. ROS production rate up to -16%; TBARS (-31%), PC (-38%), and TAC up to +48%. Motor nerve conduction velocity in SPE and ulnar nerves (+22% and +16%) and sensor conduction velocity in sural and median nerves (+22% and +5%). Patients reported a general wellness sensation improvement (+35%) at 30 days: lower limb pain sensation (-40%) and upper limbs (-23%). Conclusion The results strongly indicate that an increased antioxidant capacity plays an important role in OxS, nerve conduction velocity, pain, and general wellness improvement. Nevertheless, the effects of the antioxidant compound were found positive up to 60 days. Then, a hormesis effect was observed. Novelty of the research would be a challenge for investigators to carefully address issues, including dose range factors, appropriate administration time, and targeting population to counteract possible "boomerang effects." The great number of monitored parameters would firmly stress these conclusions.
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Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy. Neuropharmacology 2018; 131:256-270. [DOI: 10.1016/j.neuropharm.2017.12.029] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 11/27/2017] [Accepted: 12/18/2017] [Indexed: 12/22/2022]
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Chukanova EI, Chukanova AS. [Alpha-lipoic acid in the treatment of diabetic polyneuropathy]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:103-109. [PMID: 29460914 DOI: 10.17116/jnevro201811811103-109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The issues of classification, pathogenesis, pathomorphology and treatment of diabetic polyneuropathy (DPN) are addressed. Pathogenetic mechanisms of the action of alpha-lipoic acid in treatment of DPN are justified. The authors present the results of randomized placebo-controlled trials of alpha-lipoic acid that revealed the high clinical efficacy and absence of side-effects even during the long-term treatment.
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Affiliation(s)
- E I Chukanova
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A S Chukanova
- Pirogov Russian National Research Medical University, Moscow, Russia
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Peripheral Neuropathy. Integr Med (Encinitas) 2018. [DOI: 10.1016/b978-0-323-35868-2.00013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Lee J, Cho JH. Letter: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J 2017;41:275-83). Diabetes Metab J 2017; 41:417-419. [PMID: 29086540 PMCID: PMC5663681 DOI: 10.4093/dmj.2017.41.5.417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- Jeongmin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hyoung Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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Gilron I, Tu D, Holden R, Towheed T, Vandenkerkhof E, Milev R. Combination Analgesic Development for Enhanced Clinical Efficacy (CADENCE Trial): Study Protocol for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of an Alpha-Lipoic Acid - Pregabalin Combination for the Treatment of Fibromyalgia Pain. JMIR Res Protoc 2017; 6:e154. [PMID: 28778847 PMCID: PMC5705061 DOI: 10.2196/resprot.8001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/19/2017] [Accepted: 07/21/2017] [Indexed: 01/22/2023] Open
Abstract
Background Fibromyalgia is a clinical disorder commonly presenting with chronic widespread pain as well as sleep disturbance, fatigue, depression, and cognitive dysfunction. There is an urgent need for treatment strategies that provide better pain relief and fewer adverse effects (AEs). Efforts to develop rational combinations of specific fibromyalgia treatments have demonstrated potential for measurable improvements in pain relief, quality of life, and health care utilization. More than half of fibromyalgia patients receive 2 or more analgesics but current combination use is based on limited evidence. As an early proof-of-concept project from the Canadian Institutes of Health Research–Strategy on Patient-Oriented Research Chronic Pain Network, this trial protocol is expected to advance the field by rigorously evaluating a new treatment combination for fibromyalgia. Objective We will test the hypothesis that analgesic combinations containing at least one nonsedating agent would be as safe but more effective than either monotherapy because of additive pain relief without increasing overall AEs. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for fibromyalgia, and the antioxidant, alpha-lipoic acid (ALA), one of the only nonsedating systemic agents proven effective for neuropathic pain, is currently being evaluated in fibromyalgia. Thus, we will conduct a clinical trial to compare a PGB+ALA combination to each monotherapy for fibromyalgia. Methods Using a double-blind, double-dummy, crossover design, 54 adults with fibromyalgia will be randomly allocated to 1 of 6 sequences of treatment with PGB, ALA, and PGB+ALA combination. During each of 3 different treatment periods, participants will take 2 sets of capsules containing (1) ALA (or placebo) and (2) PGB (or placebo) for 31 days, followed by an 11-day taper/washout period. The primary outcome will be mean daily pain intensity (0 to 10 scale) at maximal tolerated doses (MTDs) during each period. Secondary outcomes, assessed at MTD, will include global improvement, adverse events, mood, and quality of life. Results This trial attained ethics approval March 6, 2017 (Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board protocol number ANAE-313-17), and recruitment is set to start in August 2017. Conclusions This trial will provide rigorous evidence comparing the efficacy of a PGB-ALA combination to PGB alone and ALA alone in the treatment of fibromyalgia. Trial Registration International Standard Randomized Controlled Trial Number ISRCTN14939460; https://www.isrctn.com/ ISRCTN1493946 (Archived by WebCite at http://www.webcitation.org/6sFqAjxkt)
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Affiliation(s)
- Ian Gilron
- Queen's University, Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada
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Lee SJ, Jeong SJ, Lee YC, Lee YH, Lee JE, Kim CH, Min KW, Cha BY. Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea. Diabetes Metab J 2017; 41:275-283. [PMID: 28868825 PMCID: PMC5583405 DOI: 10.4093/dmj.2017.41.4.275] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 04/21/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV). METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes. RESULTS Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by -3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms² in the ALA group, whereas it declined by -15.04 ms² in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by -0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events. CONCLUSION Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.
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Affiliation(s)
- Sol Jae Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Su Jin Jeong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Yu Chang Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Yong Hoon Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Jung Eun Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Chong Hwa Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea.
| | - Kyung Wan Min
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Bong Yun Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential. Inflamm Res 2017; 66:947-959. [PMID: 28676917 DOI: 10.1007/s00011-017-1079-6] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 06/20/2017] [Accepted: 06/27/2017] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The molecular nature of lipoic acid (LA) clarifies its capability of taking part to a variety of biochemical reactions where redox state is meaningful. The pivotal action of LA is the antioxidant activity due to its ability to scavenge and inactivate free radicals. Furthermore, LA has been shown to chelate toxic metals both directly and indirectly by its capability to enhance intracellular glutathione (GSH) levels. This last property is due to its ability to interact with GSH and recycle endogenous GSH. LA exhibits significant antioxidant activity protecting against oxidative damage in several diseases, including neurodegenerative disorders. Interestingly, LA is unique among natural antioxidants for its capability to satisfy a lot of requirements, making it a potentially highly effective therapeutic agent for many conditions related with oxidative damage. In particular, there are evidences showing that LA has therapeutic activity in lowering glucose levels in diabetic conditions. Similarly, LA supplementation has multiple beneficial effects on the regression of the mitochondrial function and on oxidative stress associated with several diseases and aging. AIM The aim of the present review is to describe the molecular mechanisms underlying the beneficial effects of LA under various experimental conditions and disease and how to exploit such effect for clinical purposes. CONCLUSION LA has pleiotropic effects in different pathways related with several diseases, its use as a potential therapeutic agent is very promising.
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Gilron I, Tu D, Holden R, Jackson AC, Ghasemlou N, Duggan S, Vandenkerkhof E, Milev R. Pain Improvement With Novel Combination Analgesic Regimens (PAIN-CARE): Randomized Controlled Trial Protocol. JMIR Res Protoc 2017; 6:e111. [PMID: 28596150 PMCID: PMC5481665 DOI: 10.2196/resprot.7493] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/21/2017] [Accepted: 04/24/2017] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Neuropathic pain (NP) (including painful diabetic neuropathy, postherpetic neuralgia, etc) affects approximately 7% to 8% of the population and is associated with a devastating symptom burden as well as a profound economic impact for patients, their families, and the health care system. Current therapies have limited efficacy and dose-limiting adverse effects (AEs). Rational combination therapy with carefully selected NP drugs has shown potential for measurable improvements in pain relief, quality of life, and health care use. Today, over half of NP patients concurrently receive 2 or more analgesics but combination use is based on little evidence. Research is urgently needed to identify safer, more effective combinations. OBJECTIVE We hypothesize that analgesic combinations containing at least 1 nonsedating agent would be as safe but more effective than either monotherapy without increasing overall AEs because of additive pain relief. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for NP; the antioxidant alpha-lipoic acid (ALA) is one of the only nonsedating systemic agents proven effective for NP. Thus, we will conduct a clinical trial to compare a PGB+ALA combination to each monotherapy for NP. METHODS Using a double-blind, double-dummy, crossover design, 54 adults with NP will be randomly allocated to 1 of 6 sequences of treatment with PGB, ALA and PGB+ALA combination. During each of 3 different treatment periods, participants will take 2 sets of capsules containing (1) ALA or placebo and (2) PGB or placebo for 31 days, followed by an 11-day taper/washout period. The primary outcome will be mean daily pain intensity (0-10) at maximally tolerated dose (MTD) during each period. Secondary outcomes, assessed at MTD, will include global improvement, adverse events, mood, and quality of life. RESULTS Participant recruitment is expected to begin September 1, 2017. The proposed trial was awarded external peer-reviewed funding by the Canadian Institutes of Health Research (Canada) on July 15, 2016. CONCLUSIONS This trial will provide rigorous evidence comparing the efficacy of a PGB+ALA combination to PGB alone and ALA alone in the treatment of NP. TRIAL REGISTRATION International Standard Randomized Controlled Trial Number ISRCTN14577546; http://www.isrctn.com/ISRCTN14577546?q=&filters=conditionCategory:Signs%20and%20Symptoms,trialStatus: Ongoing,recruitmentCountry:Canada&sort=&offset=1&totalResults=2&page=1&pageSize=10&searchType=basic-search (Archived by WebCite at http://www.webcitation.org/6qvHFDc6m).
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Affiliation(s)
- Ian Gilron
- Queen's University, Department of Anesthesiology and Perioperative Medicine, Kingston, ON, Canada
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