Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Flavonoids as Potential Therapeutic Agents for the Management of Diabetic Neuropathy

Author(s): Ankita Sood, Bimlesh Kumar*, Sachin Kumar Singh, Pankaj Prashar, Anamika Gautam, Monica Gulati, Narendra Kumar Pandey, Indu Melkani, Ankit Awasthi, Subhini A Saraf, Giovani Vidari, Mehmet Ozdemir, Faiq Hama Saeed Hussain, Esra Tariq Anwar, Muath Sheet Mohammed Ameen, Saurabh Gupta and Omji Porwal

Volume 26 , Issue 42 , 2020

Page: [5468 - 5487] Pages: 20

DOI: 10.2174/1381612826666200826164322

Price: $65


Flavonoids are secondary metabolites that are widely distributed in plants. These phenolic compounds are classified into various subgroups based on their structures: flavones, flavonols, isoflavones, flavanones, and anthocyanins. They are known to perform various pharmacological actions like antioxidant, anti-inflammatory, anticancer, antimicrobial, antidiabetic and antiallergic, etc. Diabetes is a chronic progressive metabolic disorder that affects several biochemical pathways and leads to secondary complications such as neuropathy, retinopathy, nephropathy, and cardiomyopathy. Among them, the management of diabetic neuropathy is one of the major challenges for physicians as well as the pharmaceutical industries. Naturally occurring flavonoids are extensively used for the treatment of diabetes and its related complications due to their antioxidant properties. Moreover, flavonoids inhibit various pathways that are involved in the progression of diabetic neuropathy like the reduction of oxidative stress, decrease in glycogenolysis, increase glucose utilization, decrease in the formation of advanced glycation end products, and inhibition of the α-glucosidase enzyme. This review entails current updates on the therapeutic perspectives of flavonoids in the treatment of neuropathic pain. This manuscript explains the pathological aspects of neuropathic pain, the chemistry of flavonoids, and their application in amelioration of neuropathic pain through preclinical studies either alone or in combination with other therapeutic agents.

Keywords: Flavonoids, diabetic neuropathy, oxidative stress, glycogenolysis, α-glucosidase, cardiomyopathy.

Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The possible role of flavonoids in the prevention of diabetic complications. Nutrients 2016; 8(5): 310.
[] [PMID: 27213445]
Pietta P-G. Flavonoids as antioxidants. J Nat Prod 2000; 63(7): 1035-42.
[] [PMID: 10924197]
Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond) 2015; 12: 60.
[] [PMID: 26705405]
Robak J, Gryglewski RJ. Bioactivity of flavonoids. Pol J Pharmacol 1996; 48(6): 555-64.
[PMID: 9112694]
Grotewold E. The science of flavonoids. Springer 2006.
Jovanovic SV, Steenken S, Tosic M, Marjanovic B, Simic MG. Flavonoids as antioxidants. J Am Chem Soc 1994; 116: 4846-51.
Dejgaard A. Pathophysiology and treatment of diabetic neuropathy. Diabet Med 1998; 15(2): 97-112.
[<97:AID-DIA523>3.0.CO;2-5] [PMID: 9507909]
Gabbay KH. Hyperglycemia, polyol metabolism, and complications of diabetes mellitus. Annu Rev Med 1975; 26: 521-36.
[] [PMID: 238458]
Varma SD, Mikuni I, Kinoshita JH. Flavonoids as inhibitors of lens aldose reductase. Science 1975; 188(4194): 1215-6.
[] [PMID: 1145193]
Wagner H, Farkas L. Synthesis of flavonoids The Flavonoids. Springer 1975; pp. 127-213.
Bianco A, Cavarischia C, Guiso M. The Heck coupling reaction using aryl vinyl ketones: synthesis of flavonoids. Eur J Org Chem 2004; 2004: 2894-8.
Kim J, Lee Y, Kim H, et al. Synthesis of naringenin amino acid esters as potential CDK2 inhibitors. Bull Korean Chem Soc 2005; 26: 2065.
Rahman M, Riaz M, Desai UR. Synthesis of biologically relevant biflavanoids--a review. Chem Biodivers 2007; 4(11): 2495-527.
[] [PMID: 18027351]
Wong E, Grisebach H. Further studies on the role of chalcone and flavanone in biosynthesis of flavonoids. Phytochemistry 1969; 8: 1419-26.
Wong E. The role of chalcones and flavanones in flavonoid biosynthesis. Phytochemistry 1968; 7: 1751-8.
Wang Q, Yang J, Zhang X-m, Zhou L, Liao X-L, Yang B. Practical synthesis of naringenin. J Chem Res 2015; 39: 455-7.
Tominaga T, Sumida M. Synthesis of dihydrokaempferol tetramethyl ether. Yakugaku Zasshi 1962; 82: 780-1.
[] [PMID: 13921745]
Augustyn JA, Barend C, Ferreira D. Enantioselective synthesis of flavonoids. Part 1. Poly-Oxygenated chalcone epoxides. Tetrahedron 1990; 46: 2651-60.
Narayana KR, Reddy MS, Chaluvadi M, Krishna D. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol 2001; 33: 2-16.
Lin Y, Shi R, Wang X, Shen H-M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 2008; 8(7): 634-46.
[] [PMID: 18991571]
Svehliková V, Bennett RN, Mellon FA, et al. Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita [L.] Rauschert). Phytochemistry 2004; 65(16): 2323-32.
[] [PMID: 15381003]
Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 2008; 74(14): 1667-77.
[] [PMID: 18937165]
Dajas F, Juan Andres A-C, Florencia A, Carolina E, Felicia R-M. Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents) 2013; 13: 30-5.
Nabavi SF, Braidy N, Gortzi O, et al. Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Res Bull 2015; 119(Pt A): 1-11.
[] [PMID: 26361743]
Aherne SA, O’Brien NM. Dietary flavonols: chemistry, food content, and metabolism. Nutrition 2002; 18(1): 75-81.
[] [PMID: 11827770]
Herrmann K. Flavonols and flavones in food plants: a review. Int J Food Sci Technol 1976; 11: 433-48.
Woodman OL, Chan ECh. Vascular and anti-oxidant actions of flavonols and flavones. Clin Exp Pharmacol Physiol 2004; 31(11): 786-90.
[] [PMID: 15566394]
Dok-Go H, Lee KH, Kim HJ, et al. Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res 2003; 965(1-2): 130-6.
[] [PMID: 12591129]
Lamson DW, Brignall M. Antioxidants and cancer, part 3: quercetin. Altern Med Rev 2000; 5: 196-208.
Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem 2011; 11: 298-344.
Ong KC, Khoo H-E. Biological effects of myricetin. Gen Pharmacol 1997; 29(2): 121-6.
[] [PMID: 9251891]
Davis W. Determination of flavanones in citrus fruits. Anal Chem 1947; 19: 476-8.
Felgines C, Texier O, Morand C, et al. Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 2000; 279(6): G1148-54.
[] [PMID: 11093936]
Patel K, Singh GK, Patel DK. A review on pharmacological and analytical aspects of naringenin. Chin J Integr Med 2018; 24(7): 551-60.
[] [PMID: 25501296]
Testai L, Calderone V. Nutraceutical value of citrus flavanones and their implications in cardiovascular disease. Nutrients 2017; 9(5): 502.
[] [PMID: 28509871]
Setchell KD, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr 1999; 129(3): 758S-67.
[] [PMID: 10082786]
Liggins J, Bluck LJ, Runswick S, Atkinson C, Coward WA, Bingham SA. Daidzein and genistein contents of vegetables. Br J Nutr 2000; 84(5): 717-25.
[] [PMID: 11177186]
Liggins J, Bluck LJ, Runswick S, Atkinson C, Coward WA, Bingham SA. Daidzein and genistein content of fruits and nuts. J Nutr Biochem 2000; 11(6): 326-31.
[] [PMID: 11002128]
Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996; 17(2): 271-5.
[] [PMID: 8625449]
Williams CA, Grayer RJ. Anthocyanins and other flavonoids. Nat Prod Rep 2004; 21(4): 539-73.
[] [PMID: 15282635]
Ghosh D, Konishi T. Anthocyanins and anthocyanin-rich extracts: role in diabetes and eye function. Asia Pac J Clin Nutr 2007; 16(2): 200-8.
[PMID: 17468073]
Einbond LS, Reynertson KA, Luo X-D, Basile MJ, Kennelly EJ. Anthocyanin antioxidants from edible fruits. Food Chem 2004; 84: 23-8.
Vehl kov V, Rep k M. Apigenin chemotypes of Matricaria chamomilla L. Biochem Syst Ecol 2006; 34: 654-7.
Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001; 49(6): 3106-12.
[] [PMID: 11410016]
Heitz A, Carnat A, Fraisse D, Carnat A-P, Lamaison J-L. Luteolin 3′-glucuronide, the major flavonoid from Melissa officinalis subsp. officinalis. Fitoterapia 2000; 71(2): 201-2.
[] [PMID: 10727822]
Chowdhury AR, Sharma S, Mandal S, Goswami A, Mukhopadhyay S, Majumder HK. Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J 2002; 366(Pt 2): 653-61.
[] [PMID: 12027807]
Fang J, Zhou Q, Shi XL, Jiang BH. Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis 2007; 28(3): 713-23.
[] [PMID: 17065200]
Chen X, Long X, Wang Z, et al. Determination of the content of luteolin in honeysuckle by HPLC. Hunan Nongye Daxue Xuebao 2009; 35: 127-9.
Chen K-H, Weng M-S, Lin J-K. Tangeretin suppresses IL-1β-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem Pharmacol 2007; 73(2): 215-27.
[] [PMID: 17067555]
Lee YY, Lee E-J, Park J-S, Jang S-E, Kim D-H, Kim H-S. Anti-inflammatory and antioxidant mechanism of tangeretin in activated microglia. J Neuroimmune Pharmacol 2016; 11(2): 294-305.
[] [PMID: 26899309]
Ogawa K, Kawasaki A, Omura M, Yoshida T, Ikoma Y, Yano M. 3′,5′-Di-C-β-glucopyranosylphloretin, a flavonoid characteristic of the genus Fortunella. Phytochemistry 2001; 57(5): 737-42.
[] [PMID: 11397442]
Horowitz R. Flavonoids of citrus. I. Isolation of diosmin from lemons (Citrus limon). J Org Chem 1956; 21: 1184-5.
Naoi M, Inaba-Hasegawa K, Shamoto-Nagai M, Maruyama W. Neurotrophic function of phytochemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intracellular signaling and gene expression. J Neural Transm (Vienna) 2017; 124(12): 1515-27.
[] [PMID: 29030688]
Morel I, Lescoat G, Cogrel P, et al. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 1993; 45(1): 13-9.
[] [PMID: 8424806]
Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992; 340(8828): 1136-9.
[] [PMID: 1359218]
Park Y-M, Won J-H, Yun K-J, et al. Preventive effect of Ginkgo biloba extract (GBB) on the lipopolysaccharide-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 via suppression of nuclear factor-kappaB in RAW 264.7 cells. Biol Pharm Bull 2006; 29(5): 985-90.
[] [PMID: 16651732]
Gutiérrez-del-Río I, Villar CJ, Lombó F. Therapeutic uses of kaempferol: anticancer and antiinflammatory activity biosynthesis, food sources and therapeutic uses 2016; 71
Yamashita Y, Kawada S, Nakano H. Induction of mammalian topoisomerase II dependent DNA cleavage by nonintercalative flavonoids, genistein and orobol. Biochem Pharmacol 1990; 39(4): 737-44.
[] [PMID: 2154993]
Yang J, Guo J, Yuan J. In vitro antioxidant properties of rutin. Lebensm Wiss Technol 2008; 41: 1060-6.
Jiménez-Aliaga K, Bermejo-Bescós P, Benedí J, Martín-Aragón S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci 2011; 89(25-26): 939-45.
[] [PMID: 22008478]
Raghav SK, Gupta B, Agrawal C, Goswami K, Das HR. Anti-inflammatory effect of Ruta graveolens L. in murine macrophage cells. J Ethnopharmacol 2006; 104(1-2): 234-9.
[] [PMID: 16207519]
Ortega JT, Serrano ML, Suarez AI, Baptista J, Pujol FH, Rangel HR. Methoxyflavones from Marcetia taxifolia as HIV-1 reverse transcriptase inhibitors. Nat Prod Commun 2017; 12.
Huang X, Yao J, Zhao Y, Xie D, Jiang X, Xu Z. Efficient rutin and quercetin biosynthesis through flavonoids-related gene expression in Fagopyrum tataricum Gaertn. hairy root cultures with UV-B irradiation. Front Plant Sci 2016; 7: 63.
[] [PMID: 26870075]
Yoneyama M, Iritani S, Miyake T. α-glycosyl quercetin, and its preparation and uses. In: Google Patents In: 1996.
Kim HJ, Kim SH, Yun J-M. Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence Based Compliment Alt Med 2012; 2012639469
Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The clinical potential of senolytic drugs. J Am Geriatr Soc 2017; 65(10): 2297-301.
[] [PMID: 28869295]
Gutiérrez-Venegas G, Contreras-Sánchez A, Ventura-Arroyo JA. Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. J Asian Nat Prod Res 2014; 16(10): 1009-17.
[] [PMID: 25263652]
Lahmer N, Belboukhari N, Cheriti A, Sekkoum K. Hesperidin and hesperitin preparation and purification from Citrus sinensis peels. Cheriti and K. Sekkoum. Der Pharma Chemical 2015; 7: 1-4.
Garg A, Garg S, Zaneveld LJ, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res 2001; 15(8): 655-69.
[] [PMID: 11746857]
Wilcox LJ, Borradaile NM, Huff MW. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc Drug Rev 1999; 17: 160-78.
Yang W, Ma J, Liu Z, Lu Y, Hu B, Yu H. Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats. Neurol Sci 2014; 35(5): 741-51.
[] [PMID: 24337945]
Hsueh T-P, Sheen J-M, Pang J-HS, et al. The anti-atherosclerotic effect of naringin is associated with reduced expressions of cell adhesion molecules and chemokines through NF-κB Pathway. Molecules 2016; 21: 195.
McIntosh CA, Mansell RL. Biosynthesis of naringin in Citrus paradisi: UDP-glucosyl-transferase activity in grapefruit seedlings. Phytochemistry 1990; 29: 1533-8.
Vaid M, Katiyar SK. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (Review). Int J Oncol 2010; 36(5): 1053-60.
[PMID: 20372777]
Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994; 27(2): 105-12.
[PMID: 8640239]
Hashmat MA, Hussain R. A review on Acacia catechu Willd. Interdiscip J Contemp Res Bus 2013; 5: 593-600.
Murase T, Misawa K, Haramizu S, Hase T. Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway. Biochem Pharmacol 2009; 78(1): 78-84.
[] [PMID: 19447226]
Fernando W, Rupasinghe HP, Hoskin DWW, Hoskin D. Regulation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling by plant flavonoids. Mini Rev Med Chem 2015; 15(6): 479-89.
[] [PMID: 25873069]
Shiota S, Shimizu M, Mizushima T, et al. Marked reduction in the minimum inhibitory concentration (MIC) of β-lactams in methicillin-resistant Staphylococcus aureus produced by epicatechin gallate, an ingredient of green tea (Camellia sinensis). Biol Pharm Bull 1999; 22(12): 1388-90.
[] [PMID: 10746177]
Ghosh P, Fenner GP. Improved method for gas chromatographic analysis of genistein and daidzein from soybean (Glycine max) seeds. J Agric Food Chem 1999; 47(9): 3455-6.
[] [PMID: 10552671]
Park S-S, Kim Y-N, Jeon YK, et al. Genistein-induced apoptosis via Akt signaling pathway in anaplastic large-cell lymphoma. Cancer Chemother Pharmacol 2005; 56(3): 271-8.
[] [PMID: 15883821]
Li Y, Sarkar FH. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 2002; 8(7): 2369-77.
[PMID: 12114442]
Kudou S, Shimoyamada M, Imura T, Uchida T, Okubo K. A new isoflavone glycoside in soybean seeds (Glycine max MERRILL), glycitein 7-O-β-D-(6”-O-acetyl) glucopyranoside. Agric Biol Chem 1991; 55: 859-60.
Winzer M, Rauner M, Pietschmann P. Glycitein decreases the generation of murine osteoclasts and increases apoptosis. Wien Med Wochenschr 2010; 160(17-18): 446-51.
[] [PMID: 20714813]
Kim J-E, Kwon JY, Seo SK, et al. Cyanidin suppresses ultraviolet B-induced COX-2 expression in epidermal cells by targeting MKK4, MEK1, and Raf-1. Biochem Pharmacol 2010; 79(10): 1473-82.
[] [PMID: 20096264]
Schwinn K, Miosic S, Davies K, et al. The B-ring hydroxylation pattern of anthocyanins can be determined through activity of the flavonoid 3′-hydroxylase on leucoanthocyanidins. Planta 2014; 240(5): 1003-10.
[] [PMID: 25269395]
Xu Y. Identifications of polyphenols and quantification of anthocyanidins in grapes and grape-derived products. Rutgers University-Graduate School-New Brunswick 2011.
Hwang MK, Kang NJ, Heo Y-S, Lee KW, Lee HJ. Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-α. Biochem Pharmacol 2009; 77(7): 1213-22.
[] [PMID: 19174152]
Freyre R, Griesbach R. Studies of flower color in Anagallis monelli L 2006; 1050: 139-44.
Paixao J, Dinis TC, Almeida LM. Protective role of malvidin-3-glucoside on peroxynitrite-induced damage in endothelial cells by counteracting reactive species formation and apoptotic mitochondrial pathway. Oxid Med Cell Longev 2012; 2012428538
Kader F, Rovel B, Girardin M, Metche M. Fractionation and identification of the phenolic compounds of highbush blueberries (Vaccinium corymbosum, L.). Food Chem 1996; 55: 35-40.
Hu C, Zawistowski J, Ling W, Kitts DD. Black rice (Oryza sativa L. indica) pigmented fraction suppresses both reactive oxygen species and nitric oxide in chemical and biological model systems. J Agric Food Chem 2003; 51(18): 5271-7.
[] [PMID: 12926869]
Bhadada S, Sahay R, Jyotsna V, Agrawal J. Diabetic neuropathy: current concepts. J Indian Acad Clin Med 2001; 2: 305-18.
Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000; 47(2): 123-8.
[] [PMID: 10670912]
Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 2008; 31(Suppl. 2): S255-61.
[PMID: 18227494]
Melkani I, Kumar B, Panchal S, et al. Comparison of sildenafil, fluoxetine and its co-administration against chronic constriction injury induced neuropathic pain in rats: An influential additive effect. Neurol Res 2019; 41(10): 875-82.
[] [PMID: 31238812]
Kumar B, Garg V, Singh S, et al. Impact of spray drying over conventional surface adsorption technique for improvement in micromeritic and biopharmaceutical characteristics of self-nanoemulsifying powder loaded with two lipophilic as well as gastrointestinal labile drugs. Powder Technol 2018; 326: 425-42.
Kaur M, Singh A, Kumar B, et al. Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats. Eur J Pharmacol 2017; 805: 58-66.
[] [PMID: 28315678]
Jyoti J, Anandhakrishnan NK, Singh SK, et al. A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability. Drug Deliv Transl Res 2019; 9(4): 848-65.
[] [PMID: 30911996]
Kumar B, Malik AH, Sharma P, et al. Validated reversed-phase high-performance liquid chromatography method for simultaneous estimation of curcumin and duloxetine hydrochloride in tablet and self-nanoemulsifying drug delivery systems. J Pharm Res 2017; 11: 1166.
Ziegler D. Painful diabetic neuropathy: treatment and future aspects. Diabetes Metab Res Rev 2008; 24(Suppl. 1): S52-7.
[] [PMID: 18395890]
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280(21): 1831-6.
[] [PMID: 9846777]
Verma V, Singh N, Singh Jaggi A. Pregabalin in neuropathic pain: evidences and possible mechanisms. Curr Neuropharmacol 2014; 12(1): 44-56.
[] [PMID: 24533015]
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015; (7): CD008242
[PMID: 26146793]
Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol 2008; 8: 29.
[] [PMID: 18673529]
Agathos E, Tentolouris A, Eleftheriadou I, et al. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res 2018; 46(5): 1779-90.
[] [PMID: 29517942]
Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28(1): 89-94.
[] [PMID: 15616239]
Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014; (7): CD010958
[] [PMID: 25058164]
Groninger H, Schisler RE. Topical capsaicin for neuropathic pain #255. J Palliat Med 2012; 15(8): 946-7.
[] [PMID: 22849599]
Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev 2017; 6CD003726
[PMID: 28616956]
Freo U, Romualdi P, Kress HG. Tapentadol for neuropathic pain: a review of clinical studies. J Pain Res 2019; 12: 1537-51.
[] [PMID: 31190965]
Przewlocki R, Przewlocka B. Opioids in neuropathic pain. Curr Pharm Des 2005; 11(23): 3013-25.
[] [PMID: 16178760]
Abotaleb M, Kubatka P, Kajo K, Büsselberg D. Flavonoids and their anti-diabetic effects: cellular mechanisms and effects to improve blood sugar levels. Biomolecules 2019; 9: 430.
Prasath GS, Sundaram CS, Subramanian SP. Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats. Endocrine 2013; 44(2): 359-68.
[] [PMID: 23277230]
Sriram Prasath G, Subramanian S. Fistein, a bioflavonoid ameliorates hyperglycemia in STZ induced experimental diabetes in rats. Int J Pharm Sci Rev Res 2011; 6: 68-74.
Prasath GS, Subramanian SP. Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Eur J Pharmacol 2011; 668(3): 492-6.
[] [PMID: 21816145]
Kim KH, Lee KW, Kim DY, Park HH, Kwon IB, Lee HJ. Optimal recovery of high-purity rutin crystals from the whole plant of Fagopyrum esculentum Moench (buckwheat) by extraction, fractionation, and recrystallization. Bioresour Technol 2005; 96(15): 1709-12.
[] [PMID: 16023574]
Chua LS. A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 2013; 150(3): 805-17.
[] [PMID: 24184193]
Gonnet J-F. Colour effects of co-pigmentation of anthocyanins revisited-2. A colorimetric look at the solutions of cyanin co-pigmented byrutin using the CIELAB scale. Food Chem 1999; 66: 387-94.
Qu J, Zhou Q, Du Y, et al. Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion. Br J Pharmacol 2014; 171(15): 3702-15.
[] [PMID: 24758388]
Dimpfel W. Rat electropharmacograms of the flavonoids rutin and quercetin in comparison to those of moclobemide and clinically used reference drugs suggest antidepressive and/or neuroprotective action. Phytomedicine 2009; 16(4): 287-94.
[] [PMID: 19303757]
Nassiri-Asl M, Shariati-Rad S, Zamansoltani F. Anticonvulsive effects of intracerebroventricular administration of rutin in rats. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(4): 989-93.
[] [PMID: 18262708]
Pedriali CA, Fernandes AU. Bernusso LdC, Polakiewicz B. The synthesis of a water-soluble derivative of rutin as an antiradical agent. Quim Nova 2008; 31: 2147-51.
Moghbelinejad S, Nassiri-Asl M, Farivar TN, et al. Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. Toxicol Lett 2014; 224(1): 108-13.
[] [PMID: 24148604]
Hao HH, Shao ZM, Tang DQ, et al. Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci 2012; 91(19-20): 959-67.
[] [PMID: 23000098]
Niture NT, Ansari AA, Naik SR. Anti-hyperglycemic activity of rutin in streptozotocin-induced diabetic rats: an effect mediated through cytokines, antioxidants and lipid biomarkers. Indian J Exp Biol 2014; 52(7): 720-7.
Stanely Mainzen Prince P, Kannan NK. Protective effect of rutin on lipids, lipoproteins, lipid metabolizing enzymes and glycoproteins in streptozotocin-induced diabetic rats. J Pharm Pharmacol 2006; 58(10): 1373-83.
[] [PMID: 17034661]
Tian R, Yang W, Xue Q, et al. Rutin ameliorates diabetic neuropathy by lowering plasma glucose and decreasing oxidative stress via Nrf2 signaling pathway in rats. Eur J Pharmacol 2016; 771: 84-92.
[] [PMID: 26688570]
Al-Enazi MM. Protective effects of combined therapy of Rutin with Silymarin on experimentally-induced diabetic neuropathy in rats. Pharmacol Pharm 2014; 5(9): 876-89.
van Acker FA, Schouten O, Haenen GR, van der Vijgh WJ, Bast A. Flavonoids can replace α-tocopherol as an antioxidant. FEBS Lett 2000; 473(2): 145-8.
[] [PMID: 10812062]
Annadurai T, Muralidharan AR, Joseph T, Hsu MJ, Thomas PA, Geraldine P. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. J Physiol Biochem 2012; 68(3): 307-18.
[] [PMID: 22234849]
Dureshahwar K, Mubashir M, Une HD. Quantification of quercetin obtained from Allium cepa Lam. leaves and its effects on streptozotocin-induced diabetic neuropathy. Pharmacognosy Res 2017; 9(3): 287-93.
[] [PMID: 28827972]
Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012; 83(4): 650-9.
[] [PMID: 22343014]
Kishore L, Kaur N, Singh R. Effect of Kaempferol isolated from seeds of Eruca sativa on changes of pain sensitivity in Streptozotocin-induced diabetic neuropathy. Inflammopharmacology 2018; 26(4): 993-1003.
[] [PMID: 29159712]
Valsecchi AE, Franchi S, Panerai AE, Rossi A, Sacerdote P, Colleoni M. The soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotrophic and vasculature deficits in diabetes mouse model. Eur J Pharmacol 2011; 650(2-3): 694-702.
[] [PMID: 21050844]
Addepalli V, Suryavanshi SV. Catechin attenuates diabetic autonomic neuropathy in streptozotocin induced diabetic rats. Biomed Pharmacother 2018; 108: 1517-23.
[] [PMID: 30372853]
Baluchnejadmojarad T, Roghani M, Khastehkhodaie Z. Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat. Phytother Res 2010; 24(8): 1120-5.
[PMID: 19960427]
Visnagri A, Kandhare AD, Chakravarty S, Ghosh P, Bodhankar SL. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharm Biol 2014; 52(7): 814-28.
[] [PMID: 24559476]
Al-Rejaie SS, Aleisa AM, Abuohashish HM, et al. Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy. Neurol Res 2015; 37(10): 924-33.
[] [PMID: 26187552]
Sandireddy R, Yerra VG, Komirishetti P, Areti A, Kumar A. Fisetin imparts neuroprotection in experimental diabetic neuropathy by modulating Nrf2 and NF-κB pathways. Cell Mol Neurobiol 2016; 36(6): 883-92.
[] [PMID: 26399251]
Mittal R, Kumar A, Singh DP, Bishnoi M, Nag TC. Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway. Inflammopharmacology 2018; 26(3): 755-68.
[] [PMID: 29094308]
Sundaram R, Shanthi P, Sachdanandam P. Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats. Phytomedicine 2014; 21(6): 793-9.
[] [PMID: 24629597]
Pu P, Wang X-A, Salim M, et al. Baicalein, a natural product, selectively activating AMPKα(2) and ameliorates metabolic disorder in diet-induced mice. Mol Cell Endocrinol 2012; 362(1-2): 128-38.
[] [PMID: 22698522]
Jain D, Bansal MK, Dalvi R, Upganlawar A, Somani R. Protective effect of diosmin against diabetic neuropathy in experimental rats. J Integr Med 2014; 12(1): 35-41.
[] [PMID: 24461593]
Tang L, Li K, Zhang Y, et al. Quercetin liposomes ameliorate streptozotocin-induced diabetic nephropathy in diabetic rats. Sci Rep 2020; 10(1): 2440.
[] [PMID: 32051470]
Hanchang W, Khamchan A, Wongmanee N, Seedadee C. Hesperidin ameliorates pancreatic β-cell dysfunction and apoptosis in streptozotocin-induced diabetic rat model. Life Sci 2019; 235116858
[] [PMID: 31505195]
Stavniichuk R, Drel VR, Shevalye H, et al. Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Exp Neurol 2011; 230(1): 106-13.
[] [PMID: 21515260]
Baluchnejadmojarad T, Roghani M. Chronic oral epigallocatechin-gallate alleviates streptozotocin-induced diabetic neuropathic hyperalgesia in rat: involvement of oxidative stress. Iran J Pharm Res 2012; 11(4): 1243-53.
[PMID: 24250559]
Raposo D, Morgado C, Pereira-Terra P, Tavares I. Nociceptive spinal cord neurons of laminae I-III exhibit oxidative stress damage during diabetic neuropathy which is prevented by early antioxidant treatment with epigallocatechin-gallate (EGCG). Brain Res Bull 2015; 110: 68-75.
[] [PMID: 25522867]
Marrazzo G, Bosco P, La Delia F, et al. Neuroprotective effect of silibinin in diabetic mice. Neurosci Lett 2011; 504(3): 252-6.
[] [PMID: 21970972]
Anjaneyulu M, Chopra K. Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27(6): 1001-5.
[] [PMID: 14499317]
Kumar A, Kaundal RK, Iyer S, Sharma SS. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci 2007; 80(13): 1236-44.
[] [PMID: 17289084]
Nagasawa T, Tabata N, Ito Y, Aiba Y, Nishizawa N, Kitts DD. Dietary G-rutin suppresses glycation in tissue proteins of streptozotocin-induced diabetic rats. Mol Cell Biochem 2003; 252(1-2): 141-7.
[] [PMID: 14577587]
Coskun O, Kanter M, Korkmaz A, Oter S. Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and β-cell damage in rat pancreas. Pharmacol Res 2005; 51(2): 117-23.
[] [PMID: 15629256]
Jung UJ, Lee M-K, Park YB, Kang MA, Choi M-S. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem Cell Biol 2006; 38(7): 1134-45.
[] [PMID: 16427799]
Tadera K, Minami Y, Takamatsu K, Matsuoka T. Inhibition of α-glucosidase and α-amylase by flavonoids. J Nutr Sci Vitaminol (Tokyo) 2006; 52(2): 149-53.
[] [PMID: 16802696]
Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 2001; 30(4): 433-46.
[] [PMID: 11182299]
Wu C-H, Yen G-C. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 2005; 53(8): 3167-73.
[] [PMID: 15826074]
Spencer JP. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2007; 2(3): 257-73.
[] [PMID: 18850181]
Hou D-X, Kumamoto T. Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Antioxid Redox Signal 2010; 13(5)
Mansuri ML, Parihar P, Solanki I, Parihar MS. Flavonoids in modulation of cell survival signalling pathways. Genes Nutr 2014; 9(3): 400.
[] [PMID: 24682883]
Khan H, Ullah H, Tundis R, et al. Dietary flavonoids in the management of Huntington’s disease: Mechanism and clinical perspective. eFood 2020; 1: 38-52.
Khan F, Niaz K, Maqbool F, et al. Molecular targets underlying the anticancer effects of quercetin: an update. Nutrients 2016; 8(9): 529.
[] [PMID: 27589790]
Zhang H-W, Hu J-J, Fu R-Q, et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci Rep 2018; 8(1): 11255.
[] [PMID: 30050147]
Wang R, Sun Y, Huang H, Wang L, Chen J, Shen W. Rutin, a natural flavonoid protects PC12 cells against sodium nitroprusside-induced neurotoxicity through activating PI3K/Akt/mTOR and ERK1/2 pathway. Neurochem Res 2015; 40(9): 1945-53.
[] [PMID: 26255195]
Newton AC. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 2001; 101(8): 2353-64.
[] [PMID: 11749377]
Chang Y-S, Kan H-W, Hsieh Y-L. Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy. J Pain Res 2019; 12: 317-26.
[] [PMID: 30679921]
Akbar S. Flavonoids in neuropathic pain management: A new player on an old target. African J Pharmacol Pharm 2019; 13(9): 100-12.
Qu Z, Liu A, Li P, et al. Advances in physiological functions and mechanisms of (-)-epicatechin. Crit Rev Food Sci Nutr 2020; 1-23.
[] [PMID: 32090598]
Qin C, Xia T, Li G, Zou Y, Cheng Z, Wang Q. Hawthorne leaf flavonoids prevent oxidative stress injury of renal tissues in rats with diabetic kidney disease by regulating the p38 MAPK signaling pathway. Int J Clin Exp Pathol 2019; 12(9): 3440-6.
[PMID: 31934188]
Peng Y, Hu M, Lu Q, et al. Flavonoids derived from Exocarpium Citri Grandis inhibit LPS-induced inflammatory response via suppressing MAPK and NF-κB signalling pathways. Food Agric Immunol 2019; 30: 564-80.
Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P. Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice. Biomed Pharmacother 2020; 122109772
[] [PMID: 31918290]
Ali MY, Zaib S, Rahman MM, et al. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chem Biol Interact 2019; 305: 180-94.
[] [PMID: 30928401]
Bakoyiannis I, Daskalopoulou A, Pergialiotis V, Perrea D. Phytochemicals and cognitive health: Are flavonoids doing the trick? Biomed Pharmacother 2019; 109: 1488-97.
[] [PMID: 30551400]
Sharma P, Kumar A, Singh D. Dietary flavonoids interaction with CREB-BDNF pathway: An unconventional approach for comprehensive management of epilepsy. Curr Neuropharmacol 2019; 17(12): 1158-75.
[] [PMID: 31400269]
Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics 2007; 8(5): 271-306.
[] [PMID: 19384426]
Kaur G, Bali A, Singh N, Jaggi AS. Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats. An Acad Bras Cienc 2015; 87(1): 417-29.
[] [PMID: 25673470]
Kaur G, Jaggi AS, Singh N. Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats. J Brachial Plex Peripher Nerve Inj 2010; 5: 3.
[PMID: 20181005]
Tölle TR. Challenges with current treatment of neuropathic pain. Eur J Pain Suppl 2010; 4: 161-5.
Quintans JS, Antoniolli ÂR, Almeida JR, Santana-Filho VJ, Quintans-Júnior LJ. Natural products evaluated in neuropathic pain models - a systematic review. Basic Clin Pharmacol Toxicol 2014; 114(6): 442-50.
[] [PMID: 24252102]
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168): 1959-64.
[] [PMID: 10371588]
Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132(3): 237-51.
[] [PMID: 17920770]
Dworkin RH, O’connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clinic Proceedings Elsevier 2010; S3-14
Vo T, Rice AS, Dworkin RH. Non-steroidal anti-inflammatory drugs for neuropathic pain: how do we explain continued widespread use? Pain 2009; 143(3): 169-71.
[] [PMID: 19362418]
Ngo LT, Okogun JI, Folk WR. 21st century natural product research and drug development and traditional medicines. Nat Prod Rep 2013; 30(4): 584-92.
[] [PMID: 23450245]
Butler MS. Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 2008; 25(3): 475-516.
[] [PMID: 18497896]
Li JW-H, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science 2009; 325(5937): 161-5.
[] [PMID: 19589993]
Gangadhar M, Kumar Mishra R, Sriram D, Yogeeswari P. Future directions in the treatment of neuropathic pain: A review on various therapeutic targets. CNS Neurol Disord Drug Targets 2014; 13(1)
Dworkin RH, Turk DC. Accelerating the development of improved analgesic treatments: the ACTION public-private partnership. Pain Med 2011; 12(Suppl. 3): S109-17.
[] [PMID: 21752182]
Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013; 154(12): 2616-25.
[] [PMID: 23732189]
Ye W, Zhao Y, Robinson RL, Swindle RW. Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder. BMC Psychiatry 2011; 11: 19.
[] [PMID: 21281479]
Arya A, Al-Obaidi MMJ, Shahid N, et al. Synergistic effect of quercetin and quinic acid by alleviating structural degeneration in the liver, kidney and pancreas tissues of STZ-induced diabetic rats: a mechanistic study. Food Chem Toxicol 2014; 71: 183-96.
[] [PMID: 24953551]
Zhang BW, Li X, Sun WL, et al. Dietary flavonoids and acarbose synergistically inhibit α-glucosidase and lower postprandial blood glucose. J Agric Food Chem 2017; 65(38): 8319-30.
[] [PMID: 28875706]
Zhang J, Lv C, Wang HN, Cao Y. Synergistic interaction between total glucosides and total flavonoids on chronic constriction injury induced neuropathic pain in rats. Pharm Biol 2013; 51(4): 455-62.
[] [PMID: 23336442]
Oboh G, Ademosun AO, Ayeni PO, Omojokun OS, Bello F. Comparative effect of quercetin and rutin on α-amylase, α-glucosidase, and some pro-oxidant-induced lipid peroxidation in rat pancreas. Comp Clin Pathol 2015; 24: 1103-10.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy