Abstract
One of the common clinical complications of diabetes is diabetic neuropathy affecting the nervous system. Painful diabetic neuropathy is widespread and highly prevalent. At least 50% of diabetes patients eventually develop diabetic neuropathy. The four main types of diabetic neuropathy are peripheral neuropathy, autonomic neuropathy, proximal neuropathy (diabetic polyradiculopathy), and mononeuropathy (Focal neuropathy). Glucose control remains the common therapy for diabetic neuropathy due to limited knowledge on early biomarkers that are expressed during nerve damage, thereby limiting the cure through pharmacotherapy. Glucose control dramatically reduces the onset of neuropathy in type 1 diabetes but proves to be less effective in type 2 diabetes. Therefore, the focus is on various herbal remedies for prevention and treatment. There is numerous research on the use of anticonvulsants and antidepressants for the management of pain in diabetic neuropathy. Extensive research is being conducted on natural products, including the isolation of pure compounds like flavonoids from plants and their effect on diabetic neuropathy. This review focuses on the use of important flavonoids such as flavanols (e.g., quercetin, rutin, kaempferol, and isorhamnetin), flavanones (e.g., hesperidin, naringenin and class eriodictyol), and flavones (e.g., apigenin, luteolin, tangeretin, chrysin, and diosmin) for the prevention and treatment of diabetic neuropathy. The mechanisms of action of flavonoids against diabetic neuropathy by their antioxidant, anti-inflammation, anti-glycation properties, etc., are also covered in this review article.
Keywords: Diabetic neuropathy, flavonoids, streptozotocin, protein kinase C, tumor necrosis factor-α, reactive oxygen species.
Graphical Abstract
[http://dx.doi.org/10.1016/j.diabres.2019.107843] [PMID: 31518657]
[http://dx.doi.org/10.4103/jncd.jncd_39_20]
[http://dx.doi.org/10.1016/j.jhep.2018.10.033] [PMID: 30414863]
[http://dx.doi.org/10.2337/dc09-9036] [PMID: 19875608]
[http://dx.doi.org/10.1038/s41572-019-0092-1] [PMID: 31197153]
[http://dx.doi.org/10.1136/jnnp.74.suppl_2.ii15] [PMID: 12754324]
[http://dx.doi.org/10.1016/j.pharmthera.2008.05.005] [PMID: 18616962]
[http://dx.doi.org/10.1039/c3np20120a] [PMID: 23450245]
[http://dx.doi.org/10.1007/s11655-012-1188-6] [PMID: 22855031]
[http://dx.doi.org/10.1016/0891-5849(95)02227-9] [PMID: 8743980]
[http://dx.doi.org/10.1016/j.brainres.2008.10.012] [PMID: 18992719]
[http://dx.doi.org/10.1016/j.ajps.2017.08.004] [PMID: 32104374]
[http://dx.doi.org/10.1111/j.1749-6632.1998.tb09922.x] [PMID: 9928450]
[http://dx.doi.org/10.1002/9780470650301.ch4]
[http://dx.doi.org/10.2187/bss.18.255] [PMID: 15858393]
[http://dx.doi.org/10.1126/science.268.5211.686] [PMID: 17832380]
[http://dx.doi.org/10.1104/pp.110.161430] [PMID: 20921162]
[http://dx.doi.org/10.1136/bmj.312.7029.478] [PMID: 8597679]
[http://dx.doi.org/10.1002/ana.23594] [PMID: 22535616]
[http://dx.doi.org/10.1007/s00204-014-1330-7] [PMID: 25182418]
[http://dx.doi.org/10.1016/0006-2952(93)90371-3] [PMID: 8424806]
[http://dx.doi.org/10.1016/j.ijantimicag.2005.09.002] [PMID: 16323269]
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.04.034] [PMID: 15223063]
[http://dx.doi.org/10.1007/s12263-009-0135-4] [PMID: 19680703]
[http://dx.doi.org/10.3389/fnut.2017.00019] [PMID: 28560212]
[http://dx.doi.org/10.1016/j.biopha.2018.10.086] [PMID: 30551400]
[http://dx.doi.org/10.1016/S0197-4580(02)00075-1] [PMID: 12392791]
[http://dx.doi.org/10.1111/j.1471-4159.2007.04841.x] [PMID: 17961201]
[http://dx.doi.org/10.1017/S0007114508965776] [PMID: 18503736]
[http://dx.doi.org/10.1007/s12263-009-0136-3] [PMID: 19685255]
[http://dx.doi.org/10.1016/j.abb.2009.10.003] [PMID: 19822127]
[http://dx.doi.org/10.1007/s11095-005-4584-1] [PMID: 15948033]
[http://dx.doi.org/10.1016/j.jnutbio.2015.01.002] [PMID: 25762527]
[http://dx.doi.org/10.1016/j.biopha.2020.110147] [PMID: 32559841]
[http://dx.doi.org/10.1016/j.phrs.2019.02.018] [PMID: 30794922]
[http://dx.doi.org/10.1039/C7FO01383C] [PMID: 29152632]
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.037] [PMID: 27890642]
[http://dx.doi.org/10.1007/s11010-010-0393-x] [PMID: 20229291]
[http://dx.doi.org/10.1053/ajkd.2001.27438] [PMID: 11576950]
[http://dx.doi.org/10.1002/phy2.230] [PMID: 24744899]
[http://dx.doi.org/10.1900/RDS.2015.12.110] [PMID: 26676664]
[http://dx.doi.org/10.1016/S1262-3636(07)70270-7] [PMID: 16799396]
[http://dx.doi.org/10.1016/j.diabres.2011.03.019] [PMID: 21514683]
[http://dx.doi.org/10.1016/j.tifs.2017.07.008]
[http://dx.doi.org/10.1007/s10787-017-0413-5] [PMID: 29094308]
[http://dx.doi.org/10.5897/AJPP2012.1534]
[http://dx.doi.org/10.1186/1744-8069-9-53] [PMID: 24152430]
[http://dx.doi.org/10.1007/s00210-014-0994-0] [PMID: 24908156]
[http://dx.doi.org/10.1097/j.pain.0000000000000492] [PMID: 27115670]
[http://dx.doi.org/10.1007/s10787-017-0416-2] [PMID: 29159712]
[http://dx.doi.org/10.3889/oamjms.2014.073]
[http://dx.doi.org/10.1007/s10753-013-9789-6] [PMID: 24337631]
[http://dx.doi.org/10.1016/j.jchemneu.2019.101709] [PMID: 31698018]
[http://dx.doi.org/10.1002/rcm.2814] [PMID: 17154349]
[http://dx.doi.org/10.1016/j.bcab.2019.101175]
[http://dx.doi.org/10.3390/ijms18081816] [PMID: 28829356]
[http://dx.doi.org/10.1111/j.2042-7158.1994.tb03753.x] [PMID: 8021799]
[http://dx.doi.org/10.1271/bbb.61.102] [PMID: 9028038]
[http://dx.doi.org/10.1016/j.tox.2006.06.018] [PMID: 16919860]
[http://dx.doi.org/10.1159/000078083] [PMID: 15240993]
[http://dx.doi.org/10.3164/jcbn.09-82] [PMID: 20104270]
[http://dx.doi.org/10.3109/13880209.2013.870584] [PMID: 24559476]
[http://dx.doi.org/10.1096/fasebj.4.6.2180767] [PMID: 2180767]
[http://dx.doi.org/10.1002/bies.950140705] [PMID: 1445287]
[PMID: 16625819]
[http://dx.doi.org/10.1161/hh2001.097797] [PMID: 11597991]
[http://dx.doi.org/10.1016/j.lfs.2006.12.036] [PMID: 17289084]
[http://dx.doi.org/10.1093/jn/134.10.2499] [PMID: 15465737]
[PMID: 2818676]
[http://dx.doi.org/10.1016/0955-2863(95)00168-9]
[http://dx.doi.org/10.1039/C9FO00881K] [PMID: 32400767]
[http://dx.doi.org/10.1179/1743132815Y.0000000079] [PMID: 26187552]
[http://dx.doi.org/10.1007/s13105-014-0369-5]
[http://dx.doi.org/10.3390/nu9050502] [PMID: 28509871]
[http://dx.doi.org/10.1016/j.bcp.2012.03.019] [PMID: 22484312]
[http://dx.doi.org/10.1002/jcb.27848] [PMID: 30317656]
[http://dx.doi.org/10.3390/ijms20061305] [PMID: 30875872]
[http://dx.doi.org/10.1152/ajprenal.00393.2016] [PMID: 28566504]
[http://dx.doi.org/10.1007/s12565-019-00486-2] [PMID: 30949912]
[http://dx.doi.org/10.13040/IJPSR.0975-8232.3(2).300-304]
[http://dx.doi.org/10.1155/2011/323171] [PMID: 21584231]
[http://dx.doi.org/10.1046/j.1523-1755.2000.07702.x] [PMID: 10997684]
[http://dx.doi.org/10.1073/pnas.0802865105] [PMID: 18490655]
[http://dx.doi.org/10.2174/138955709787001712] [PMID: 19149659]
[http://dx.doi.org/10.1016/j.lfs.2007.09.028] [PMID: 17977562]
[http://dx.doi.org/10.1023/B:MCBI.0000044364.73144.fe] [PMID: 15543940]
[http://dx.doi.org/10.1152/ajprenal.00099.2005] [PMID: 16403839]
[http://dx.doi.org/10.1016/j.numecd.2005.08.007] [PMID: 17015185]
[http://dx.doi.org/10.1097/01.ASN.0000019782.37851.BF] [PMID: 12089371]
[http://dx.doi.org/10.1681/ASN.2004080648] [PMID: 15563560]
[http://dx.doi.org/10.1097/00029330-200605020-00004] [PMID: 16732983]
[http://dx.doi.org/10.1681/ASN.V115965] [PMID: 10770977]
[http://dx.doi.org/10.1152/physrev.00011.2005] [PMID: 16601269]
[http://dx.doi.org/10.1089/ars.2007.1811] [PMID: 17845132]
[http://dx.doi.org/10.1016/j.tibs.2004.03.006] [PMID: 15130559]
[http://dx.doi.org/10.2337/diabetes.55.03.06.db05-0771] [PMID: 16505232]
[http://dx.doi.org/10.1634/stemcells.2008-0800] [PMID: 19038792]
[http://dx.doi.org/10.1124/jpet.108.145557] [PMID: 19131585]
[PMID: 26617718]
[http://dx.doi.org/10.1016/j.biopha.2018.03.169] [PMID: 29710524]
[http://dx.doi.org/10.1091/mbc.e14-03-0800] [PMID: 24943838]
[http://dx.doi.org/10.1002/ptr.2652] [PMID: 19003945]
[http://dx.doi.org/10.1016/j.febslet.2008.09.014] [PMID: 18801363]
[http://dx.doi.org/10.2337/diab.46.5.847] [PMID: 9133554]
[http://dx.doi.org/10.1016/j.jphs.2016.03.005] [PMID: 27103328]
[http://dx.doi.org/10.1016/j.ejphar.2017.09.039] [PMID: 28970015]
[http://dx.doi.org/10.1080/19768354.2020.1765019] [PMID: 33209194]
[http://dx.doi.org/10.1016/j.neuroscience.2011.12.041] [PMID: 22244975]
[http://dx.doi.org/10.1016/0304-3959(92)90003-T]
[PMID: 25932190]
[http://dx.doi.org/10.1016/j.neulet.2005.02.001] [PMID: 15882794]
[http://dx.doi.org/10.1111/j.1745-7254.2005.00123.x] [PMID: 15960884]
[http://dx.doi.org/10.1371/journal.pone.0078239] [PMID: 24244296]
[http://dx.doi.org/10.1186/s12990-015-0052-z] [PMID: 26272725]
[http://dx.doi.org/10.1016/0006-8993(79)90616-4] [PMID: 581478]
[PMID: 6152613]
[PMID: 3612540]
[http://dx.doi.org/10.1007/s11418-014-0840-1] [PMID: 24789169]
[http://dx.doi.org/10.1016/S2095-4964(14)60001-7] [PMID: 24461593]
[http://dx.doi.org/10.1007/s10753-016-0413-4] [PMID: 27492452]
[http://dx.doi.org/10.1038/s41598-019-38711-7] [PMID: 30804434]
[http://dx.doi.org/10.1056/NEJM197304192881609] [PMID: 4266466]
[http://dx.doi.org/10.1016/S0074-7742(02)50082-9] [PMID: 12198816]
[http://dx.doi.org/10.2337/diab.42.6.801] [PMID: 8495803]
[http://dx.doi.org/10.1111/j.2040-1124.2010.00070.x] [PMID: 24843457]
[http://dx.doi.org/10.1016/j.jtusci.2015.09.006]
[http://dx.doi.org/10.1089/ars.2009.2484] [PMID: 19489690]
[http://dx.doi.org/10.1073/pnas.79.21.6546] [PMID: 6959136]
[http://dx.doi.org/10.1021/jf048550u] [PMID: 15826074]
[http://dx.doi.org/10.1111/j.1529-8027.2012.00389.x] [PMID: 22548617]
[http://dx.doi.org/10.1096/fj.201700206R] [PMID: 28904018]
[http://dx.doi.org/10.1016/j.neuron.2017.02.005] [PMID: 28334605]
[http://dx.doi.org/10.1016/S0828-282X(10)71056-4] [PMID: 20386755]
[http://dx.doi.org/10.1038/35008121] [PMID: 10783895]
[http://dx.doi.org/10.1023/A:1024287327107] [PMID: 12815947]
[http://dx.doi.org/10.2337/diab.43.1.1] [PMID: 8262306]
[http://dx.doi.org/10.2337/diabetes.47.6.859] [PMID: 9604860]
[http://dx.doi.org/10.2337/diab.43.9.1122] [PMID: 8070612]
[http://dx.doi.org/10.2337/diabetes.54.6.1615] [PMID: 15919781]
[http://dx.doi.org/10.2337/diabetes.48.10.2090] [PMID: 10512378]
[http://dx.doi.org/10.1016/0006-2952(89)90309-2] [PMID: 2730676]
[http://dx.doi.org/10.3390/ijms18112296] [PMID: 29104252]
[http://dx.doi.org/10.1210/en.2019-00311] [PMID: 31318414]
[http://dx.doi.org/10.1039/c0fo00103a] [PMID: 21776454]
[http://dx.doi.org/10.1146/annurev.neuro.24.1.1217] [PMID: 11520933]
[http://dx.doi.org/10.1093/jnen/60.3.263] [PMID: 11245210]
[http://dx.doi.org/10.1155/2018/2309108] [PMID: 30648113]
[http://dx.doi.org/10.2147/DDDT.S96936] [PMID: 26730179]
[http://dx.doi.org/10.3892/ijo.23.1.17] [PMID: 12792772]
[http://dx.doi.org/10.3390/nu10040438]
[http://dx.doi.org/10.1093/toxsci/kfw139] [PMID: 27492224]
[http://dx.doi.org/10.1016/0272-0590(92)90181-G] [PMID: 1459373]
[http://dx.doi.org/10.2147/IJN.S124696] [PMID: 29593400]
[http://dx.doi.org/10.2174/1871520619666190705150214] [PMID: 31284873]
[http://dx.doi.org/10.4155/fmc-2018-0152] [PMID: 30526035]
[http://dx.doi.org/10.1111/iwj.13299] [PMID: 31876118]
[http://dx.doi.org/10.2147/IJN.S146978] [PMID: 29123394]
[http://dx.doi.org/10.3390/nano11102658] [PMID: 34685098]
[http://dx.doi.org/10.1088/0957-4484/27/37/375101] [PMID: 27491690]
[http://dx.doi.org/10.1016/j.pharep.2017.04.002] [PMID: 28624598]
[http://dx.doi.org/10.1007/s13346-012-0063-5] [PMID: 25786720]
[http://dx.doi.org/10.1039/C6RA04821H]
[http://dx.doi.org/10.2741/4771] [PMID: 30844733]
[http://dx.doi.org/10.1186/s40880-017-0217-4] [PMID: 28629389]
[http://dx.doi.org/10.1016/j.chroma.2005.10.045] [PMID: 16288764]
[http://dx.doi.org/10.1016/j.talanta.2007.05.040] [PMID: 18371609]
[http://dx.doi.org/10.1021/jf400712n] [PMID: 23713789]
[http://dx.doi.org/10.1016/j.indcrop.2013.08.017]
[http://dx.doi.org/10.3390/nu5093367] [PMID: 23989753]
[http://dx.doi.org/10.1055/s-2006-957450] [PMID: 9619120]