Abstract
Diabetic neuropathy (DN) is a common and debilitating complication of diabetes mellitus that affects the peripheral nerves and causes pain, numbness, and impaired function. The pathogenesis of DN involves multiple molecular mechanisms, such as oxidative stress, inflammation, and pathways of advanced glycation end products, polyol, hexosamine, and protein kinase C. Phytochemicals are natural compounds derived from plants that have various biological activities and therapeutic potential. Flavonoids, terpenes, alkaloids, stilbenes, and tannins are some of the phytochemicals that have been identified as having protective potential for diabetic neuropathy. These compounds can modulate various cellular pathways involved in the development and progression of neuropathy, including reducing oxidative stress and inflammation and promoting nerve growth and repair. In this review, the current evidence on the effects of phytochemicals on DN by focusing on five major classes, flavonoids, terpenes, alkaloids, stilbenes, and tannins, are summarized. This compilation also discusses the possible molecular targets of numerous pathways of DN that these phytochemicals modulate. These phytochemicals may offer a promising alternative or complementary approach to conventional drugs for DN management by modulating multiple pathological pathways and restoring nerve function.
Keywords: Diabetes, neuropathy, inflammation, phytochemicals, flavonoids, alkaloids.
[http://dx.doi.org/10.1038/ncpneuro0504] [PMID: 17549059]
[http://dx.doi.org/10.1055/s-0035-1558983]
[http://dx.doi.org/10.1136/pgmj.2005.036137] [PMID: 16461471]
[http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]
[http://dx.doi.org/10.2337/dc16-2042] [PMID: 27999003]
[http://dx.doi.org/10.1016/S1474-4422(12)70065-0] [PMID: 22608666]
[http://dx.doi.org/10.1080/19390211.2018.1441203] [PMID: 29580105]
[http://dx.doi.org/10.2337/diacare.26.6.1790] [PMID: 12766111]
[http://dx.doi.org/10.1159/000052078] [PMID: 10023127]
[http://dx.doi.org/10.1001/jama.280.21.1863] [PMID: 9846782]
[http://dx.doi.org/10.1002/dmrr.360] [PMID: 12577252]
[http://dx.doi.org/10.1016/j.neuron.2017.02.005] [PMID: 28334605]
[http://dx.doi.org/10.1111/j.2040-1124.2010.00083.x] [PMID: 24843458]
[http://dx.doi.org/10.3113/FAI.2008.1049] [PMID: 18851825]
[http://dx.doi.org/10.1111/j.1526-4637.2007.00347.x] [PMID: 18828198]
[http://dx.doi.org/10.1016/j.nurt.2009.07.004] [PMID: 19789069]
[http://dx.doi.org/10.2337/dc09-2314] [PMID: 20587724]
[http://dx.doi.org/10.1007/s001250051227] [PMID: 10440118]
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a072307] [PMID: 2507085]
[http://dx.doi.org/10.1016/j.phrs.2013.12.005] [PMID: 24373831]
[http://dx.doi.org/10.1016/S0074-7742(02)50082-9] [PMID: 12198816]
[http://dx.doi.org/10.2337/db07-0339] [PMID: 18039814]
[http://dx.doi.org/10.1172/JCI118117] [PMID: 7635966]
[http://dx.doi.org/10.1007/s001250051439] [PMID: 10550410]
[http://dx.doi.org/10.1007/s00125-008-1136-3] [PMID: 18802679]
[http://dx.doi.org/10.1016/S0074-7742(08)60283-4] [PMID: 2557297]
[http://dx.doi.org/10.1152/ajpendo.00029.2011] [PMID: 21810933]
[http://dx.doi.org/10.2174/138945008783431718] [PMID: 18220713]
[http://dx.doi.org/10.1111/j.1085-9489.2004.09105.x] [PMID: 14871451]
[http://dx.doi.org/10.1016/j.trsl.2011.12.004] [PMID: 22500508]
[http://dx.doi.org/10.1038/414813a] [PMID: 11742414]
[http://dx.doi.org/10.1161/01.RES.84.5.489] [PMID: 10082470]
[http://dx.doi.org/10.1677/joe.1.06269] [PMID: 16214939]
[http://dx.doi.org/10.1016/j.neuint.2005.12.009] [PMID: 16524643]
[http://dx.doi.org/10.1111/j.1529-8027.2009.00237.x] [PMID: 20021567]
[http://dx.doi.org/10.1046/j.1525-1381.1999.99220.x] [PMID: 10354364]
[http://dx.doi.org/10.1111/j.1440-1746.2009.05823.x] [PMID: 19646010]
[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/10.1194/jlr.R067629] [PMID: 27080715]
[http://dx.doi.org/10.1016/S0024-3205(97)01143-0] [PMID: 9570335]
[http://dx.doi.org/10.1083/jcb.201312123] [PMID: 24687278]
[http://dx.doi.org/10.1194/jlr.M086843] [PMID: 30442656]
[http://dx.doi.org/10.1210/er.2001-0039] [PMID: 12372842]
[http://dx.doi.org/10.1007/s11892-010-0120-8] [PMID: 20464532]
[http://dx.doi.org/10.1161/CIRCRESAHA.110.217117] [PMID: 20431074]
[http://dx.doi.org/10.1002/dmrr.307] [PMID: 12203947]
[http://dx.doi.org/10.1046/j.1529-8027.2003.03016_14.x]
[http://dx.doi.org/10.1016/j.pharmthera.2008.05.005] [PMID: 18616962]
[http://dx.doi.org/10.1211/jpp.61.09.0002] [PMID: 19703362]
[http://dx.doi.org/10.1073/pnas.97.22.12222] [PMID: 11050244]
[http://dx.doi.org/10.1172/JCI119875] [PMID: 9421478]
[http://dx.doi.org/10.1074/jbc.271.25.15237] [PMID: 8663078]
[http://dx.doi.org/10.1074/jbc.273.14.8225] [PMID: 9525928]
[http://dx.doi.org/10.1146/annurev.biochem.66.1.315] [PMID: 9242909]
[http://dx.doi.org/10.1172/JCI11235] [PMID: 11696579]
[http://dx.doi.org/10.1016/S0021-9258(19)67706-9] [PMID: 2002019]
[http://dx.doi.org/10.2337/diabetes.54.12.3435] [PMID: 16306359]
[http://dx.doi.org/10.1111/j.2040-1124.2010.00070.x] [PMID: 24843457]
[http://dx.doi.org/10.2337/diabetes.51.8.2619] [PMID: 12145179]
[http://dx.doi.org/10.1172/JCI18058] [PMID: 15599399]
[http://dx.doi.org/10.1155/2013/168039]
[http://dx.doi.org/10.2337/db11-0807] [PMID: 22025779]
[http://dx.doi.org/10.1016/j.bbadis.2011.03.008] [PMID: 21439372]
[http://dx.doi.org/10.1016/j.ejphar.2016.08.022] [PMID: 27568833]
[http://dx.doi.org/10.3892/ijo.10.6.1093] [PMID: 21533489]
[http://dx.doi.org/10.1161/hh0102.102657] [PMID: 11786525]
[http://dx.doi.org/10.1161/01.RES.83.1.85] [PMID: 9670921]
[http://dx.doi.org/10.3892/ijmm.20.6.783] [PMID: 17982684]
[http://dx.doi.org/10.1007/s00125-004-1356-0] [PMID: 15298348]
[http://dx.doi.org/10.2337/db06-1176] [PMID: 17626889]
[http://dx.doi.org/10.2337/diabetes.53.3.711] [PMID: 14988256]
[http://dx.doi.org/10.1016/j.freeradbiomed.2007.09.013] [PMID: 17976390]
[http://dx.doi.org/10.1016/j.expneurol.2007.03.019] [PMID: 17475250]
[http://dx.doi.org/10.2337/diabetes.50.12.2837] [PMID: 11723068]
[http://dx.doi.org/10.1083/jcb.150.2.293] [PMID: 10908573]
[http://dx.doi.org/10.1167/iovs.08-2191] [PMID: 19098320]
[http://dx.doi.org/10.2337/db06-0147] [PMID: 17065336]
[http://dx.doi.org/10.1073/pnas.052712399] [PMID: 11854472]
[http://dx.doi.org/10.1096/fj.99-0803com]
[http://dx.doi.org/10.1155/2018/9591845] [PMID: 30622618]
[http://dx.doi.org/10.1016/0955-2863(95)00168-9]
[http://dx.doi.org/10.1111/j.1749-6632.1998.tb09922.x] [PMID: 9928450]
[http://dx.doi.org/10.1016/S0271-5317(98)00169-9]
[http://dx.doi.org/10.1146/annurev.nutr.22.111401.144957] [PMID: 12055336]
[http://dx.doi.org/10.1016/0891-5849(94)90202-X] [PMID: 8070690]
[http://dx.doi.org/10.1016/0306-3623(93)90159-U] [PMID: 8224739]
[http://dx.doi.org/10.1002/jmv.1890150110] [PMID: 2981979]
[http://dx.doi.org/10.3748/wjg.v19.i38.6416] [PMID: 24151360]
[http://dx.doi.org/10.1016/j.biopha.2020.110147] [PMID: 32559841]
[http://dx.doi.org/10.1016/j.ejphar.2020.173266] [PMID: 32553736]
[http://dx.doi.org/10.1002/jcp.27091] [PMID: 30145789]
[http://dx.doi.org/10.1016/j.jdiacomp.2005.05.011] [PMID: 16112498]
[http://dx.doi.org/10.1016/S0278-5846(03)00160-X] [PMID: 14499317]
[http://dx.doi.org/10.3390/foods6100092] [PMID: 29065496]
[http://dx.doi.org/10.1016/j.ejphar.2013.11.033] [PMID: 24315931]
[http://dx.doi.org/10.7150/ijms.5224] [PMID: 23471081]
[http://dx.doi.org/10.1016/j.neulet.2013.12.019] [PMID: 24370596]
[http://dx.doi.org/10.3389/fnins.2017.00755] [PMID: 29422835]
[http://dx.doi.org/10.1155/2021/8787231] [PMID: 33532012]
[http://dx.doi.org/10.1590/s0102-865020180060000008] [PMID: 30020315]
[http://dx.doi.org/10.1016/j.neuropharm.2017.11.007] [PMID: 29122628]
[http://dx.doi.org/10.1097/FBP.0b013e3283512c00] [PMID: 22411174]
[http://dx.doi.org/10.1007/s11130-004-0049-7] [PMID: 15678717]
[http://dx.doi.org/10.3889/oamjms.2014.073]
[http://dx.doi.org/10.1007/s10787-017-0416-2] [PMID: 29159712]
[http://dx.doi.org/10.3390/nu14122387] [PMID: 35745117]
[http://dx.doi.org/10.3109/13880209.2013.870584] [PMID: 24559476]
[http://dx.doi.org/10.1016/j.exger.2022.112064] [PMID: 36528304]
[PMID: 35946912]
[http://dx.doi.org/10.1080/19768354.2020.1765019] [PMID: 33209194]
[http://dx.doi.org/10.5530/ijper.56.3s.154]
[http://dx.doi.org/10.1016/j.cbi.2023.110402] [PMID: 36804429]
[http://dx.doi.org/10.1002/jcp.28488] [PMID: 30916403]
[http://dx.doi.org/10.1007/s10072-014-1784-7] [PMID: 24737349]
[http://dx.doi.org/10.1016/j.cyto.2016.08.002] [PMID: 27529541]
[http://dx.doi.org/10.4103/0973-1296.191453] [PMID: 27761071]
[http://dx.doi.org/10.1139/cjpp-2014-0412] [PMID: 26863330]
[http://dx.doi.org/10.3389/fphar.2021.639840] [PMID: 33854437]
[http://dx.doi.org/10.1016/j.jnutbio.2022.108967] [PMID: 35189328]
[http://dx.doi.org/10.1007/s11356-022-18754-6] [PMID: 35119637]
[http://dx.doi.org/10.3389/fimmu.2021.712608] [PMID: 34249019]
[http://dx.doi.org/10.1016/j.phrs.2020.105264] [PMID: 33166734]
[http://dx.doi.org/10.1093/cdn/nzaa025] [PMID: 32391511]
[http://dx.doi.org/10.3389/fphar.2022.873090] [PMID: 35529431]
[http://dx.doi.org/10.3390/life12122111] [PMID: 36556476]
[http://dx.doi.org/10.1016/j.fitote.2012.01.010] [PMID: 22343014]
[http://dx.doi.org/10.1089/ars.2012.4901] [PMID: 23121441]
[http://dx.doi.org/10.1007/s10571-015-0272-9] [PMID: 26399251]
[http://dx.doi.org/10.1016/j.phrs.2015.10.007] [PMID: 26520392]
[http://dx.doi.org/10.3344/kjp.2019.32.3.160] [PMID: 31257824]
[http://dx.doi.org/10.1016/S2095-4964(14)60001-7] [PMID: 24461593]
[http://dx.doi.org/10.3390/ph12010011] [PMID: 30634637]
[http://dx.doi.org/10.1007/s13105-014-0369-5] [PMID: 25407136]
[http://dx.doi.org/10.1179/1743132815Y.0000000079] [PMID: 26187552]
[http://dx.doi.org/10.1039/C9FO00881K] [PMID: 32400767]
[http://dx.doi.org/10.1146/annurev.arplant.59.032607.092730] [PMID: 18251710]
[http://dx.doi.org/10.1007/978-3-319-74210-6_8]
[http://dx.doi.org/10.1007/978-3-540-79116-4_2]
[http://dx.doi.org/10.1002/med.21703] [PMID: 32729169]
[http://dx.doi.org/10.3389/fphar.2018.00557] [PMID: 30186157]
[http://dx.doi.org/10.1016/j.ejphar.2016.02.007] [PMID: 26849937]
[http://dx.doi.org/10.1142/S0192415X17500926] [PMID: 29121795]
[http://dx.doi.org/10.1089/jmf.2012.2648] [PMID: 23734996]
[http://dx.doi.org/10.1016/j.neuropharm.2017.12.029] [PMID: 29273519]
[http://dx.doi.org/10.1177/2058738419866379] [PMID: 31337260]
[http://dx.doi.org/10.1155/2012/164219]
[http://dx.doi.org/10.1016/j.ejphar.2018.08.025] [PMID: 30130525]
[http://dx.doi.org/10.2174/092986712801323171] [PMID: 22680628]
[http://dx.doi.org/10.1248/bpb.32.597] [PMID: 19336890]
[http://dx.doi.org/10.1001/archinte.1991.00400110079017] [PMID: 1953227]
[http://dx.doi.org/10.2217/pmt-2021-0025] [PMID: 35152709]
[http://dx.doi.org/10.1038/s41598-021-81427-w] [PMID: 33462325]
[http://dx.doi.org/10.1093/bja/aer260] [PMID: 21852280]
[http://dx.doi.org/10.3389/fphar.2021.639020] [PMID: 33859564]
[http://dx.doi.org/10.1155/2015/827308] [PMID: 26229546]
[http://dx.doi.org/10.1016/B978-0-323-91097-2.00006-6]
[http://dx.doi.org/10.1016/j.phytochem.2022.113128] [PMID: 35183567]
[http://dx.doi.org/10.1016/B978-0-12-401717-7.00049-6]
[http://dx.doi.org/10.2174/09298673113209990151] [PMID: 24206125]
[http://dx.doi.org/10.1016/j.lfs.2020.117350] [PMID: 31982401]
[http://dx.doi.org/10.1016/j.jocn.2005.12.010] [PMID: 17258134]
[http://dx.doi.org/10.1016/j.bbrc.2003.08.105] [PMID: 13679076]
[http://dx.doi.org/10.1016/j.bbrc.2010.03.014] [PMID: 20211601]
[http://dx.doi.org/10.1093/brain/aws097] [PMID: 22561641]
[http://dx.doi.org/10.1111/j.1472-8206.2006.00455.x] [PMID: 17227449]
[http://dx.doi.org/10.1016/j.lfs.2006.12.036] [PMID: 17289084]
[http://dx.doi.org/10.1016/j.biopha.2019.109767] [PMID: 32058210]
[http://dx.doi.org/10.18632/aging.202830] [PMID: 33770763]
[http://dx.doi.org/10.1002/ptr.2070] [PMID: 17199240]
[http://dx.doi.org/10.1517/13543776.2014.870154] [PMID: 24387185]
[http://dx.doi.org/10.1089/jmf.2018.0157] [PMID: 30864870]
[http://dx.doi.org/10.3390/molecules25010106] [PMID: 31892132]
[http://dx.doi.org/10.4236/pp.2012.34053]
[http://dx.doi.org/10.1016/B978-0-08-045316-3.00008-9]
[PMID: 22556651]
[http://dx.doi.org/10.1016/j.bcab.2019.101342]
[http://dx.doi.org/10.1039/b101061l] [PMID: 11820762]
[http://dx.doi.org/10.1016/j.foodchem.2023.135645] [PMID: 36821920]
[http://dx.doi.org/10.1111/bph.13630] [PMID: 27646690]
[http://dx.doi.org/10.1016/j.brainresbull.2014.12.004] [PMID: 25522867]
[PMID: 24250559]
[http://dx.doi.org/10.1016/j.ejphar.2011.11.037] [PMID: 22173123]
[http://dx.doi.org/10.1002/jbt.22508] [PMID: 32275810]
[http://dx.doi.org/10.1016/j.neulet.2011.12.070] [PMID: 22249118]
[http://dx.doi.org/10.1093/bja/aen339] [PMID: 19059929]
[http://dx.doi.org/10.1007/s13300-018-0550-x] [PMID: 30565054]
[http://dx.doi.org/10.3390/life12081185] [PMID: 36013364]
[http://dx.doi.org/10.1016/S0028-3908(01)00172-1] [PMID: 11804619]
[http://dx.doi.org/10.1136/bmj.j4441] [PMID: 28947423]
[http://dx.doi.org/10.1111/j.1468-1331.2010.02999.x] [PMID: 20402746]
[http://dx.doi.org/10.1212/WNL.37.4.589] [PMID: 2436092]
[http://dx.doi.org/10.2337/dc10-1793] [PMID: 21355098]
[http://dx.doi.org/10.23937/2572-3987.1510001]
[http://dx.doi.org/10.1016/0304-3959(91)90157-S] [PMID: 1861872]
[http://dx.doi.org/10.1056/NEJM199205073261904] [PMID: 1560801]
[http://dx.doi.org/10.1002/dmrr.1225] [PMID: 21695762]
[http://dx.doi.org/10.2165/00003088-200443130-00004] [PMID: 15509185]
[PMID: 28616956]
[http://dx.doi.org/10.2165/00002512-199507040-00007] [PMID: 8535059]
[http://dx.doi.org/10.1016/j.biopha.2022.113439] [PMID: 36076554]
[http://dx.doi.org/10.1016/j.clinthera.2017.02.010] [PMID: 28365034]