Abstract
Cerebral ischemic stroke is a disease with high prevalence and incidence. Its management focuses on rapid reperfusion with intravenous thrombolysis and endovascular thrombectomy. Both therapeutic strategies reduce disability, but the therapy time window is short, and the risk of bleeding is high. Natural products (NPs) have played a key role in drug discovery, especially for cancer and infectious diseases. However, they have made little progress in clinical translation and pose challenges to the treatment of stroke. Recently, with the investigation of precise mechanisms in cerebral ischemic stroke and the technological development of NP-based drug discovery, NPs are addressing these challenges and opening up new opportunities in cerebral stroke. Thus, in this review, we first summarize the structure and function of diverse NPs, including flavonoids, phenols, terpenes, lactones, quinones, alkaloids, and glycosides. Then we propose the comprehensive neuroprotective mechanism of NPs in cerebral ischemic stroke, which involves complex cascade processes of oxidative stress, mitochondrial damage, apoptosis or ferroptosis-related cell death, inflammatory response, and disruption of the blood-brain barrier (BBB). Overall, we stress the neuroprotective effect of NPs and their mechanism on cerebral ischemic stroke for a better understanding of the advances and perspective in NPs application that may provide a rationale for the development of innovative therapeutic regimens in ischemic stroke.
Keywords: Ischemic stroke, natural products, neuroprotection, antioxidation, mitochondrial dysfunction, ER stress, apoptosis, inflammation.
[http://dx.doi.org/10.1161/CIR.0000000000001052] [PMID: 35078371]
[http://dx.doi.org/10.1038/nn.2953] [PMID: 22030546]
[http://dx.doi.org/10.1161/STR.0b013e318296aeca] [PMID: 23652265]
[http://dx.doi.org/10.1038/s41572-019-0118-8] [PMID: 31601801]
[http://dx.doi.org/10.1016/S0140-6736(14)60584-5] [PMID: 25106063]
[http://dx.doi.org/10.1016/S0140-6736(16)00163-X] [PMID: 26898852]
[http://dx.doi.org/10.1002/med.21817] [PMID: 33957000]
[http://dx.doi.org/10.1172/JCI11003] [PMID: 10995780]
[http://dx.doi.org/10.1001/jamaneurol.2013.6299] [PMID: 24590416]
[http://dx.doi.org/10.3389/fneur.2018.00249] [PMID: 29740385]
[http://dx.doi.org/10.1016/j.pharmthera.2020.107749] [PMID: 33227325]
[http://dx.doi.org/10.1039/C5NP00121H] [PMID: 26739749]
[http://dx.doi.org/10.1126/science.1168243] [PMID: 19589993]
[http://dx.doi.org/10.1038/nature03194] [PMID: 15602548]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01120] [PMID: 29140691]
[http://dx.doi.org/10.1038/s41573-020-00114-z] [PMID: 33510482]
[http://dx.doi.org/10.1021/jm300288g] [PMID: 22537178]
[http://dx.doi.org/10.1016/j.biotechadv.2015.08.001] [PMID: 26281720]
[http://dx.doi.org/10.1038/nrd4510] [PMID: 25614221]
[http://dx.doi.org/10.3390/molecules21060807] [PMID: 27338339]
[http://dx.doi.org/10.1038/s41582-018-0082-z] [PMID: 30315270]
[http://dx.doi.org/10.1038/s41598-018-36138-0] [PMID: 30584250]
[http://dx.doi.org/10.1016/j.pharmthera.2020.107695] [PMID: 32998014]
[http://dx.doi.org/10.1078/09447110260571760] [PMID: 12222672]
[http://dx.doi.org/10.1186/s12974-019-1516-2] [PMID: 31291966]
[http://dx.doi.org/10.1016/S1474-4422(19)30078-X] [PMID: 31296369]
[http://dx.doi.org/10.1161/STROKEAHA.112.659656] [PMID: 22933588]
[http://dx.doi.org/10.1038/nrneurol.2014.207] [PMID: 25385337]
[http://dx.doi.org/10.3892/mmr.2020.11003] [PMID: 32323760]
[http://dx.doi.org/10.1186/1750-1326-6-11] [PMID: 21266064]
[http://dx.doi.org/10.1016/j.tibtech.2020.01.008] [PMID: 32497514]
[http://dx.doi.org/10.1016/j.tplants.2006.11.006] [PMID: 17161643]
[http://dx.doi.org/10.1080/10408398.2012.656770] [PMID: 24915384]
[http://dx.doi.org/10.1007/s10753-010-9254-8] [PMID: 20859668]
[http://dx.doi.org/10.1016/j.brainresbull.2011.05.002] [PMID: 21600966]
[http://dx.doi.org/10.1016/j.brainres.2012.06.026] [PMID: 22796597]
[http://dx.doi.org/10.1155/2013/120261] [PMID: 23878589]
[http://dx.doi.org/10.1016/j.neuroscience.2007.09.033] [PMID: 17942241]
[http://dx.doi.org/10.1111/j.1471-4159.2009.06561.x] [PMID: 20050973]
[http://dx.doi.org/10.1016/j.brainres.2016.03.019] [PMID: 27016057]
[http://dx.doi.org/10.14336/AD.2017.0829] [PMID: 29344420]
[http://dx.doi.org/10.1016/j.phrs.2020.104795] [PMID: 32278035]
[http://dx.doi.org/10.3892/mmr.2013.1671] [PMID: 24026460]
[http://dx.doi.org/10.7150/ijbs.17751] [PMID: 28367097]
[http://dx.doi.org/10.1186/1423-0127-16-9] [PMID: 19272172]
[http://dx.doi.org/10.1016/j.biopha.2017.03.039] [PMID: 28343073]
[http://dx.doi.org/10.1021/acschemneuro.0c00697] [PMID: 33270442]
[http://dx.doi.org/10.1155/2022/9749461] [PMID: 35251482]
[http://dx.doi.org/10.1016/j.biopha.2021.112039] [PMID: 34392086]
[http://dx.doi.org/10.1186/s12974-014-0226-z] [PMID: 25600517]
[http://dx.doi.org/10.1111/j.1745-7254.2005.00239.x] [PMID: 16297343]
[http://dx.doi.org/10.3390/molecules170910667] [PMID: 22955455]
[http://dx.doi.org/10.1155/2018/7017204] [PMID: 30622670]
[http://dx.doi.org/10.1039/D0FO02555K] [PMID: 33599218]
[http://dx.doi.org/10.1016/j.biopha.2018.01.067] [PMID: 29710456]
[http://dx.doi.org/10.1016/j.phymed.2015.01.009] [PMID: 25837275]
[http://dx.doi.org/10.1155/2017/8526438] [PMID: 29317985]
[http://dx.doi.org/10.1016/j.ceca.2008.12.007] [PMID: 19201465]
[http://dx.doi.org/10.1016/j.neulet.2008.12.045] [PMID: 19135132]
[http://dx.doi.org/10.3390/ijms12118181] [PMID: 22174658]
[http://dx.doi.org/10.1038/s41598-017-03404-6] [PMID: 28596571]
[http://dx.doi.org/10.1161/STROKEAHA.115.008921] [PMID: 25908459]
[http://dx.doi.org/10.1016/j.arr.2017.02.004] [PMID: 28235660]
[http://dx.doi.org/10.1161/STROKEAHA.117.018562] [PMID: 29018134]
[http://dx.doi.org/10.1161/STROKEAHA.115.009876] [PMID: 26159789]
[http://dx.doi.org/10.1021/acsami.8b20594] [PMID: 30618231]
[http://dx.doi.org/10.1016/S1043-6618(02)00123-8] [PMID: 12220971]
[http://dx.doi.org/10.1016/j.msec.2020.111314] [PMID: 32919674]
[http://dx.doi.org/10.1155/2021/1552127] [PMID: 34630845]
[http://dx.doi.org/10.1016/j.biopha.2022.112719] [PMID: 35168073]
[PMID: 11324448]
[http://dx.doi.org/10.1016/j.phymed.2009.01.007] [PMID: 19481432]
[http://dx.doi.org/10.1016/j.biomaterials.2013.05.021] [PMID: 23768781]
[http://dx.doi.org/10.1007/s12975-017-0526-6] [PMID: 28243834]
[http://dx.doi.org/10.1155/2017/4517486] [PMID: 28690763]
[http://dx.doi.org/10.1016/j.apsb.2019.01.010] [PMID: 31193821]
[http://dx.doi.org/10.1016/j.phrs.2021.105989] [PMID: 34800628]
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.09.006] [PMID: 27609227]
[http://dx.doi.org/10.1038/s41401-020-00568-2] [PMID: 33303991]
[http://dx.doi.org/10.1155/2022/2152746] [PMID: 35222793]
[http://dx.doi.org/10.1139/apnm-2016-0651] [PMID: 28388366]
[http://dx.doi.org/10.1111/bcpt.13282] [PMID: 31237736]
[http://dx.doi.org/10.1007/s10495-021-01684-y] [PMID: 34269920]
[http://dx.doi.org/10.2174/138945010791170842] [PMID: 20298150]
[http://dx.doi.org/10.1016/j.phrs.2022.106240] [PMID: 35513225]
[http://dx.doi.org/10.1038/jcbfm.1990.17] [PMID: 2298830]
[http://dx.doi.org/10.1002/ptr.7018] [PMID: 33452698]
[http://dx.doi.org/10.1111/cns.12577] [PMID: 27306494]
[http://dx.doi.org/10.4103/1673-5374.232476] [PMID: 30028328]
[http://dx.doi.org/10.1016/j.phrs.2015.10.008] [PMID: 26546042]
[http://dx.doi.org/10.7150/ijbs.6.443] [PMID: 20827397]
[http://dx.doi.org/10.1155/2017/5058609] [PMID: 28785376]
[http://dx.doi.org/10.1016/j.phymed.2020.153300] [PMID: 32866905]
[http://dx.doi.org/10.1186/s12974-021-02216-w] [PMID: 34372857]
[http://dx.doi.org/10.1186/s12974-018-1124-6] [PMID: 29540209]
[http://dx.doi.org/10.1155/2022/7420507] [PMID: 35035665]
[http://dx.doi.org/10.3389/fnins.2020.00847] [PMID: 32848589]
[http://dx.doi.org/10.1016/j.taap.2015.10.001] [PMID: 26440581]
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.027] [PMID: 19272442]
[http://dx.doi.org/10.1055/s-0042-120544] [PMID: 27894149]
[http://dx.doi.org/10.2147/NDT.S179845] [PMID: 31213817]
[http://dx.doi.org/10.1159/000452672] [PMID: 28049198]
[http://dx.doi.org/10.1039/C5NP00006H] [PMID: 25976887]
[http://dx.doi.org/10.1089/ars.2016.6885] [PMID: 28186440]
[http://dx.doi.org/10.1155/2022/3079577] [PMID: 35154564]
[http://dx.doi.org/10.1080/21691401.2019.1699831] [PMID: 31851841]
[http://dx.doi.org/10.1186/s12974-014-0167-6] [PMID: 25256700]
[http://dx.doi.org/10.1055/s-2003-40447] [PMID: 13130395]
[http://dx.doi.org/10.1016/j.neuroscience.2006.08.037] [PMID: 17014966]
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.03.028] [PMID: 24681253]
[http://dx.doi.org/10.3389/fphar.2020.00979] [PMID: 32676033]
[http://dx.doi.org/10.1016/j.phymed.2022.154111] [PMID: 35512628]
[http://dx.doi.org/10.1016/j.phymed.2021.153884] [PMID: 34929562]
[http://dx.doi.org/10.1021/acs.jafc.6b04979] [PMID: 28169530]
[http://dx.doi.org/10.1039/C7CS00553A] [PMID: 29099127]
[http://dx.doi.org/10.1039/c2np00086e] [PMID: 22382850]
[http://dx.doi.org/10.1016/j.msec.2020.111619] [PMID: 33321661]
[http://dx.doi.org/10.3390/ijms21082899] [PMID: 32326191]
[http://dx.doi.org/10.1039/D1FO01144H] [PMID: 34286782]
[http://dx.doi.org/10.3969/j.issn.1673-5374.2013.15.002] [PMID: 25206430]
[http://dx.doi.org/10.1146/annurev.arplant.59.032607.092730] [PMID: 18251710]
[http://dx.doi.org/10.1016/j.ejmech.2014.11.021] [PMID: 25466923]
[http://dx.doi.org/10.1016/j.bioorg.2020.103795] [PMID: 32240871]
[http://dx.doi.org/10.1111/bph.14102] [PMID: 29161771]
[http://dx.doi.org/10.1111/j.1745-7254.2007.00514.x] [PMID: 17302993]
[http://dx.doi.org/10.3389/fphar.2021.710358] [PMID: 34393790]
[http://dx.doi.org/10.1016/j.ejphar.2019.04.028] [PMID: 31004602]
[http://dx.doi.org/10.1161/STROKEAHA.110.589895] [PMID: 20947850]
[http://dx.doi.org/10.1155/2017/7150376] [PMID: 28690765]
[http://dx.doi.org/10.1111/cns.13146] [PMID: 31087454]
[http://dx.doi.org/10.1007/s11011-019-00505-1] [PMID: 31728890]
[http://dx.doi.org/10.3389/fphar.2021.609693] [PMID: 33995012]
[http://dx.doi.org/10.1038/s41401-018-0160-1] [PMID: 30266998]
[http://dx.doi.org/10.1007/s10571-019-00675-7] [PMID: 31020571]
[http://dx.doi.org/10.1021/ar200296m] [PMID: 22493991]
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.11.033] [PMID: 30502455]
[http://dx.doi.org/10.3390/molecules24091838] [PMID: 31086091]
[http://dx.doi.org/10.3892/ijmm.2020.4777] [PMID: 33416112]
[http://dx.doi.org/10.1159/000503361] [PMID: 31825924]
[http://dx.doi.org/10.1155/2017/8424326] [PMID: 28303172]
[http://dx.doi.org/10.3389/fphar.2020.580428] [PMID: 33536907]
[http://dx.doi.org/10.3390/cells7120270] [PMID: 30545139]
[http://dx.doi.org/10.2147/DDDT.S160776] [PMID: 29872270]
[http://dx.doi.org/10.1080/10408398.2019.1653822] [PMID: 31456411]
[http://dx.doi.org/10.1016/j.redox.2022.102363] [PMID: 35696763]
[http://dx.doi.org/10.1021/jacs.0c10836] [PMID: 33439015]
[http://dx.doi.org/10.1016/j.phrs.2019.04.021] [PMID: 31048033]
[http://dx.doi.org/10.3389/fphar.2022.766744] [PMID: 35401225]
[http://dx.doi.org/10.1016/j.neuroscience.2021.08.006] [PMID: 34416342]
[http://dx.doi.org/10.1038/aps.2012.35] [PMID: 22543703]
[http://dx.doi.org/10.1016/j.ejphar.2012.01.016] [PMID: 22306244]
[http://dx.doi.org/10.1186/1472-6882-13-236] [PMID: 24066702]
[http://dx.doi.org/10.1038/aps.2010.66] [PMID: 20644551]
[http://dx.doi.org/10.1093/brain/awh316] [PMID: 15469948]
[http://dx.doi.org/10.1016/j.neuron.2019.03.029] [PMID: 30982627]
[http://dx.doi.org/10.1016/j.pneurobio.2013.10.003] [PMID: 24157661]
[http://dx.doi.org/10.1016/S0896-6273(03)00496-3] [PMID: 12925277]
[http://dx.doi.org/10.1007/s001090000077] [PMID: 10759025]
[http://dx.doi.org/10.1002/jnr.490380103] [PMID: 8057391]
[http://dx.doi.org/10.1038/s41598-018-22852-2] [PMID: 29615639]
[http://dx.doi.org/10.2174/1389203720666190507102948] [PMID: 31060485]
[http://dx.doi.org/10.1038/jcbfm.2011.77] [PMID: 21587268]
[http://dx.doi.org/10.1080/14756366.2017.1396457] [PMID: 29185359]
[http://dx.doi.org/10.1152/physrev.00026.2013] [PMID: 24987008]
[http://dx.doi.org/10.1038/nm1577] [PMID: 17486089]
[http://dx.doi.org/10.1196/annals.1341.022] [PMID: 16093501]
[http://dx.doi.org/10.1016/j.neuropharm.2014.11.020] [PMID: 25510970]
[http://dx.doi.org/10.1016/j.mam.2011.10.006] [PMID: 22020111]
[http://dx.doi.org/10.1039/C3NP70065H] [PMID: 24292194]
[http://dx.doi.org/10.1038/aps.2016.156] [PMID: 28216621]
[http://dx.doi.org/10.1038/s41580-020-0210-7] [PMID: 32071438]
[http://dx.doi.org/10.1016/j.redox.2018.03.002] [PMID: 29549824]
[http://dx.doi.org/10.1124/pharmrev.121.000418] [PMID: 35302047]
[http://dx.doi.org/10.18632/aging.101931] [PMID: 31043575]
[http://dx.doi.org/10.1146/annurev-pharmtox-010715-103155] [PMID: 26566156]
[http://dx.doi.org/10.1056/NEJMra1215233] [PMID: 24304053]
[http://dx.doi.org/10.1371/journal.pone.0020655] [PMID: 21647385]
[http://dx.doi.org/10.1016/j.bbrc.2015.03.045] [PMID: 25791474]
[http://dx.doi.org/10.1038/cdd.2012.18] [PMID: 22388349]
[http://dx.doi.org/10.1016/j.neuroscience.2013.03.015] [PMID: 23523995]
[http://dx.doi.org/10.1016/j.ejphar.2013.04.033] [PMID: 23685326]
[http://dx.doi.org/10.1007/s11064-014-1315-1] [PMID: 24777807]
[http://dx.doi.org/10.1007/s12035-015-9627-y] [PMID: 26687185]
[http://dx.doi.org/10.1016/j.biopha.2019.109295] [PMID: 31545255]
[http://dx.doi.org/10.1021/np3008182] [PMID: 23421714]
[http://dx.doi.org/10.1038/s41580-020-00324-8] [PMID: 33495651]
[http://dx.doi.org/10.1038/mp.2017.171] [PMID: 28886009]
[http://dx.doi.org/10.1016/j.phrs.2021.105580] [PMID: 33781874]
[http://dx.doi.org/10.1111/j.1750-3639.2000.tb00262.x] [PMID: 10764048]
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[http://dx.doi.org/10.1016/S0092-8674(00)81589-5] [PMID: 9727491]
[http://dx.doi.org/10.1124/pr.57.2.6] [PMID: 15914467]
[http://dx.doi.org/10.1002/anie.200502698] [PMID: 16404760]
[http://dx.doi.org/10.1038/nrd1554] [PMID: 15558860]
[http://dx.doi.org/10.1016/j.tibtech.2003.08.006] [PMID: 14573360]
[http://dx.doi.org/10.1016/S0278-5846(03)00022-8] [PMID: 12657366]
[http://dx.doi.org/10.1002/ptr.2913] [PMID: 19585476]
[http://dx.doi.org/10.1007/s10495-012-0715-4] [PMID: 22453599]
[http://dx.doi.org/10.1016/j.ejmech.2020.113030] [PMID: 33248849]
[http://dx.doi.org/10.1038/s41598-017-12788-4] [PMID: 29018243]
[http://dx.doi.org/10.1038/s41586-019-1548-x] [PMID: 31511692]
[http://dx.doi.org/10.1016/j.phrs.2021.105756] [PMID: 34237440]
[http://dx.doi.org/10.4161/auto.3412] [PMID: 17035724]
[http://dx.doi.org/10.1080/15548627.2018.1531196] [PMID: 30304977]
[http://dx.doi.org/10.4161/auto.25132] [PMID: 23800795]
[http://dx.doi.org/10.1111/bpa.12472] [PMID: 27936516]
[http://dx.doi.org/10.1038/cddis.2017.330] [PMID: 28726776]
[http://dx.doi.org/10.4161/auto.6412] [PMID: 18567942]
[http://dx.doi.org/10.1080/15548627.2015.1132134] [PMID: 26727396]
[http://dx.doi.org/10.4161/auto.28264] [PMID: 24674959]
[http://dx.doi.org/10.1016/j.biotechadv.2018.03.012] [PMID: 29597027]
[http://dx.doi.org/10.1097/WNR.0000000000000975] [PMID: 29360689]
[http://dx.doi.org/10.3390/ijms20071523] [PMID: 30934670]
[http://dx.doi.org/10.1016/j.ejphar.2018.05.029] [PMID: 29787772]
[http://dx.doi.org/10.1016/S1474-4422(12)70238-7] [PMID: 23237905]
[http://dx.doi.org/10.1002/jnr.20631] [PMID: 16175570]
[http://dx.doi.org/10.1146/annurev-immunol-032414-112116] [PMID: 25493331]
[http://dx.doi.org/10.1038/sj.cdd.4401373] [PMID: 14685163]
[http://dx.doi.org/10.1016/j.pharmthera.2005.05.008] [PMID: 16140387]
[http://dx.doi.org/10.1038/nrm3270] [PMID: 22251901]
[http://dx.doi.org/10.1007/BF01986687] [PMID: 7725971]
[http://dx.doi.org/10.1039/C4NP00102H] [PMID: 25703279]
[http://dx.doi.org/10.1093/brain/aws269] [PMID: 23169919]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4529] [PMID: 16651429]
[http://dx.doi.org/10.1126/science.7732382] [PMID: 7732382]
[http://dx.doi.org/10.1038/ni0107-11] [PMID: 17179963]
[http://dx.doi.org/10.1080/08923973.2017.1344988] [PMID: 28703078]
[http://dx.doi.org/10.1039/C5SC00633C] [PMID: 28717468]
[http://dx.doi.org/10.1007/s10753-015-0137-x] [PMID: 25687641]
[http://dx.doi.org/10.1016/j.fct.2012.08.047] [PMID: 22960133]
[http://dx.doi.org/10.1142/S0192415X13500080] [PMID: 23336510]
[http://dx.doi.org/10.1016/j.ijdevneu.2009.08.008] [PMID: 19712738]
[http://dx.doi.org/10.1248/bpb.31.1387] [PMID: 18591780]
[http://dx.doi.org/10.1142/S0192415X15500639] [PMID: 26364663]
[http://dx.doi.org/10.1016/j.nbd.2003.12.016] [PMID: 15207256]
[http://dx.doi.org/10.1002/ana.410010502] [PMID: 617259]
[http://dx.doi.org/10.1016/j.addr.2021.01.015] [PMID: 33497734]
[http://dx.doi.org/10.3233/JAD-190357] [PMID: 31306129]
[http://dx.doi.org/10.1161/STROKEAHA.117.017287] [PMID: 29724893]
[http://dx.doi.org/10.1101/cshperspect.a020412] [PMID: 25561720]
[PMID: 12528312]
[http://dx.doi.org/10.2174/1389450118666170427151657] [PMID: 28460607]
[http://dx.doi.org/10.1186/s12906-015-0678-4] [PMID: 26012470]
[http://dx.doi.org/10.1016/j.phymed.2010.03.017] [PMID: 20570121]
[http://dx.doi.org/10.1016/j.expneurol.2012.07.017] [PMID: 22868201]
[http://dx.doi.org/10.1016/j.jep.2013.05.018] [PMID: 23707212]
[http://dx.doi.org/10.1016/j.neuropharm.2008.01.005] [PMID: 18308346]
[http://dx.doi.org/10.1016/j.ejmech.2018.11.014] [PMID: 30445263]
[http://dx.doi.org/10.1007/s11910-022-01172-z] [PMID: 35138587]
[http://dx.doi.org/10.3390/brainsci11091164] [PMID: 34573185]
[http://dx.doi.org/10.3390/ijerph18041415] [PMID: 33546463]
[http://dx.doi.org/10.1136/svn-2020-000431] [PMID: 32616524]
[http://dx.doi.org/10.1177/0271678X18793324] [PMID: 30114967]
[http://dx.doi.org/10.1161/STROKEAHA.108.540781] [PMID: 19211488]