Review Article

Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications

Table 1

Neuroprotective flavonoids and their functional mechanisms and targetsa.

CompoundsMechanisms and targetsRef.

Flavones (15)
 ApigeninAnti-inflammation: iNOS↓, COX-2↓, p-p38↓, p-JNK↓; histone deacetylases↓; BDNF/CREB/Syn-1↑[77, 125]
 APGAntioxidation: p-STAT3↑[126]
 VitexinAntiapoptosis: p-Erk↑, p-JNK↓, p-p38↓[127]
 BaicaleinAnti-inflammation: NF-κB↓, p-MAPKs↓, arachidonic acid release↓: 12/15-LOX/p38 MAPK/cPLA2↓; antiapoptosis; antiautophagy: PI3K/Akt/mTOR↑[82, 109]
 BaicalinAntiapoptosis: p-CaMKII↓; antioxidation: peroxynitrite scavenging↑; anti-inflammation: TLR2/4/NF-κB↓; mitochondrial function↑: Drp-1↓, Mfn2↓, AMPKα1↑[94, 128131]
 ChrysinAnti-inflammation: NF-κB↓, COX-2↓, iNOS↓; antioxidation[78, 132, 133]
 DiosminBcl-2/Bax↑; JAK2/STAT3↑[134]
 GinkgetinAntioxidation; anti-inflammation: JAK2/STAT3/SIRT1↓[135]
 HispidulinNLRP3-mediated pyroptosis↓; AMPK/GSK3β[136]
 LuteolinAnti-inflammation: TLR4/5/p38/NF-κB↓; antioxidation; antiapoptosis[95, 137, 138]
 LuteolosideAnti-inflammation: PPARγ↑/Nrf2↑/NF-κB↓[139]
 OrientinAntioxidation; anti-inflammation: TLR4/NF-κB/TNF-α↓; AQP-4↓[140]
 NobiletinAnti-inflammation: TLR4/NF-κB↓; antioxidation: Nrf2/HO-1↑; antiapoptosis: Akt/mTOR↑; BDNF-Akt/CREB↑; BBB permeability↓[60, 141143]
 ScutellarinAnti-inflammation: ACE/Ang II/AT1R↓, microglial activation↓, microglial-mediated astrogliosis↑, Notch-1/Nestin↑; neurotrophin expression↑: BDNF/NGF/GDNF-Akt/CREB↑; antioxidation[67, 144147]
 Tricin 7-glucosideAnti-inflammation: NF-κB activation↓, HMGB1 expression↓[148]
Flavanones (7)
 EriodictyolAnti-inflammation[152]
 Eriodictyol-7-O-glucosideAntioxidation in astrocytes: Nrf2/ARE↑[153]
 HesperidinAntioxidation: NO pathway↓[154]
 NaringeninBBB protection: NOD2/RIP2/NF-κB/MMP-9↓; antiapoptosis; anti-inflammation: NF-κB↓; antioxidation: Nrf2[61, 85, 155]
 NaringinONOO-mediated excessive mitophagy↓[156]
 NeohesperidinAntiapoptosis; antioxidation: Akt/Nrf2/HO-1↑[157]
 PinocembrinAntiapoptosis; autophagy↑; anti-inflammation: sEH/EETs↓; neuronal loss↓; astrocyte proliferation↓[29, 158160]
Flavanols (3)
 (−)-Epicatechin (EC)Anti-inflammation: microglial activation↓; antioxidation: Nrf2/HO-1↑[68, 163]
 (−)-Epigallocatechin-3-Gallate (EGCG)Calcium modulation and antiexcitotoxicity: TRPC6 degradation↓/MEK/Erk/CREB↑, balance between the excitatory and inhibitory amino acids↑; antiapoptosis: PI3K/Akt/eNOS↑; antioxidation: Nrf2/ARE↑; anti-inflammation: NF-κB↓; BBB protection: MMP-2↓, MMP-9↓; ER stress↓[37, 164170]
 Procyanidin B2BBB protection; antioxidation: Nrf2↑[171]
Flavonols (10)
 FisetinAnti-inflammation: macrophage infiltration↓, microglial activation↓, JNK/NF-κB↓[69]
 GalanginMicroenvironment of the neurovascular unit (NVU)↑: Wnt/β-catenin↑, HIF-1α/VEGF↑; mitochondrial protection and antiapoptosis: Bax/Bcl-2↓[101, 175]
 IcariinHDAC↓/CREB↑; SIRT1/PGC-1α↑; anti-inflammation: PPARα/γ↑, NF-κB↓[89, 176, 177]
 Kaempferol-3-O-rutinoside (KRS)/glucoside (KGS)Anti-inflammation: STAT3↓, NF-κB↓[178]
 Kaempferide-7-O-(4-O-acetylrhamnosyl)-3-O-rutinosideAnti-inflammation; antioxidation; antiapoptosis[179]
 QuercetinEnergy metabolism↑; antioxidation; PP2A subunit B↑; antiapoptosis[180182]
 RutinEstrogen receptors↑: BDNF/TrkB/Akt↑ and NGF/TrkA/CREB↑; BBB protection: MMP-9 activity↓[119, 183]
 IsoquercetinAntiapoptosis; anti-inflammation and antioxidation: Nrf2↑, NOX4/ROS/NF-κB↓, MAPK/TLR4/NF-κB↓[54, 184]
 IsorhamnetinNrf2/HO-1↑; iNOS/NO↓[185]
 MyricetinAnti-inflammation: p38/NF-κB↓; antioxidation; p-Akt↑[186]
Isoflavones (6)
 CalycosinAnti-inflammation: microglial activation↓; antiapoptosis; antiautophagy; BDNF/TrkB↑; calcium modulation: TRPC6/CREB[43, 70, 190, 191]
 Calycosin-7-O-β-D-glucosideBBB protection: NO↓/Cav-1↑/MMPs↓[192]
 FormononetinBax/Bcl-2↓; PI3K/Akt↑[193]
 GenisteinAntioxidation: Nrf2↑; antiapoptosis: PI3K/Akt/mTOR↑; Erk activation↑; ROS/NF-κB↓; antiplatelet aggregation; vascular protection[194199]
 DaidzeinROS production↓[200]
 PuerarinAntiautophagy; anti-inflammation: neutrophil activation↓, HIF-1α↓, α7nAchR↑; antiapoptosis: PI3K/Akt1/GSK-3β/MCL-1↑; BDNF secret↑[70, 109, 110]
Anthocyanidins, chalcones, and flavonolignans (5)
 Cyanidin-3-O-glucosideAntiapoptosis: oxidative stress-induced AIF release↓[211]
 Hydroxysafflor yellow A (HSYA)Antioxidation↓; anti-inflammation: TLR4/MAPK/NF-κB↓; antiapoptosis: PI3K/Akt/GSK3β↑, mPTP opening↓; neurotrophin release↑: BDNF↑, GFAP↑, NGF↑; autophagy↑: Akt↑; mitochondrial function and biogenesis↑; phenylalanine synthesis↓[98, 106, 212215]
 XanthohumolAnti-inflammation; antiapoptosis; platelet activation↓[216]
 Silibinin/silybinAnti-inflammation; antioxidation; antiapoptosis and antiautophagy: PI3K/Akt/mTOR↑[104, 217]
 SilymarinAntioxidation; antiapoptosis[218]

aNotes: ↑: activation or upregulation; ↓: inhibition or downregulation. Abbreviations do not appear in the text. ACE: angiotensin-converting enzyme; Ang II: angiotensin II; AT1R: angiotensin type 1 receptor; AQP-4: aquaporin-4; Drp-1: dynamin-related protein 1; GFAP: glial fibrillary acidic protein; Mfn2: mitofusin 2; NOD2: nucleotide oligomerization domain 2; RIP2: receptor-interacting protein kinase 2; Syn-1: synaptophysin-1; VEGF: vascular endothelial growth factor.