Table 1. Flavonoid/stilbene administration in rodent stroke models: comparison of treatment regimens, outcomes, and suggested mechanisms.
| Class | Model | Species | Extract | Dose/Route | Infarct | Function | Mechanism | Ref. |
|---|---|---|---|---|---|---|---|---|
| Flavanols | tMCAO (90 minutes) |
C57 mouse (m): WT, Nrf2−/−, HO1−/− |
EC | Dose response (2.5, 5, 15, 30 mg/kg); 90 minutes pre; 3.5 or 6 hours post; p.o. |
+WT pre (5, 15, 30 mg/ kg) and post (30 mg/kg); UC Nrf2−/−; UC HO1−/− |
+WT NDS pre and post; UC Nrf2−/−; UC HO1−/− |
Nrf2 and HO1 required for protection |
35 |
| BCCAO (10 minutes) |
ddY mouse (m) | EC or CA |
100 mg/kg ~5 minutes pre; s.c. ori.v. |
UC necrosis of cortex or hippocampus |
+Retention of passive avoidance (EC and CA); UC locomotor activity |
NA | 36 | |
| tMCAO (80 minutes) |
C57 mouse (m) | EGCG | 50 mg/kg immediately post; i.p. |
+Total volume | N/A | Reduced MMP-9 activity | 37 | |
| tMCAO (30, 60, or 90 minutes) |
Gerbil (m) | EGCG | Dose response (25 or 50 mg/kg); 30 minutes pre and immediately post; i.p. |
+50 mg/kg total volume (60 minutes tMCAO) |
N/A | Reduced lipid peroxidation (MDA) and BBB degradation (water content) |
38 | |
| BCCAO (3 minutes) |
Gerbil (m) | EGCG | Dose response (10, 25, or 50 mg/kg) immediately post; i.p. |
+CA1 hippocampal neurons (25 and 50 mg/kg) |
N/A | N/A | 39 | |
| tMCAO (2 hours) |
SD rat (m) | EGCG | 50 mg/kg immediately post; i.p. |
+Cortex; UC total and striatum |
+Sticky tape 10 days post but UC 1, 5, 14 days; UC hindlimb weight bearing |
N/A | 40 | |
| BCCAO (5 minutes) |
Gerbil (f) | GTE | Dose response (0.5, 2%); 3 weeks pre; oral ad libitum |
+Total and cortex(0.5 and 2%); +striatum (2%) |
+Locomotor activity (blocked increase) |
Reduced H2O2, lipid peroxidation, and apoptotic cells (TUNEL) (0.5 and 2%) |
41 | |
| tMCAO (2 hours) |
SD rat (m) | TOFs | Dose response (100 or 200 mg/kg 4 days pre and post; p.o. |
+Total injury, cortex, and striatum neuronal injury (100 and 200 mg/kg) |
+NDS, elevated plus maze, open field |
Reduced excitotoxicity and oxidative stress (reduced glutamate and GSH; increased SOD); reduced lipid peroxidation |
42 | |
| Flavones | pMCAO | SD rat (m) | Bai | 30 mg/kg immediately post; i.v. |
+Total infarct | +NDS | Reduced p38 MAPK, 12/15-LOX, and cPLA2α (lipid peroxidation) |
43 |
| pMCAO or tMCAO (2 hours) |
SD rat (m) | Bai | 20mg/kg 30 minutes pre, 2 and 4 hours post; i.p. |
+Total, cortex for tMCAO; UC for pMCAO |
+NDS for pMCAO (3 and 24 hours) and tMCAO (24 hours) |
Reduced apoptosis for tMCAO: caspase 3 and TUNEL |
44 | |
| tMCAO (2 hours) |
CD1 mouse (m) | Bai | 300 mg/kg immediately pre; i.p. |
N/A | N/A | Reduced apoptosis (AIF expression and colocalization with 12/15-LOX) |
45 | |
| tMCAO (2 hours) |
Wistar rat (m) | Bai | Dose response (50, 100, or 200 mg/kg immediately post); i.v. |
+Total infarct (dose dependent) |
N/A | Reduced NFkB p65 subunit (all doses) |
46 | |
| tMCAO (90 minutes) |
C57 mouse (m): WT, LOX15−/− |
Bai | 300 mg/kg immediately pre; i.v. |
+total volume for Bai and LOX15−/− |
N/A | Reduced claudin 5 degradation and edema (retention of BBB) |
47 | |
| pMCAO | SD rat (m) | Wog | 20 mg/kg 30 minutes pre and 4 hours post; i.p. |
+Total area, cortex and striatum |
+NDS | N/A | 48 | |
| tMCAO | SD rat (f) | Lut | 5 or 20 mg/kg; 6 hours pre and daily for 13 days; i.p. |
+Total area and striatum (5 and 20 mg/kg) |
+NDS (20 mg/kg at 7 days and both doses at 14 days); +Beam balance (7 and 14 days) |
Decreased ROS, GSH, and catalase (20 mg/kg effective for all; 5 mg/kg only in some brain regions) |
49 | |
| Flavonols | Focal ischemia (photo- thromb) |
SD rat (m) | Quer | 25 μmol/kg 1 hour post then daily for 3 days; i.p. |
N/A | +Locomotor activity | Reduced BBB permeability, brain water content, neuronal MMP-9 protein expression |
50 |
| tMCAO (1 hour) |
Wistar rat (m) | Kae | Dose response (50, 100, or 200 μM 30 minutes pre and immediately post); i.v. |
+Total area, cortex and striatum (100 μM only) |
N/A | Reduced MMP activity, nitrosylation, apoptosis (100 μM only) |
51 | |
| Flavanones | BCCAO (5 minutes) |
Laca mouse (m) |
Nar | Dose response (50, 100 mg/kg) 7 days pre and post; i.p. |
N/A | +NDS; +locomotor activity | Altered levels of various ROS/ redox enzymes and substrates |
52 |
| Stilbenes | pMCAO or tMCAO (2 hours) |
Balb/c mouse (m) |
Resv | Time course 50 mg/kg (5 minutes pre; 24 or 72 hours post); p.o. |
+Total volume pre- pMCAO and pre-tMCAO; UC post |
+NDS pre-pMCAO and pre-tMCAO; UC post |
Reduced MMP-2 and increased VEGF (pre only) |
53 |
| tMCAO (2 hours) |
Balb/c mouse (m) |
Resv | 50 mg/kg 7 days pre; p.o. | +Total area and total % | N/A | Reduced MMP-9 | 54 | |
| tMCAO (90 minutes) |
C57 mouse (m): WT, HO1−/− |
Resv | Dose response (5, 10, 20 mg/kg); Acute or chronic (2 hours or 7 days pre); p.o. |
+Cortex, hemisphere and striatum for WT (20 mg/ kg); UC for HO1−/− |
N/A | HO1 required for protection | 55 | |
| tMCAO (30 minutes) |
C57 mouse (m and f) |
Resv | Dose response (1, 2.5 or 5 mg/kg); Time course (3 or 6 hours post); i.v. |
+(m): total volume and cortex (5 mg/kg 3 hours post only); UC striatum and 6 hours treatments; (f): total volume (1 mg/kg only) |
N/A | Reduced ROS (superoxide) and inflammation (TNFalpha, IL1beta, Iba1) (5 mg/kg 3 hours post); showed (m) only |
56 | |
| tMCAO (2 hours) |
Wistar rat (m) | Resv | 20 mg/kg 3 weeks pre; i.p. |
+Infarct volume | +Rotorod, locomotor activity |
Reduced lipid peroxidation and oxidative stress (MDA and GSH) |
57 | |
| Isoflavones | tMCAO (90 minutes) |
Wistar rat (m) | TIF (high- soy diet) |
5 weeks pre and post; oral ad libitum |
+Cortex, striatum and total volume; +total % but UC cortex and striatum % |
+NDS | N/A | 58 |
| tMCAO (90 minutes) |
SD rat (f) (ovx) | TIF (high- soy diet) |
3 weeks pre and post; oral ad libitum |
+Total volume | N/A | Reduced apoptosis (caspase 3, TUNEL, spectrin cleavage, Bcl2, nuclear AIF); increased Bcl-xL |
59 | |
| tMCAO (90 minutes) |
SD rat (f) (ovx) | TIF (high- soy diet) |
5 weeks pre and post; oral ad libitum |
+Cortex, striatum and total % |
N/A | N/A | 60 |
−/−, knockout; +, improved outcome; AIF, apoptosis inducing factor; Bai, baicalein; BBB, blood–brain barrier; C57, C57BL/6; CA, (+)-catechin; EC, (−)-epicatechin; EGCG, (−)-epigallocatechin gallate; f, female; GTE, green tea extract; HO1, hemeoxygenase 1; i.p., intraperitoneal administration; i.v., intravenous administration; Kae, kaempferol; LOX, lipoxygenase; Lut, luteolin; m, male; MMP, matrix metalloproteinase; N/A, not applicable; Nar, naringin; NDS, neurological deficit scores; ovx, ovariectomized; p.o., oral administration; photo-thromb, cortical microvessel photothrombosis; Quer, quercetin; Resv, resveratrol; ROS, reactive oxygen species; s.c., subcutaneous administration; SD, Sprague Dawley; TIF, total isoflavones; TOF, total oligomeric flavonoids; UC, unchanged outcome; VEGF, vascular endothelial growth factor; Wog, wogonin.