Table 1.
In vivo experimental studies reporting the endogenous modulation of Nrf2 and/or Nrf2-downstream proteins after cerebral ischemia or ischemia-reperfusion.
| Species (Sex; Age) |
Experimental Model | #Findings Indicating Endogenous Modulation of Nrf2 after Ischemic Stroke | Tissue | Ref. | ||
|---|---|---|---|---|---|---|
| Specific Findings | General Effect |
|||||
| MICE | ICR mice (M; 8 weeks) |
MCAO/R (1 h/2, 8, 24, 72 h) |
↑ Nrf2, HO-1 and Trx protein expression ↓ Keap1 protein expression |
↑ | ischemic brain tissue | [90] |
| ddY mice (M; 8–12 weeks) |
MCAO/R (1 h/6, 24, 48 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic cortex and striatum | [82] | |
| CD-1 mice (M; NI) |
pMCAO (24 h) |
↑ nuclear Nrf2 translocation ↑ HO-1 protein expression ↑ SOD activity |
↑ | ischemic cerebral cortex | [91] | |
| ICR mice (M; 8–10 weeks) |
MCAO/R (1 h/24 h) |
↑ Nrf2 and HO-1 mRNA levels ↑ nuclear Nrf2 and HO-1 protein expression |
↑ | ischemic cerebral cortex | [92] | |
| OKD48 mice (M, F; 11–13 weeks) |
MCAO/R (45 min/ 12, 24, 72 h, 7 d) |
↑ Nrf2 and HO-1 protein expression | ↑ | peri-ischemic brain tissue | [93] | |
| Mice (NI) (M; 12 weeks) |
MCAO/R (2 h/24 h) |
↑ Nrf2, HO-1, GCL protein expression | ↑ | ischemic brain tissue | [94] | |
| C57BL/6 mice (M; 8 weeks) |
BCCAO/R (20 min/24 h) |
↑ Nrf2 DNA binding activity ↑ nuclear Nrf2, HO-1 and NQO1 protein expression |
↑ | striatum | [95] | |
| C57BL/6J mice (M; 8–10 weeks) |
MCAO/R (1 h/24 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [96] | |
| ICR mice (M; 6 weeks) |
MCAO/R (1 h/24–72 h, 7 d) |
↑ Nrf2 protein expression ↓ Keap1 protein expression |
↑ | ischemic brain tissue | [97] | |
| C57BL/6 mice (M; 10–18 weeks) |
pMCAO (1 d–3 d) |
↑ NQO1, HO-1, SOD2 and GPX-1 protein expression | ↑ | ischemic brain tissue | [89] | |
| C57BL/6 mice (M; 10–12 weeks) |
MCAO/R (1.5 h/7 d) |
↑ Nrf2 and SOD1 protein expression | ↑ | ischemic brain tissue | [98] | |
| ddY mice (M; 5–8 weeks) |
MCAO/R (2 h/2, 6, 22 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [99] | |
| CD-1 mice (M; 4 weeks) |
MCAO/R (1 h/24 h) |
↑ Nrf2 and HO-1 mRNA ↑ Nrf2 and HO-1 protein ↑ HO-1 activity |
↑ | ischemic brain tissue | [100] | |
| C57BL/6 mice (M; 12 weeks) |
MCAO/R (1 h/3 d) |
↑ nuclear Nrf2, HO-1 and NQO1 protein expression | ↑ | cerebral tissue | [101] | |
| ICR mice (M; NI) |
MCAO/R (2 h/24 h) |
↑ cytosolic Nrf2, HO-1 and NQO1 protein expression | ↑ | hippocampus | [102] | |
| BALB/c mice (M; 7 weeks) |
MCAO/R (1.5 h/24–72 h) |
↑ Nrf2, HO-1 and iNOS protein expression ↓ SOD activity |
↑ | ischemic brain tissue | [103] | |
| ICR mice (M; 8 weeks) |
p dMCAO (7 d) |
↑ Nrf2 protein expression | ↑ | ischemic cerebral cortex | [104] | |
| C57BL/6J mice (M; NI) |
MCAO/R (1.5 h/24 h) |
↓ SOD 2, HO-1, NQO1 and Nrf2 protein expression ↓ SOD activity ↑ NADPH oxidase protein expression |
↓ | ischemic brain tissue | [105] | |
| C57BL/6 mice (M; NI) |
MCAO/R (1 h/72 h) |
↓ Nrf2 protein expression | ↓ | hippocampus and cerebral cortex | [106] | |
| RATS | SD rats (M; adult) |
MCAO/R (2 h/2, 6, 24 h) |
↑ Nrf2 and HO-1 protein expression ↑ Nrf2 and HO-1 mRNA levels |
↑ | ischemic cerebral cortex | [107] |
| SD rats (M; NI) |
pMCAO (72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic cerebral cortex | [108] | |
| SD rats (M; adult) |
pMCAO (72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [109] | |
| SD rats (M; NI) |
MCAO/R (70min/ 4, 24, 72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [110] | |
| SD rats (M; 9 weeks) |
MCAO/R (1 h/24 h) |
↑ Nrf2 and NQO1 protein expression ↑ Nrf2 binding activity to ARE |
↑ | ischemic brain tissue | [111] | |
| SD rats (M; adult) |
MCAO/R (2 h/22 h) |
↑ Nrf2 (nuclear) and HO-1 protein expression | ↑ | cerebral cortex | [112] | |
| SD rats (M; adult) |
MCAO/R (2 h/24 h) |
↑ Nrf2 protein expression ↑ HO-1 protein expression |
↑ | ischemic brain tissue | [113] | |
| SD rats (M; NI) |
pMCAO (24 h) |
↑ nuclear Nrf2 translocation ↑ HO-1 protein expression ↑ Nrf2 and HO-1 mRNA levels |
↑ | ischemic brain tissue | [114] | |
| SD rats (M; NI) |
pMCAO (24 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [115] | |
| SD rats (M; adult) |
MCAO/R (1 h/ 72 h) |
↑ Nrf2 and NQO1 protein expression | ↑ | ischemic cerebral cortex | [116] | |
| Wistar rats (M; NI) |
MCAO/R (1 h/72 h) |
↑ Nrf2, HO-1 and NQO1 mRNA levels | ↑ | ischemic brain tissue | [117] | |
| Wistar rats (M; 6 months) |
BCCAO/R (30 min/72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | hippocampus | [118] | |
| SD rats (M; NI) |
pMCAO (72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [119] | |
| SD rats (M; 10–12 weeks) |
MCAO/R (1 h/24 h) |
↑ Nrf2, Txr-1, Prdx1, Prdx2, Prdx3 and Prdx4 protein expression ↑ Nrf2, Txr-1, Prdx1, Prdx2, Prdx3 and Prdx4 mRNA levels |
↑ | ischemic brain tissue | [120] | |
| SD rats (M; NI) |
MCAO/R (2 h/24 h) |
↑ Nrf2 protein expression ↑ Nrf2 mRNA levels ↓ SOD activity |
↑ | ischemic brain tissue | [121] | |
| SD rats (NI; NI) |
BCCAO/R (10 min/1–7 d) |
↑ Nrf2 and HO-1 protein expression | ↑ | ischemic brain tissue | [122] | |
| SD rats (M; adult) |
MCAO/R (1.5 h/24 h) |
↑ Nrf2 and HO-1 protein expression ↑ Nrf2 and HO-1 mRNA levels |
↑ | hippocampus | [123] | |
| SD rats (M; adult) |
pMCAO (24 h) |
↑ nuclear Nrf2 translocation ↑ HO-1 and SOD1 protein expression ↑ HO-1 mRNA levels ↑ SOD1 activity |
↑ | ischemic cerebral cortex | [124] | |
| SD rats (M; adult) |
MCAO/R (2 h/ 72 h) |
↑ Nrf2 protein expression ↑ HO-1 protein expression |
↑ | ischemic brain tissue | [125] | |
| SD rats (M; NI) |
MCAO/R (2 h/7 d) |
↑ Nrf2 protein expression | ↑ | ischemic brain tissue | [126] | |
| SD rats (M; adult) |
MCAO/R (1 h/24 h) |
↑ Nrf2, NQO1 and Srnx1 protein expression ↑ Prdx 1, Prdx 2, Prdx 3, Prdx 4 protein expression |
↑ | ischemic brain tissue | [127] | |
| Hannover-Wistar rats (M; NI) |
MCAO/R (1 h/24 h) |
↑ Nrf2 protein expression ↑ SOD and GPx activity |
↑ | hippocampus | [128] | |
| Wistar rats (M; adult) |
BCCAO/R (45 min/24 h) |
↑ iNOS and Nrf2 protein expression | ↑ | hippocampus | [129] | |
| SD rats (M; 60–80 days) |
MCAO/R (1 h/24 h) |
↑ Nrf2 and Trx1 mRNA levels ↑ Trx1 protein expression |
↑ | ischemic brain tissue | [130] | |
| SD rats (F; adult) |
MCAO/R (1.5 h/72 h) |
↑ Nrf2 and NQO1 protein expression | ↑ | ischemic brain tissue | [131] | |
| Wistar rats (M; adult) |
MCAO/R (1.5 h/72 h) |
↑ Nrf2, HO-1 and NQO1 mRNA levels | ↑ | ischemic brain tissue | [132] | |
| SD rats (M; adult) |
PCI (20 min) |
↑ Nrf2 and HO-1 protein expression | ↑ | cerebral cortex ischemic penumbra | [133] | |
| SD rats (M; NI) |
Focal PTI | ↑ Nrf2 and HO-1 protein expression | ↑ | penumbra of cerebral infarction | [134] | |
| SD rats (M; 7–10 weeks) |
MCAO/R (2 h/72 h) |
↑ Nrf2 and HO-1 protein expression | ↑ | cerebral cortex and striatum | [135] | |
| SD rats (M; NI) |
MCAO/R (1 h/6 or 24 h) |
↑ Nrf2 protein expression ↓ SOD activity |
↑ | ischemic penumbra | [136] | |
| SD rats (M; Adult) |
MCAO/R (2 h/72 h) |
↑ nuclear Nrf2 protein expression ↓ cytosolic Nrf2, NQO1 and HO-1 protein expression ↓ SOD activity |
↑ | ischemic brain tissue | [137] | |
| SD rats (M; 8 weeks) |
MCAO/R (2 h/24 h) |
↑ HO-1 protein expression ↓ Nrf2 and Trx protein expression |
↑↓ | cerebral cortex | [113] | |
| SD rats (M; adult) |
MCAO/R (2 h/72 h) |
↓ SOD activity ↓ Nrf2, HO-1 and NQO1 protein expression |
↓ | ipsilateral ischemic tissue | [138] | |
| SD rats (M; 10 months) |
MCAO/R (2 h/48 h) |
↓ HO-1 protein expression ↓ SOD activity |
↓ | ipsilateral ischemic tissue | [139] | |
| Wistar rats (M; NI) |
MCAO/R (2 h/24 h) |
↓ GPx and SOD activity ↓ Nrf2 and NQO1 protein expression |
↓ | ischemic brain tissue | [140] | |
| SD rats (M; 3 months) |
MCAO/R (1.5 h/72 h) |
↓ NQO1, HO-1 and cytoplasmic Nrf2 protein expression | ↓ | ischemic brain tissue | [141] | |
| SD rats (M; 7–8 weeks) |
MCAO/R (1.5 h/7 d) |
↓ Nrf2 mRNA levels | ↓ | ischemic brain tissue | [142] | |
| SD rats (M; NI) |
MCAO/R (2 h/7 d) |
↓ SOD activity ↓ nuclear Nrf2, HO-1 and NQO1 protein expression ↓ Nrf2, HO-1 and NQO1 mRNA levels |
↓ | cerebral cortex | [143] | |
| SD rats (NI; NI) |
BCCAO/R (10 min occlusion + 10 min reperfusion + 10 min occlusion) |
↓ Nrf2, NQO1 and HO-1 protein expression ↓ SOD activity |
↓ | ischemic brain tissue | [144] | |
| SD rats (F; NI) |
MCAO/R (1 h/24 h) |
↓ Nrf2 protein expression | ↓ | hippocampus | [145] | |
| SD rats (M; NI) |
MCAO/R (1.5 h/14 d) |
↓ Nrf2 protein expression ↑ Keap-1 protein expression ↓ SOD and catalase activities |
↓ | ischemic brain tissue | [146] | |
Abbreviations and symbols: ↑, activation. ↓, inhibition. M, male; F, female. SD rats, Sprague-Dawley rats. NI, not informed. BCCAO, bilateral common carotid arteries occlusion. MCAO, middle cerebral artery occlusion. MCAO/R, middle cerebral artery occlusion followed by reperfusion. PCI, photochemical cerebral ischemia. pdMCAO, permanent distal middle cerebral artery occlusion. pMCAO, permanent middle cerebral artery occlusion. PTI, photothrombotic ischemia model. ARE, antioxidant response element. HO-1, heme oxygenase 1. NQO1, NAD(P)H:quinone oxidoreductase 1. Prdx, peroxiredoxin. SOD, superoxide dismutase. Srnx1, sulfiredoxin-1. Trx1, thioredoxin. Notes: # Only significant differences between control/sham and ischemic animals were evaluated. HO-1, Heme oxygenase 1: Nrf2-downstream protein catalyzing the degradation of heme, producing biliverdin, ferrous iron and carbon monoxide. NQO1, NAD(P)H:quinone oxidoreductase 1: Nrf2-downstream protein catalyzing the two-electron reduction of quinones and a wide range of other organic compounds. Its physiological role is partly related to the reduction of free radical load in cells and the detoxification of xenobiotics. Prdxs, peroxiredoxins: ubiquitous family of Nrf2-downstream antioxidant enzymes involved in the reduction of peroxides (specifically hydrogen peroxide). SODs, superoxide dismutases: enzymes catalyzing the dismutation of the superoxide radical into molecular oxygen and hydrogen peroxide. Srnx, Sulfiredoxin: Nrf2-downstream protein member of the oxidoreductases family catalyzing reduction of oxidative modifications (i.e., sulfinic, disulfides, etc.). Trx, Thioredoxin: class of small redox (Nrf2-downstream) proteins playing important roles in redox signaling.