Table 1.
Summary of the experimental studies involving natural compounds able to modulate Nrf2 pathway in in vivo stroke models.
| Natural Compound | Sources | Experimental Model | Tested Doses and Administration | Results | Nrf2 Mechanism | Ref. |
|---|---|---|---|---|---|---|
| Theaflavin | Black tea | In vivo: Rats subjected to tMCAO; In vitro: Primary rat NSCs exposed to OGD |
In vivo: 10, 50 mg/kg i.v. 2 h after MCAO, daily for a week; In vitro: 2 and 10 µM for 2 h before OGD. |
In vivo: ↓ infarct volume and oxidative stress; ↑ memory and learning. In vitro: ↓ apoptosis and oxidative stress; ↑ proliferation. |
↓ miRNA-128-3p ↑ Nrf2 and downstream antioxidant enzymes |
[28] |
| (-)-Epigallocatechin-3-gallate | Green tea | Mice subjected to tMCAO | 50 mg/kg i.p at the end of surgery and daily for a week | ↓ infarct volume; ↑ neurologic function and angiogenesis. | ↑ ERK/Nrf2 | [30] |
| (-)-epicatechin | Green tea | WT and Nrf−/− mice subjected to pdMCAO | 15 mg/kg by gavage 90 min before pdMCAO | ↓ infarct volume | - | [31] |
| (-)-epicatechin | Green tea | Mouse WT and Nrf−/− astrocytes treated with hemoglobin | 10 µM before or after hemoglobin treatment | ↓ oxidative stress and AP-1 | ↑ Nrf2/SOD1 | [35] |
| Nomilin | Citrus fruits | In vivo: Rats subjected to tMCAO; In vitro: SH-SY5Y cells exposed to OGD |
In vivo: 50 mg/kg orally 2 h before MCAO (for neurobehavioral tests: 2 h before tests every day for 6 days); In vitro: 0.1, 0.25, 0.5, 1, 2, 4, 8 μM for 12 h after OGD |
In vivo: ↓ infarct volume, brain edema, BBB disruption, and oxidative stress; ↑ neurological score. In vitro: ↓ apoptosis and oxidative stress |
↑ Nrf2 and antioxidant enzymes | [39] |
| Naringenin | Citrus fruits | In vivo: Rats subjected to MCAO; In vitro: rat cortical neurons exposed to OGD |
In vivo: 80 μM i.p. after MCAO; In vitro: 20, 40, and 80 μM after OGD. |
In vivo: ↓ brain edema and apoptosis; ↑ neurological score. In vitro: ↓ apoptosis and oxidative stress; ↑ proliferation. |
↑ antioxidant enzymes | [41] |
| Nobiletin | Citrus peel | Rats subjected to pMCAO | 10 and 25 mg/kg i.p. daily starting 3 days before MCAO induction and a dose after | ↓ brain edema, infarct volume, oxidative stress, and inflammation; ↑ neurological score. | ↑ Nrf2 and antioxidant enzymes | [43] |
| Linalool | Citrus peel and citrus essential oils | In vivo: rats subjected to tMCAO; In vitro: rat primary astrocyte and microglial cultures treated with glutamate |
In vivo: 25 mg/kg intranasal daily for one month In vitro: 100 nM for 24 h |
In vivo: ↓ infarct volume and inflammation; ↑ neurological score. In vitro: ↓ inflammation. |
- | [46] |
| S-allyl cysteine | Garlic | In vivo: WT and Nrf2−/− mice subjected to tMCAO; In vitro: rat cortical neurons exposed to OGD |
In vivo: 300 mg/kg i.p. 30 min before MCAO; In vitro: 10, 25, and 50 µM pre-treated for 2 h before OGD and also after OGD. |
In vivo: ↓ infarct volume, JNK, and p38; ↑ neurological score. In vitro: ↓ JNK and p38; ↑ cell viability. |
↑ Nrf2 and downstream antioxidant enzymes | [55] |
| Diallyl trisulfide | Garlic | In vivo: rats subjected to tMCAO | 15 mg/kg, i.p. 4 doses once a day. The first dose 5 min before the onset of reperfusion | ↓ brain damage, infarct volume, oxidative stress, and MMP9; ↑ motor function. | ↑ Nrf2 and downstream antioxidant enzymes | [56] |
| Dihydrocapsaicin | Chili peppers | Rats subjected to tMCAO | 2.5, 5 and 10 mg/kg i.p. 15 min previous cerebral reperfusion | ↓ neurological deficits, infarct area, BBB damage, inflammation, and oxidative stress | ↑ Nrf2 and antioxidant enzymes | [57] |
| Rosmarinic acid | Rosemary and Lamiaceae herbs | Mice subjected to tMCAO | 10, 20, or 40 mg/kg i.p. at reperfusion | ↓ apoptosis, infarct volume, and oxidative stress; ↑ neurological function | ↑ PI3K/Akt ↑ Nrf2 and antioxidant enzymes | [58] |
| Curcumin | Turmeric | Rats subjected to tMCAO | 300 mg/kg i.p. 30 min after occlusion. | ↓ BBB disruption, brain edema, infarct volume, inflammation, and oxidative stress; ↑ neurological function | ↑ Nrf2 | [59] |
| Hexahydrocurcumin | Turmeric | Rats subjected to MCAO | 10, 20, and 40 mg/kg i.p. at reperfusion onset | ↓ infarct volume, apoptosis inflammation, and oxidative stress; ↑ neurological function | ↑ Nrf2 and antioxidant enzymes | [60] |
| Lyciumamide A | Lycium barbarum | In vivo: Rats subjected to tMCAO; In vitro: differentiated SH-SY5Y cells exposed to OGD |
In vivo: 40 mg/kg i.p.at the end of MCAO surgery In vitro: 10, 20, 40 µM for 8 h before OGD |
In vivo: ↓ infarct volume and oxidative stress; ↑ neurologic function. In vitro: ↓ apoptosis and oxidative stress. |
↑ PKCε/Nrf2/antioxidant enzymes | [62] |
| Mangiferin | Mango and papaya | Rats subjected to tMCAO | 25, 50, and 100 mg/kg i.g. daily for 3 days before the MCAO | ↓ infarct volume, brain edema, inflammation, and oxidative stress; ↑ neurologic function. | ↑ Nrf2 and antioxidant enzymes | [63] |
| Resveratrol | Grape | In vitro: rat astrocytes In vivo: WT and Nrf2−/− rats subjected to tMCAO |
In vitro: 25 μmol/L for 2 h In vivo: 10 mg/kg i.p. 48 h before occlusion |
In vivo: ↓ infarct volume. In vitro: ↑ antioxidant enzyme. |
↑ Nrf2/NQO1 | [65] |
| Procyanidin B2 | Cocoa, apples, grapes | Rats subjected to tMCAO | To evaluate the effect on infarct size and brain edema: 40, 20, or 10 mg/kg i.g 3 h after MCAO. For BBB permeability and other evaluations: 40 mg/kg i.g. once a day, the first 3 h after MCAO. To evaluate neurological function: 40 mg/kg i.g. daily, the first a day after MCAO. | ↓ infarct volume, brain edema, BBB disruption, and oxidative stress; ↑ neurologic function. | ↑ Nrf2 and downstream antioxidant enzymes | [68] |
| Myricetin | Vegetables, berries, tea, wine | In vivo: Rats subjected to tMCAO; In vitro: SH-SY5Y cells exposed to OGD |
In vivo: 20, 10, 5 mg/kg i.g. 2 h before and every day after MCAO. In vitro: 10, 3.3, 1, 0.33, 0.1 nM for 3 h before OGD |
In vivo: ↓ infarct volume and oxidative stress; ↑ neurologic function. In vitro: ↓ apoptosis and oxidative stress. |
↑ Nrf2 and antioxidant enzymes | [70] |
| Chlorogenic acid | Coffea species | Rats subjected to I/R (common carotid arteries occlusion) | In vivo: 500, 100, 20 mg/kg orally | ↓ infarct volume, brain edema, apoptosis, and oxidative stress; ↑ neurologic function. | ↑ Nrf2 and antioxidant enzymes | [71] |
| Tocovid | Edible oils | Mice subjected to tMCAO | 200 mg/kg orally daily for 1 month as pre-treatment | ↓ infarct volume, apoptosis, and oxidative stress | ↑ Nrf2 | [73] |
| 3H-1,2-dithiole-3-thione | Cruciferous vegetables | In vivo: WT and Nrf2−/− mice subjected to tMCAO; In vitro: mouse microglial cell line BV2 and primary WT and Nrf2−/− microglia treated with LPS |
In vivo: 50 mg/kg i.p. 3 h post reperfusion In vitro: 100 µM |
↓ infarct volume, brain edema, BBB disruption, immune cell infiltration, microglia activation, and oxidative stress; ↑ neurologic function and survival. | ↑ Nrf2/HO-1 | [74] |
| Sulforaphane | Cruciferous vegetables | In vivo: Nrf−/− and WT mice and rats subjected to autologous blood injection In vitro: microglia |
In vivo: 5 mg/kg i.p. 30 min and a day after ICH In vitro: 1–10 µM |
In vivo: ↑ hematoma clearance; In vitro: ↓ oxidative stress ↑ red blood cell phagocytosis | ↑ Nrf2 | [75] |
| Genistein | Soybeans | Ovariectomized rats subjected to tMCAO | 10 mg/kg i.p. once a day two weeks before MCAO | ↓ infarct volume, neuronal damage, and oxidative stress; ↑ neurologic function. | ↑ Nrf2/NQO1 | [77] |
| Biochanin A | Soybeans | Rats subjected to tMCAO | 10, 20 and 40 mg/kg i.p. for 2 weeks before MCAO | ↓ infarct volume, brain edema, inflammation and oxidative stress; ↑ neurologic function. | ↑ Nrf2 and antioxidant enzymes | [78] |
| Xanthohumol | Humulus lupulus | In vivo: Rats subjected to tMCAO; In vitro: rat primary cortical neurons exposed to OGD. |
In vivo: 0.4 mg/kg i.p. 10 min before MCAO In vitro: 0.5 μg/mL for 10 min before OGD |
In vivo: ↓ infarct volume, neuronal damage, apoptosis, and oxidative stress; ↑ neurologic function and survival rate. In vitro: ↓ apoptosis and oxidative stress |
↑ Nrf2 and downstream antioxidant enzymes | [79] |
| Alpha-lipoic acid | red meat and vegetables | In vivo: Rats subjected to tMCAO; In vitro: rat cortical neurons exposed to OGD |
In vivo: 10, 20, 40, and 80 mg/kg i.v. after reperfusion In vitro: 1, 10 and 100 μM for 1 h before 24 h OGD. |
In vivo: ↓ infarct volume, brain edema, and oxidative stress; ↑ neurologic function. In vitro: ↓ oxidative stress; ↑ cell viability |
↑ Nrf2 and antioxidant enzymes | [81] |
| Isoquercetin | medicinal and dietary plants | In vivo: Rats subjected to tMCAO; In vitro: primary culture of rat hippocampal neurons exposed to OGD |
In vivo: 5, 10, and 20 mg/kg by gavage after MCAO once a day for 3 days; | In vivo: ↓ infarct volume, brain edema, apoptosis, and oxidative stress; ↑ neurologic function. In vitro: ↓ oxidative stress and apoptosis; ↑ cell viability |
↑ Nrf2 ↓ NOX4/ROS/NF-κB | [83] |
| Corilagin | Phyllanthus emblica | In vivo: Rats subjected to tMCAO; In vitro: rat primary cortical neurons exposed to OGD |
In vivo: 30 mg/kg i.p. once a day for a week, the first 3 h after MCAO. In vitro: 10, 25, and 50 µM pretreatment for 2 h before OGD and for other 24 h after OGD |
In vivo: ↓ infarct volume, apoptosis, and oxidative stress; ↑ neurologic function and angiogenesis. In vitro: ↑ cell viability |
↑ Nrf2 and antioxidant enzymes | [85] |
| 6″-O-succinylapigenin | In vivo: Rats subjected to tMCAO; In vitro: HT-22 cells exposed to OGD |
In vivo: 20, 40, and 60 mg/kg i.p. immediately post occlusion In vitro: 1, 5, or 10 μM 24 h pre-incubation or 5 μM apigenin |
In vivo: ↓ infarct volume and oxidative stress; ↑ neurologic function. In vitro: ↑ cell viability |
↑ antioxidant enzymes | [86] | |
| Luteoloside | Artichoke and other plants | Rats subjected to tMCAO | 20, 40, and 80 mg/kg i.p. immediately and 12 h after MCAO | ↓ cerebral edema, infarct volume, and inflammation; ↑ neurologic function. | ↑ Nrf2 | [89] |
| Monascin | red yeast rice | Rats subjected to intracerebral 32 hemorrhage model |
1, 5, and 10 mg/kg/day i.g. 6 h after ICH and twice a day for 1, 3, or 7 days. | ↓ BBB permeability, cerebral edema, and hematoma; ↑ neurologic function. | ↑ Nrf2 | [90] |
| Fucoxanthin | Edible brown seaweeds | In vivo: Rats subjected to tMCAO; In vitro: rat primary cortical neurons exposed to OGD |
In vivo: 30, 60, and 90 mg/kg i.g. 1 h before MCAO In vitro: 5, 10 and 20 μM before OGD |
In vivo: ↓ infarct volume, brain edema, apoptosis, and oxidative stress; ↑ neurologic function. In vitro: ↓ apoptosis and oxidative stress |
↑ Nrf2 and antioxidant enzymes | [87] |
| Korean red ginseng | Panax ginseng | WT and Nrf2−/− mice subjected to pdMCAO | 100 mg/kg once daily by gavage for 7 days before pdMCAO |
↓ infarct volume, reactive astrogliosis ↑ neurologic function |
↑ downstream antioxidant enzymes | [92] |
| Korean red ginseng | Panax ginseng | WT and Nrf2−/− mice subjected to pdMCAO | 100 mg/kg once a day by gavage for a week before pdMCAO |
↓ infarct volume, reactive astrogliosis, and microgliosis | - | [93] |
| Korean red ginseng | Panax ginseng | WT and Nrf2−/− mice subjected to cerebral hypoxia-ischemia (HI) | 100 mg/kg orally for a week before HI | ↓ neurological deficits, infarct volume, brain edema, inflammation, and reactive gliosis. | ↑ Nrf2 and downstream antioxidant enzymes | [94] |
| Korean red ginseng | Panax ginseng | WT and Nrf2−/− mice subjected to cerebral hypoxia-ischemia (HI) | 100 mg/kg orally for a week before HI | ↓ infarct volume, brain edema, hippocampal CA1 neuronal degeneration, and reactive gliosis. | ↑ downstream antioxidant enzymes | [95] |
| Ginsenoside Rg1 | Panax ginseng | In vitro: pheochromocytoma PC12 cells exposed to OGD; In vivo: rats subjected to tMCAO |
In vitro: 0.01, 0.1, 1, and 10 μM after OGD In vivo: 20 mg/kg |
In vivo: ↓ infarct volume and oxidative stress. In vitro: ↓ oxidative stress; ↑ cell viability |
↓ miR-144; ↑ Nrf2 and downstream antioxidant enzymes | [96] |
| Xueshuantong | Panax notoginseng | Rats subjected to tMCAO | 25, 50, and 100 mg/kg i.p. 1 h after the onset of reperfusion in MCAO rats and for 3 or 7 days. | ↓ oxidative stress. ↑ neuronal function and angiogenesis | ↑ Nrf2 and downstream antioxidant enzymes | [97] |
| Protocatechualdehyde | Salvia miltiorrhiza | In vivo: Rats subjected to tMCAO; In vitro: differentiated SH-SY5Y cells exposed to OGD |
In vivo: 40 mg/kg i.v. 1 h before starting reperfusion In vitro: range 10 to 100 μM for 6 h previous OGD. |
In vivo: ↓ infarct volume and oxidative stress. ↑ neurological function. In vitro: ↓ oxidative stress; ↑ cell viability |
↑ PKCε/Nrf2/HO-1 | [100] |
| TanshinoneIIA | Salvia miltiorrhiza | WT and Nrf2−/− mice subjected to tMCAO | 25 mg/kg i.p. 10 min after reperfusion | ↓ infarct volume, apoptosis, and oxidative stress. ↑ neurological function. | ↑ Nrf2 and downstream antioxidant enzymes | [101] |
| Salvianolate lyophilized injection | Salvia miltiorrhiza | Streptozotocin-induced diabetic rats subjected to tMCAO | 5.25, 10.5, and 21 mg/kg i.v. 3 h after tMCAO induction and then daily for 14 days. |
↓ neuronal damage, glucose uptake, and inflammation. | ↑ Nrf2 and downstream antioxidant enzymes | [102] |
| Diterpene ginkgolides meglumine injection | Ginkgo biloba | In vivo: rats subjected to tMCAO In vitro: PC12 cells exposed to OGD |
In vivo: 1, 3, and 10 mg/kg i.v. at the start of reperfusion and 12 h after In vitro: 10 µmol/L for each ginkgolide A, B, or C or 1, 10, and 20 µg/mL DGMI for 24 h after OGD |
In vivo: ↓ infarct volume and brain edema. ↑ neurological function. In vitro: ↑ cell viability |
↑ Akt/Nrf2 | [104] |
| Ginkgolide A, ginkgolide B, ginkgolide K and bilobalide | Ginkgo biloba | In vivo: rats subjected to tMCAO In vitro: SH-SY5Y cells exposed to OGD |
In vivo: 1, 2, and 4 mg/kg i.p. 2 h after reperfusion twice a day. In vitro: 25 mg/L after OGD for 6 h |
In vivo: ↓ infarct volume. In vitro: ↓ oxidative stress; ↑ cell viability |
↑ Akt/Nrf2 and antioxidant enzymes | [105] |
| Isorhamnetin | Ginkgo biloba and other plants | Mice subjected to tMCAO | 5 mg/kg i.p. at the starting of reperfusion, and after 24 h | ↓ infarct volume, brain edema, apoptosis, BBB disruption, oxidative stress, and inflammation. ↑ sensimotor function. | ↑ Nrf2/HO-1 | [106] |
| Tetramethylpyrazine | Rhizoma Chuanxiong | Rats subjected to pMCAO | 20 mg/kg i.p. 30 min before and an hour after the occlusion. | ↓ inflammatory cell infiltration, neuronal loss activation of circulating neutrophils | ↑ Nrf2/HO-1 | [108] |
| Z-ligustilide | Rhizoma Chuanxiong | Rats subjected to tMCAO | 15 mg/kg intranasal route for 3 days before MCAO | ↓ infarct volume, brain edema, and BBB disruption. ↑ neurological function. | ↑ NQO1 | [109] |
| Senkyunolide I | Rhizoma Chuanxiong | Rats subjected to tMCAO | 36 and 72 mg/kg i.v. 15 min after MCAO | ↓ infarct volume, brain edema, oxidative stress, and apoptosis. ↑ neurological function. | ↑ Erk1/2 ↑ Nrf2 and antioxidant enzymes |
[110] |
| Gastrodin | Gastrodia elata Blume | Mice subjected to tMCAO | 10, 50, and 100 mg/kg i.p. at the starting of cerebral reperfusion | ↓ infarct volume, apoptosis, inflammation, and oxidative stress; ↑ neurologic function. | ↑ Akt/Nrf2 and downstream antioxidant enzymes | [112] |
| Gastrodin | Gastrodia elata Blume | In vivo: Rats subjected to tMCAO; In vitro: C6 astroglial cells treated with Zn2+ |
In vivo: 20, 40, and 80 mg/kg i.p. at 1 or 6 h after MCAO In vitro: 50, 100, or 250 μM pretreatment or cotreatment |
In vivo: ↓ infarct volume; ↑ neurologic function. In vitro: ↓ oxidative stress; ↑ cell viability |
↑ Nrf2 | [113] |
| Phenolic components of Gastrodia elata Blume | Gastrodia elata Blume | In vivo: rats subjected to tMCAO; In vitro: Primary human astrocytes HA-1800 and SH-SY5Y cells exposed to H2O2 |
In vivo: 4 and 40 mg/kg intragastric once per day for a week before MCAO until the sacrifice. In vitro: 15, 25, or 50 μg/mL for 24 h before H2O2 treatment or 25 μg/mL for 1–48 h before H2O2 |
In vivo: ↓ pathological lesions; ↑ motor and cognitive function. In vitro: ↑ cell viability |
↑ Nrf2 and downstream antioxidant enzymes | [114] |
| Gastrodin | Gastrodia elata Blume | In vivo: rats subjected to intracerebral hemorrhage model In vitro: rat primary cortical neuron exposed to hemolysate |
In vivo: 100 mg/kg i.p. 2 h, a day, and 2 days after surgery In vitro: 10, 100, and 300 µM for 24 h or 100 µM for 0, 12, 24, 48, and 72 h |
In vivo: ↓ brain edema, oxidative stress, and apoptosis; ↑ neurological function. In vitro: ↑ cell viability |
↑ Nrf2 and downstream antioxidant enzymes | [115] |
| Schizandrin A | Schisandra chinensis | In vivo: rats subjected to tMCAO; In vitro: differentiated SH-SY5Y cells exposed to OGD |
In vivo: 20, 40, and 80 mg/kg i.v. before reperfusion In vitro: range 5 to 100 μM for 6 h pretreatment |
In vivo: ↓ infarct volume, inflammation, and oxidative stress; ↑ neurological function. In vitro: ↓ inflammation and oxidative stress ↑ cell viability |
↑ AMPK/Nrf2 and downstream antioxidant enzymes | [117] |
| Salidroside | Rhodiola crenulata | Rats subjected to tMCAO | 15 and 30 mg/kg i.p. once before MCAO and once after reperfusion | ↓ infarct volume and oxidative stress; ↑ neurologic function. | ↑ Nrf2 and downstream antioxidant enzymes | [119] |
| Salidroside | Rhodiola rosea | Rats subjected to pMCAO | 25, 50, and 100 mg/kg i.p. for a week after MCAO | ↓ infarct volume and inflammation; ↑ neurologic function. | ↑ PI3K/PKB/Nrf2/NFκB | [120] |
| Total glycosides | Cistanche deserticola | Rats subjected to tMCAO | 280 mg/kg i.g. daily after MCAO for 2 weeks | ↓ infarct volume and oxidative stress; ↑ neurologic function, BBB integrity, angiogenesis, and neuronal remodeling. | ↑ Nrf2 and downstream antioxidant enzymes | [121] |
| Andrographolide | Andrographis paniculata | In vitro: primary mouse cerebral endothelial cells exposed to OGD In vivo: rats subjected to tMCAO |
In vitro: 10 µM for 6 h before OGD In vivo: 0.1 mg/kg, i.p. immediately after MCAO |
In vitro: ↓ cell death In vivo: ↓ free radical formation, BBB disruption, and infarct volume. |
↑ p38/Nrf2/HO-1 | [122] |
| Forsythiaside A | Forsythia suspensa | Rats subjected to tMCAO | 50 mg/kg i.p. for a week after MCAO | ↓ apoptosis, endoplasmic reticulum stress, and oxidative stress; ↑ neurologic function, survival rate. | ↑ Nrf2 and downstream antioxidant enzymes | [123] |
| 11-Keto-β-boswellic acid | Boswellia serrata | In vivo: rats subjected to tMCAO; In vitro: rat primary astrocytes exposed to OGD |
In vivo: 25 mg/kg i.p. 1 h after reperfusion In vitro: 10, 30, and 50 µM for 24 h after OGD |
In vivo: ↓ infarct volume, apoptosis, and oxidative stress. ↑ neurologic function In vitro: ↓ cell death and oxidative stress |
↑ Nrf2 and downstream antioxidant enzymes | [124] |
| Swertiamarin | Gentiana macrophylla Pall | In vivo: mice subjected to tMCAO; In vitro: rat primary hippocampal neurons exposed to OGD |
In vivo: 25, 100, and 400 mg/kg i.p. daily for a week before MCAO In vitro: 0.1, 1, and 10 µM for 24 h after OGD |
In vivo: ↓ infarct volume, apoptosis, and oxidative stress. ↑ neurologic function In vitro: ↓ cell death and oxidative stress |
↑ Nrf2 and downstream antioxidant enzymes | [125] |
| Neferine | Nelumbo nucifera Gaertn | In vivo: rats subjected to pMCAO; In vitro: PC12 cells exposed to tert-butyl hydroperoxide |
In vivo: 12.5, 25, and 50 mg/kg i.g. In vitro: 1–10 µM for 24 h as pre- or post-treatment; |
In vivo: ↓ infarct volume, oxidative stress and mitochondrial dysfunction. ↑ neurologic function In vitro: ↓ cell death, mitochondrial dysfunction, and oxidative stress |
p62/Keap1/Nrf2 | [126] |
| Totarol | Podocarpus totara | In vivo: rats subjected to tMCAO; In vitro: primary rat cerebellar granule cells and cortical neurons exposed to OGD or glutamate |
In vivo: 0.1, 1, and 10 µg/kg i.v. at 2 h, 4 h and 6 h after MCAO In vitro: 5 µM pretreatment for 24 h |
In vivo: ↓ infarct volume and oxidative stress. ↑ neurologic function In vitro: ↓ neurotoxicity and oxidative stress |
↑ Akt and downstream antioxidant enzymes | [127] |
| Leonurine | Herba leonuri | WT and Nrf2−/− mice subjected to pMCAO | 5, 10, and 15 mg/kg 2 h i.p. after pMCAO | ↓ infarct volume and oxidative stress. ↑ neurologic function | ↑ Nrf2 and downstream antioxidant enzymes | [128] |
| Britanin | Inula lineariifolia | In vivo: rats subjected to tMCAO In vitro: rat cortical neurons exposed to OGD |
In vivo: 25 and 50 mg/kg i.g. at the start of MCAO and dosed twice after reperfusion for 8 h; 25 mg/kg once at 2 h before occlusion, at the onset of occlusion, at reperfusion or 4 h after reperfusion In vitro: 1, 2.5, and 5 µM for 6 h before or after OGD |
In vivo: ↓ infarct volume and oxidative stress. ↑ neurologic function In vitro: ↓ neurotoxicity and oxidative stress |
↓ Keap1-mediated ubiquitination of Nrf2 ↑ Nrf2 and downstream antioxidant enzymes | [129] |
| Osthole | Cnidium monnieri | In vivo: Mice subjected to global cerebral ischemia In vitro: HT22 murine hippocampal neuronal cells |
In vivo: 25, 50, and 100 mg/kg i.p. 30 min before ischemia and after reperfusion In vitro: 25, 50, and 100 µM for 24 h |
In vivo: ↓ BBB disruption and oxidative stress. ↑ cognitive function In vitro: ↑ Nrf2 |
↑ Nrf2 | [130] |
| Trilobatin | Lithocarpus polystachyus | In vivo: Rats subjected to tMCAO; In vitro: Primary rat astrocytes and cortical neurons exposed to OGD |
In vivo: 5, 10, and 20 mg/kg by gavage at reperfusion onset twice a day for 3 days; to evaluate the time window: 20 mg/kg at 1, 2, 3, 4, and 6 h after MCAO. To discover the effect of TLB on functional recovery after MCAO: 5, 10, and 20 mg/kg at the onset reperfusion twice daily for 28 days after MCAO In vitro: astrocytes: 12.5, 25, 50 μM for 48 h after OGD. Neurons: 6.25, 12.5, 25, 50 μM for 24 h after OGD. |
In vivo: ↓ cerebral edema, infarct volume, inflammation, and oxidative stress. ↑ neurological function In vitro: ↓ oxidative stress and inflammation |
↑ Nrf2 and downstream antioxidant enzymes | [131] |
| Achyranthes bidentata polypeptide k | Achyranthes bidentata Bl. | BV2 cells exposed to LPS | 0.008, 0.04, 0.2, 1, and 5 µg/mL for 30 min before LPS treatment | ↓ inflammation | ↑ Nrf2/HO-1 | [132] |
| Tryptanthrin | P. tinctorium | BV2 cells exposed to LPS | 0.1–20 µM for one hour before LPS treatment | ↓ inflammation | ↑ Nrf2/HO-1 | [133] |
| 5,3′-dihydroxy-3,7,4′-trimethoxyflavone | Siegesbeckia pubescens | Mouse hippocampal HT22 and microglia BV2 cells exposed respectively to glutamate and LPS | 20 µM | ↓ oxidative stress and inflammation | ↑ Nrf2/HO-1 | [134] |
| Longxuetongluo capsule | Dracaena cochinchinensis | BV2 microglial cells exposed to OGD or LPS | 0.5, 1 and 2 µg/mL | ↑ cell viability; ↓ inflammation | ↑ Nrf2/HO-1 | [135] |
| Gualou Guizhi Granule | Composed of 104 compounds | In vivo: Rats subjected to tMCAO; In vitro: PC12 cells exposed H2O2 |
In vivo: 3 g/kg i.g. daily for a week after MCAO In vitro: 100, 200, 300 µg/mL for 24 h before H2O2 |
In vivo: ↓ oxidative stress In vitro: ↓ oxidative stress |
↑ Nrf2/NQO1 and downstream antioxidant enzymes | [136] |
| Danshensu and hydroxysafflor yellow A (HSYA) | Danshensu: Salvia miltiorrhiza. HSYA: Carthamus tinctorius L. | In vivo: Rats subjected to tMCAO; In vitro: Primary culture of rat cortical neurons exposed to OGD |
In vivo: Danshensu group: 15 mg/kg; HSYA group: 6 mg/kg; Danshensu+HSYA group: 7.5 mg/kg Danshensu plus 3 mg/kg HSYA; i.p. In vitro: 80 μM Danshensu, 80 μM HSYA, and 40 μM Danshensu+40 μM HSYA for 24 h after OGD |
In vivo: ↓ infarct volume, apoptosis, inflammation, and oxidative stress; ↑ neurological function In vitro: ↑ cell viability |
↑ Nrf2 and downstream antioxidant enzymes | [137] |
| Safflower extract and aceglutamide | safflower extract: Carthamus tinctorius | In vivo: rats subjected to tMCAO; In vitro: differentiated PC12 cells exposed to H2O2 |
In vivo: 2.5 mL/kg SAAG; 1.25 g/kg SA; 75 mg/kg AG; i.p. In vitro: 20 µl/mL SAAG; 0.6 mg/mL AG; 10 mg/mL SA; pretreated for 24 h |
In vivo: ↓ infarct rate, inflammation, apoptosis, and oxidative stress; ↑ neurologic function. In vitro: ↓ oxidative stress; ↑ cell viability |
↑ Nrf2 and downstream antioxidant enzymes | [138] |
| Salvianolate lyophilized injection and Xueshuantong injection | Salvia miltiorrhiza and Panax notoginsen, respectively | Rats subjected to tMCAO | SLI: 21 mg/kg; XST: 100 mg/kg; combination: 100 mg/kg XST and 21 mg/kg SLI; i.v. 3 h after MCAO and daily for 3 days | ↓ infarct volume, glia activation and oxidative stress; ↑ body weights, neurobehavioral deficits, regional cerebral blood flow | ↑ Nrf2 and downstream antioxidant enzymes | [139] |
| Tao Hong Si Wu decoction | Radix Rehmanniae Praeparata, Radix Angelicae Sinensis, Rhizoma Ligustici Chuanxiong, Radix Paeoniae Alba, Semen Prunus and Flos Carthami Tinctorii | Iv vivo: rats subjected to tMCAO; In vitro: PC12 cells exposed to OGD |
In vivo: 0.5, 1, and 1.5 mg/kg for 7 days In vitro: 0.25, 0.5, and 1 mg/mL |
In vivo: ↓ infarct volume; ↑ neurologic function. In vitro: ↑ cell viability |
↑ PI3K/Akt/Nrf2 and downstream antioxidant enzymes | [140] |
| Berberine, baicalin and jasminoidin | Huang-Lian-Jie-Du-Decoction | Rats subjected to tMCAO | 20 mg/kg (Berberine 8.6 mg/kg, baicalin 6.8 mg/kg and jasminoidin 4.6 mg/kg) i.g. for 7 days | ↓ infarct volume, oxidative stress, inflammation, and apoptosis; ↑ neurologic function | ↑ Nrf2 and downstream antioxidant enzymes | [141] |
AP-1, Activator protein 1; BBB, blood brain barrier; DGMI, Diterpene ginkgolides meglumine injection; ERK, extracellular signal-related kinase; H2O2, Hydrogen peroxide; HO-1, Heme oxygenase 1; HSYA, hydroxysafflor yellow A; ICH, Intracerebral hemorrhage; i.g., intragastrically; i.p., intraperitoneal; i.v., intravenous; Keap1, Kelch- like ECH- associated protein 1; LPS, Lipopolysaccharide; MCAO, middle cerebral artery occlusion; miRNA, microRNA; MMP, Metalloproteinase; Nrf2, nuclear factor erythroid 2-related factor 2; NQO1, NAD(P)H quinone oxidoreductase 1; NSCs, neural stem cells; OGD, oxygen glucose deprivation; PKC, Protein Kinase C; PI3K, Phosphoinositide 3-kinases; pMCAO, permanent middle cerebral artery occlusion; pdMCAO, permanent distal middle cerebral artery occlusion; ROS, Reactive Oxygen Species; tMCAO, transient middle cerebral artery occlusion; SOD, Superoxide dismutase; WT, wildtype.