Table 1.
Phytochemicals from various plants possess multiple pharmacological effects via the antioxidant mechanism in various in vitro and in vivo models of TBI.
| Phytochemicals | Plants | Models | Pharmacological effects | Detected markers | Antioxidant mechanism | Ref |
|---|---|---|---|---|---|---|
| Polyphenol | ||||||
| Quercetin | Onions, tomatoes, etc. | Weight drop-induced TBI mice/rats, | Improved behavioral function, neuronal viability, and mitochondrial function; reduced brain edema and microgliosis, oxidative damage and nitrosative stress, neuronal apoptosis, inflammatory response | Motor coordination; latency period; NSS; brain water content; MDA; SOD; catalase; GPx; lipid peroxidation; neuronal morphology; cytochrome c; Bax; MMP; ATP; Iba-1; TNF-α; iNOS; cNOS; IL-1β; Nrf2; HO-1 | Nrf2 pathway | [74–77] |
| Curcumin | Curcuma longa | FPI-induced TBI rats; Feeney or weight drop-induced TBI WT, Nrf2-KO or TLR4-KO mice; LPS-induced microglia or the co-culture of neuron and microglia | Improved cognitive function; reduced axonal injury, neuronal apoptosis, inflammatory response, and oxidative damage | NSS; brain water content; Tuj1; H&E; Nissl; Congo red, silver, TUNEL, MPO, and FJC staining; caspase 3; Bcl-2; NeuN/BrdU double labeling; Iba-1; GFAP; TNF-α; IL-6; IL-1β; MCP-1; RANTES; CD11B; DCX; TLR4; MyD88; NF-κB; IkB; AQP4; Nrf2; HO-1; NQO1; PERK; eIF2α; ATF4; CHOP; GSK3β; p-tau; β-APP; NF-H | Nrf2 pathway; PERK/Nrf2 pathway | [80, 81, 86–88] |
| Formononetin | Red clover | Weight drop-induced TBI rats | Reduced brain edema, pathological lesions, inflammatory response, and oxidative damage, | NSS; brain water content; H&E and Nissl staining; neuronal ultrastructural organization; SOD; GPx; MDA; TNF-α; IL-6; COX-2; IL-10; Nrf2 | Nrf2 pathway | [91, 95] |
| Baicalin | Scutellaria baicalensis | Weight drop-induced TBI rats | Improved behavioral function and neuronal survival; reduced brain edema, oxidative damage, BBB disruption, and mitochondrial apoptosis | NSS; brain water content; EB leakage, Nissl, and TUNEL staining, grip test score; cleaved caspase 3; Bcl-2, cytochrome c, p53, SOD, MDA, GPx, NeuN, Nrf2, HO-1, NQO1, AMPK, mTOR, LC3, Beclin-1, p62 | Akt/Nrf2 pathway | [96, 97] |
| Catechin | Cocoa, tea, grapes, etc. | CCI- or weight drop-induced TBI rats | Improved long-term neurological outcomes, neuronal survival, and white matter recovery; reduced brain edema, brain lesion volume, neurodegeneration, inflammatory response, BBB disruption, neutrophil infiltration, and oxidative damage | NSS; brain water content; brain infarct volume; forelimb score; Hindlimb score; latency; quadrant time; EB extravasation; ZO-1; Occludin; TNF-α；IL-1β；IL-6; iNOS; arginase; TUNEL, PI, FJB, Cresyl violet, and MPO staining; myelin; caspase 3; caspase 8; Bcl-2; Bax; BDNF; ROS; MMP-2; MMP-9; Nrf2, Keap1, SOD1; HO-1; NQO1; NF-κB | Nrf2-dependent and Nrf2-independent pathways | [103, 104] |
| Fisetin | Cotinus coggygria, onions, cucumbers, etc. | Weight drop-induced TBI mice | Improved neurological function; reduced cerebral edema, brain lesion, oxidative damage, and BBB disruption | NSS; brain water content; grip score; EB extravasation; lesion volume; MDA; GPx Nissl and TUNEL staining; caspase 3; Bcl-2; Bax; Nrf2, HO-1; NQO1; TLR4; NF-κB; NeuN; TNF-α；IL-1β；IL-6; MPP-9; ZO-1; EB leakage | Nrf2-ARE signaling pathway | [109, 110] |
| Luteolin | Carrots, green tea, celery, etc. | Marmarou's weight drop-induced TBI mice/rats; scratch injury-induced TBI primary neurons | Improved motor performance, and learning and memory; reduced cerebral edema, apoptosis index, and oxidative damage | Latency time; brain water content; grip score; MDA; GPx; catalase; SOD; TUNEL, H&E, Cresyl violet, and TB staining; ROS; LDH release assay; Nrf2; HO-1; NQO1 | Nrf2-ARE signaling pathway | [116, 117] |
| Isoliquiritigenin | Sinofranchetia chinensis, Glycyrrhiza uralensis, and Dalbergia odorifera | CCI-induced TBI mice/rats; ODG-induced SH-SY5Y cells | Improved motor performance, cognitive function, and cell viability; reduced cerebral edema, neuronal apoptosis, inflammatory response, BBB damage, and oxidative damage | Garcia neuroscore; MWM test; beam-balance latency; beam-walk latency; brain water content; contusion volume; EB extravasation; apoptosis rate; MDA; GPx; SOD; H2O2; H&E and Nissl staining; GFAP; NFL; AQP4; caspase 3; Bcl-2; Bcl-xL; Bax; Nrf2, HO-1; NQO1; TNF-α; INF-γ; IL-1β; IL-6; IL-10; Iba-1; CD68; AKT; GSK3β; P-120; Occludin; NF-κB; IkB; CCK-8 assay | Nrf2-ARE signaling pathway | [121–123] |
| Tannic acid | Green and black tea, nuts, fruits, and vegetables | CCI-induced TBI mice/rats; ODG-induced SH-SY5Y cells | Improved behavioral performance; reduced cerebral edema, neuronal apoptosis, inflammatory response, and oxidative damage | Grip test score; Rotarod test; beam balance; brain water content; GSH; LPO; GST; GPx; CAT; SOD; Nissl staining; caspase 3; Bcl-2; Bax; PARP; Nrf2; PGC-1α; Tfam; HO-1; NQO1; TNF-α; IL-1β; 4HNE; GFAP | PGC-1α/Nrf2/HO-1 pathway | [133] |
| Ellagic acid | Various berries, walnuts, and nuts | Experimental diffuse TBI rats; CCl4-induced brain injury rats | Improved memory, hippocampus electrophysiology and long-term potentiation deficit; reduced neuronal apoptosis, inflammatory response, oxidative damage, and BBB disruption | Initial latency; step through latency; EB leakage; NSS; MDA; GSH; CAT; caspase 3; Bcl-2; NF-κB; PARP; Nrf2; Cox-2, VEGF; TNF-α； IL-1β; IL-6 | Nrf2 signaling pathway | [134, 135] |
| Breviscapine | Erigeron | Weight drop- or CCI-induced TBI rats | Improved neurobehavior; reduced neuronal apoptosis, inflammatory response, and oxidative damage | NSS; TUNEL staining; MDA; GSH; CAT; caspase 3; Bcl-2; Bax; IL-6; Nrf2; HO-1; NQO1; GSK3β; SYP | Nrf2 signaling pathway | [138–140] |
| Terpenoids | ||||||
| Asiatic acid | Centella asiatica | CCI-induced TBI rats | Improved neurological deficits; inhibited brain edema, neuronal apoptosis, and oxidative damage | NSS; brain water content; TUNEL staining; MDA; 4-HNE; 8-OhdG; Nrf2; HO-1 | Nrf2 signaling pathway | [149] |
| Aucubin | Eucommia ulmoides | Weight drop-induced TBI mice; H2O2-induced primary cortical neurons | Improved neurological deficits, and cognitive function; reduced brain edema, neuronal apoptosis and loss, inflammatory response, and oxidative damage | NSS; brain water content; TUNEL and Nissl staining; MWM test; Bcl-2; Bax; CC3; MAP2; MMP-9; MDA; SOD; GSH; GPx; 8-HdG; NeuN; Iba-1; HMGB1; TLR4; MyD88; NF-κB; iNOS; COX2; IL-1β; Nrf2; HO-1; NQO1 | Nrf2 signaling pathway | [155] |
| Ursolic acid | Apples, bilberries, lavender, hawthorn, etc. | Weight drop-induced TBI mice | Improved neurobehavioral and mitochondrial function; reduced brain edema, oxidative damage, and neuronal cytoskeletal degradation | NSS; brain water content; TUNEL and Nissl staining; MDA; SOD; GPx; AKT; 4-HNE; 3-NE; ADP rate; succinate rate; Spectrin; Nrf2; HO-1; NQO1 | AKT/Nrf2 signaling pathway | [158] |
| Carnosic acid | Rosmarinus officinalis and Salvia officinalis. | CCI-induced acute post-TBI mice; | Improved motor and cognitive function, and neuronal viability; reduced brain edema, neuronal apoptosis and loss, inflammatory response, and oxidative damage | Duration of apnea; mitochondrial respiration; Barnes maze test; novel object recognition (NOR) task; GFAP; Iba-1; NeuN; MAP2; vGlut1; HO-1 | Nrf2-ARE signaling pathway | [157–159] |
| Natural pigments | ||||||
| Fucoxanthin | Rosmarinus officinalis and Salvia officinalis | Weight drop-induced TBI mice; scratch injury-induced TBI primary cortical neurons | Improved neurobehavioral function, and neuronal viability; reduced brain edema, neuronal apoptosis, and oxidative damage | NSS; grip test score; brain water content; lesion volume; TUNEL staining; caspase 3; PARP; cytochrome c; MDA; GPx; ROS; LC3; NeuN; p62; Nrf2; HO-1; NQO1 | Nrf2-ARE and Nrf2-autophagy | [170] |
| β-Carotene | Fungi, plants, and fruits | Weight drop-induced TBI mice | Improved neurological function; reduced brain edema, BBB disruption, neuronal apoptosis, and oxidative damage | Neurological deficit score; wire hanging; brain water content; EB extravasation; MDA; SOD; NeuN; Nissl and TUNEL staining; caspase 3; Bcl-2; Keap1; Nrf2; HO-1; NQO1 | Keap1-Nrf2 signaling pathway | [174] |
| Astaxanthin | Salmon, rainbow trout, shrimp, and lobster | CCI- or weight drop-induced TBI mice; H2O2-induced primary cortical neurons | Improved neurological, motor, and cognitive function; reduced brain edema, BBB disruption, neuronal apoptosis, and oxidative damage | NSS; Rotarod test time; neurological deficit scores; rotarod performance; beam walking score; wire hanging test; MWM test; brain water content; 8-OhdG; immobility time; latency to immobility; SOD1; MDA; H2O2; GSH; ROS; CC3; Nissl, Cresyl violet, and TUNEL staining; Prx2; SIRT1; ASK1; p38; NeuN; Bax; Bcl-2; caspase 3; Nrf2; HO-1; NQO1 | Nrf2 signaling pathway; SIRT1/Nrf2/Prx2/ASK1/p38 signaling pathway | [172, 173] |
| Lutein | Calendula officinalis, spinach, and Brassica oleracea | CCI-induced STBI mice; H2O2-induced primary cortical neurons | Improved motor and cognitive function; reduced brain edema, contusion volume, inflammatory response; and oxidative damage | Forelimb reaching test; immobility time; latency to immobility; brain water content; 8-OhdG; TNF-α; IL-1β; IL-6; MCP-1; ROS; SOD; GSH; ICAM-1; COX-2 NF-κB; ET-1; MDA; H2O2; CC3; Nissl, Cresyl violet, and TUNEL staining; Prx2; SIRT1; ASK1; p38; NeuN; Bax; Bcl-2; caspase 3; Nrf2; HO-1; NQO1 | ICAM-1/Nrf-2 signaling pathway | [176, 177] |
| Others | ||||||
| Sodium aescinate | Aesculus chinensis Bunge and chestnut | Weight drop-induced TBI mice; scratch injury-induced primary cortical neurons | Improved neurological function; reduced brain edema, inflammatory response; and oxidative damage | NSS; brain water content; lesion volume; MDA; GPx; Nissl and TUNEL staining; Bax; Bcl-2; cytochrome c; caspase 3; cell survival; ROS; Nrf2; HO-1; NQO1 | Nrf2-ARE pathway | [187] |
| Melatonin | Plants, animals, fungus, and bacteria | Marmarou's weight drop-induced TBI mice | Reduced brain edema, neuronal degeneration and apoptosis, and oxidative damage | Brain water content; MDA; 3-NT; GPx; SOD; FJC staining; NeuN; Beclin-1; Nrf2; HO-1; NQO1 | Nrf2-ARE pathway | [193] |
| Sinomenine | Sinomenium acutum (Thunb.) Rehd. Et Wils. and Sinomenium acutum var. cinereum Rehd. Et Wils. | Marmarou's weight drop-induced TBI mice | Improved motor performance; reduced brain edema, neuronal apoptosis, and oxidative damage | Grip test score; brain water content; NeuN and TUNEL staining; Bcl-2; caspase 3; MDA; GPx; SOD; Nrf2; HO-1; NQO1 | Nrf2-ARE pathway | [196] |
| Sulforaphane | Vegetable, including cabbage, broccoli, and cauliflower | CCI-induced TBI mice | Improved motor performance and cognitive function, reduced brain edema, BBB permeability, mitochondrial dysfunction, and oxidative damage | MWZ test; EB extravasation; brain water content; Occludin; Claudin-5; RECA-1; vWF; EBA; ZO-1; AQP4; GPx; GSTα3; 4-HNE; ADP rate; succinate rate; NeuN; Nrf2; HO-1; NQO1 | Nrf2 signaling pathway | [158, 196–198] |