Table A1.

Summary of preclinical studies on flavonoid administration in different models of TBI.

Name of Flavonoid	Dosage and Route of Administration	Time Points	Tests and Assays	TBI Model	Main Findings	Ref
Chrysin	25, 50, or 100 mg/kg orally, started immediately post-injury and continued for up to 3 or 14 days	1 day before injury; 0, 1, 4 h, and 1, 2, 3, 4, 7, 13, 14, 28 days post-injury	VCS, rotarod test, PAT, biochemical assay, histochemical staining, TUNEL, IHC	WD	Chrysin enhanced post-injury motor function, cognitive status and neuronal loss via reduction of oxidative stress (increased concentrations of SOD, CAT, GPx, GSH, and decreased MDA level) and inhibition of the apoptotic proteins (decreased Bax and increased Bcl-2) in the cerebral cortex and CA3 hippocampal neurons	[133]
Wogonin	1, 2.5, 5 mg/kg. (i.v.) before and after moderate TBI; Alternatively, 2 µL (10 mM) injected into the lateral cerebral ventricle (i.c.v.) before and after moderate TBI	Before injury and 0.5, 1, 2, 4 h post-injury	Arterial pressure, heart rate, baroreflex and GSNA, histochemical staining of hippocampus	FPI	Wogonin administered before or after TBI significantly improved the cardiovascular changes (MAP, HR, and baroreflex) occurring after FPI.	[134]
Isoliquiritigenin (ILG)	20 mg/kg (i.p.) 1 h post-TBI	1 and 7 days after TBI	Sensorimotor Garcia test, brain water content, BBB permeability assay, histochemical staining, cell viability assay, WB, RT–qPCR, fluorescence immunoassays	CCI	ILG improved neurologic functions by reducing brain edema, BBB permeability, apoptosis (decrease in expression of cleaved caspase 3), and oxidative stress (translocation of Nrf2 into the nucleus with activation of downstream proteins).	[135]
Hesperidin	50 mg/kg orally from day 10 to 24 post-injury	Day 21 and 24 post-injury	Sucrose preference test, FST, suppressed feeding test, TST, biochemical analysis	WD	Hesperidin reduced depression symptoms, levels of IL-1β, TNF-α and MDA, and increased BDNF levels in the hippocampus	[136]
Icariin	Oral administration of 3, 10, 30  mg/kg on injury induction and daily for 7 days post-injury	0, 3, 7, 8 days post-TBI	Rotarod test, balance beam test, Y-maze, WB, IHC, histochemical staining, protein expression	Modified CCI	Icariin improved sensory motor and cognitive functions, and upregulated BDNF, SYP, and PSD-95 after injury. However, no improvement of brain histology and neuronal death were found.	[137]
Baicalin	50, 100, 150 mg/kg (i.p.) 30 min after TBI	2 h, and 1 and 3 days post-TBI	NSS, brain water content, TUNEL assay, WB Immunostaining, RT-qPCR	WD	Baicalin improved neurological function, brain edema, apoptosis, and oxidative stress via activating the Akt/Nrf2 pathways	[138]
Formononetin	Intragastrical administration of 10, 30 mg/kg/die for up to 7 days after TBI	7 days post-injury	ELISA of tissue and serum cytokines, Cytohistologic stains, RT-qPCR, WB	WD	Formononetin counteracted TBI-induced neuroinflammation by decreasing tissue and serum levels of IL-6 and BDNF, and increasing tissue and serum levels IL-10	[139]
Troxerutin	1.5 mL/kg (i.p.) for 5 days before TBI	3 days post-injury	NSS, MRI, ELISA, Nissl, TEM, WB and Immunostaining	WD	Troxerutin improved neurovascular function and integrity post-injury through action on eNOS and NO level, with consequent decrease in peroxynitrite formation	[140]
Quercetin	50 mg/kg (i.p.) at 30 min, 12 h and 24 h post-TBI	1, 3, 5 days post-injury	Brain water content, NSS, H&E staining and neuron count, IHC, WB	WD	Reduced brain edema, neural apoptosis and improved motor function (inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and activated Akt serine/threonine protein kinase phosphorylation)	[141]
Resveratrol	0.05, 0.1 mg/kg via oral gavage for 10 consecutive days, 7 days after TBI	7 days post-injury	MWM, WB, TAC, Apoptosis, DHE staining	CCI	Reduced cognitive deficits, ROS generation, and apoptosis after TBI via recovered activation of p38/Nrf2/HO1 signaling pathway	[142]
Silymarin	50 mg/kg via gavage for 20 days before injury	8–10, 11, 18–20, 21 post-injury	Open field, elevated plus-maze, light-dark box, elevated zero-maze, sucrose preference, FST, TST, TNF-α	WD	Decreased anxiety and depression-like behaviours after injury due to reduced TNF-α levels in the prefrontal cortex and hippocampus	[143]
Diosmin	100 mg/kg (p.o.) for 7 days before TBI	–1 h, 1 h, 1,2,15days post-injury	VCS, passive avoidance memory, BBB permeability, brain edema, ELISA	WD	Protective effects against TBI-induced memory and long-term potentiation impairment through reduction of TNF-α concentration in hippocampus	[144]
Catechin	1, 5, 10, 20 or 30 mg/kg daily via gavage up to 28 days post-TBI	3, 5, 7, 14, 21, 28 days pot-injury	Brain infarct volume edema, foot-fault test, MWM, BBB permeability, RT-qPCR, WB	CCI	Catechin prevented tight junction disruption and preserved BBB integrity, reducing post-injury inflammatory reaction	[145]
7,8-dihydroxyflavone	5 mg/kg (i.p) post-TBI either had access to voluntary wheel running for 7 days after injury or were sedentary	7, 14 days post-injury	Barnes maze, voluntary running wheel exercise, WB, rsfMRI	FPI	7,8-DHF enhanced the levels of cell energy metabolism (COII, PGC-1α, AMPK) and hippocampal functional connectivity	[146]
Pycnogenol	50, 100 mg/kg (i.p.) 15 min, 3 h, 6 h post-TBI	2, 5, 7, 12 days post-injury	MWM, FJB, cortical tissue sparing	CCI	No improvement of cognitive ability post-injury in MWM maze task. Pycnogenol suppressed NO through the inhibition of iNOS and also the NF-kB/AP-1 pathway.	[147]
Breviscapine	50 mg/kg (i.v.) post-TBI	1, 4, 7, 14, 21 days post-injury	NSS, RT-PCR, WB, IHC, Immunostaining, TUNEL	WD	Neurobehavioral function improved after treatment due to GSK3β signaling pathway inhibition	[148]
Hydroxysafflor yellow A	10, 30 mg/kg orally post-TBI	6 h, 12 h, 24 h post-TBI	Detection of HSYA, SOD, MDA, CAT, GSH/ GSSG	CCI	HSYA reduced oxidative stress by improving the activities of SOD and CAT, the level of GSH, and the GSH/GSSG ratio. Additionally, it decreased the levels of MDA and GSSG	[149]
Genistein	15 mg/kg (i.p.) 30 min and again 24 h after TBI	–1, 1, 2 days post-TBI	Brain oedema, BBB permeability, ICP, VCS, beam-walk task	WD	Genistein inhibited brain edema, BBB permeability, and improved ICP after TBI. It also improved neurobehavioral performance and motor disorder	[150]
Epicatechin	5, 15, 45 mg/kg by gavage at 3 h after TBI and once daily for 3 days or 15 mg/kg EC at 3 h after TBI and then once daily for 7 days	1, 2, 3, 7, 14, 21, 28 days post-TBI	Neurologic deficit score, forelimb placing test, wire-hanging test, rotarod test, TST, FST, sucrose preference test, IHC, brain water content, Hb, WB, Immunostaining	CCI	EC significantly reduced lesion volume, edema, and cell death and improved neurologic function on days 3 and 28. Cognitive performance and depression-like behaviors were also improved by activating the Nrf2 pathway, inhibiting heme oxygenase-1 protein expression, and reducing iron deposition	[151]
Procyanidins	100 mg/kg (i.v.) PC within 30 min post-TBI	24 h, and 11, 12, 13, 14 days post-injury	MWM, MDA, GSH, SOD, ELISA, WB	CCI	Procyanidins improved cognitive performance by reducing the level of MDA, increasing GSH and activity of SOD, elevating the levels of BDNF, phosphorylation-cAMP-response element-binding protein (pCREB), total CREB, and cyclic AMP (cAMP)	[152]
Proanthocyanidin	Not mentioned	72 h post-injury	Cerebral water content, TBARS, nitrite and nitrate, Thiols	Cold injury	Proanthocyanidin attenuated oxidative and nitrosative stress and decreased brain edema	[153]
(–)-epigallocatechin gallate (EGCG)	0.1% (w/v) EGCG pre- and post-TBI. Solution was prepared by dissolving the drug in drinking water	1, 3, and 7 days post-TBI	MWM, IHC, immunostaining for ssDNA and NeuN, lipid peroxidation	CCI	EGCG treatments improved cognitive impairment through inhibiting free radical-mediated neuronal degeneration and apoptotic cell death around the area damaged by TBI.	[154]
Puerarin	200 mg/kg (i.p.) before injury	24 h post-injury	WB, MDA, GSH, Naþ-Kþ-ATPase activity, Myeloperoxidase activity, FJC	WD	Puerarin ameliorated oxidative neurodegeneration after TBI through the activation of PI3K-Akt pathway	[155]
Luteolin	In vivo 10, 30, 50 (i.p.) mg/kg post-TBI In vitro 5, 10, and 25 µM post-TBI	1, 3, 7 days post-TBI	Grip test, brain water content, MDA, GPx activity, TUNEL, IHC, WB, nuclear extraction and electrophoresis mobility shift assay, RT-qPCR, cell viability	WD	Luteolin enhanced the translocation of Nrf2 to the nucleus both in vivo and in vitro, upregulation of heme oxygenase 1 (HO1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Luteolin neuroprotective effects are possibly mediated by the activation of the Nrf2–ARE pathway	[156]
Naringin	100 mg/kg orally 7 days before and 7 days after the TBI	7 days post-injury	NSS, brain water content, serum and tissue biochemical analysis, WB	WD	Naringin improved behavioral dysfunction by attenuating the increases in MDA and NO; enhancing the activation of SOD; decreasing the over-activation of iNOS; down-regulating the overexpression of IL-1b; and reducing the brain edema.	[157]
Baicalein	30 mg/kg (i.p.) immediately following injury or daily for 4 dayspost-injury	Before injury, 1, 4, 7, 14, 21 days after injury	Rotarod test, y test, mNSS, beam walk test, RT-PCR, WB, IHC, ELISA, FJB	CCI	Baicalein attenuated the contusion’s site expression of TNF-α, IL-1β and IL-6 mRNA and cytokine protein.	[158]