Table 2.

Potential natural compound Nrf2 activators for controlling TBI symptoms and improving functional recovery.

Compund	Type of Compound	TBI Time Frame	Experimental TBI Models	Targets	Potential Effects	Type of Study	Ref.
Oridonine	An organic compound	Acute TBI	Mice	Nrf2/HO-1 pathway	Oridonine ameliorated functional damage and neuropathological changes in animals with TBI, enhancing mitochondrial function and reducing oxidative stress-induced neuroinflammation through activating the Nrf2/HO-1 pathway.	In vivo	[133]
			H2O2-induced oxidant damage in N2a cells			In vitro
Breviscapine	An aglycone flavonoid	Acute TBI	Rats	Nrf2/HO-1 pathway	Breviscapin treatment ameliorated TBI-induced neuron cell apoptosis and improved neurobehavioral functions through the activation of the Nrf2 pathway and its related downstream proteins (HO-1 and NQO-1).	In vivo	[135]
Isoliquiritigenin	A flavonoid	Acute TBI	Mouse TBI and Nrf2-KO mice	Nrf2 pathway	Isoliquiritigenin treatment attenuated lesion-induced damage by counteracting oxidative stress via Nrf2 activation, highlighting its important therapeutic potential in TBI treatment.	In vivo	[137]
			SH-SY5Y OGD/R			In vitro
Baicalin	A major bioactive flavone	Acute TBI	Mice	Akt/Nrf2 pathway	Baicalin induces neuroprotection and prevents TBI-induced oxidative stress by activating the Akt/Nrf2 pathway.	In vivo	[139]
Wogonin	A flavonoid	Acute TBI	Mice	PI3K/Akt/Nrf2/HO-1 pathway	Wogonin protected the hippocampal damage TBI-induced by counteracting oxidative stress and neuronal death by activating the Nrf2/HO-1 pathway in a PI3K/Akt-dependent manner.	In vivo	[140]
Quercetin	A flavonoid	Acute TBI	Rats	Nrf2/HO-1 pathway	Quercetin activated the Nrf2/HO-1 pathway, thus protecting the animals from TBI-induced oxidative stress.	In vivo	[141]
Fisetin	A flavonoid	Acute TBI	Mice	Nrf2-ARE pathway	Fisetin treatment activated the Nrf2/HO-1 pathway, thus protecting the animals from TBI-induced oxidative stress and neuronal apoptosis.	In vivo	[144]
Curcumin	A diferuloylmethane	Acute TBI	Mice	Nrf2-ARE pathway	Curcumin attenuated the injury-induced oxidative stress and prevented neurological damage, possibly by activating the Nrf2-ARE pathway.	In vivo	[145]
Curcumin	A diferuloylmethane	Acute TBI	Mouse TBI and Nrf2-KO mice	Nrf2/HO-1 pathway	Curcumin has shown a neuroprotective role associated with the activation of the Nrf2 pathway, proving to be a potential therapeutic intervention in TBI management.	In vivo	[146]
Sodium aescinate	A triterpene saponin		Mouse TBI and Nrf2-KO mice	Nrf2-ARE pathway	Sodium aescinate, by activating the Nrf2-ARE pathway, exerts neuroprotective effects against oxidative stress and neuronal apoptosis TBI-induced, thus highlighting its promising therapeutic effects in the management of this pathology.	In vivo	[148]
			Neuron model of TBI			In vitro
β-carotene	A carotenoid	Acute TBI	Mice	Nrf2/HO-1 pathway	β-carotene ameliorated brain injury after TBI by regulating the Nrf2/Keap1-mediated antioxidant pathway.	In vivo	[149]
Astaxanthin	A carotenoid pigment	Acute TBI	Mice	Nrf2/HO-1 pathway	Astaxanthin treatment promoted neuroprotective effects in the TBI mouse model probably activating the Nrf2/HO-1 signaling pathway.	In vivo	[152]
Astaxanthin	A carotenoid pigment	Acute and chronic TBI	Mouse TBI and Nrf2-KO mice	SIRT1/Nrf2/Prx2/ASK1/p38 signaling	Astaxanthin decreased oxidative stress and neuronal death regulating the SIRT1/Nrf2/Prx2/ASK1/p38 signaling pathway, highlighting its promising therapeutic potential in TBI even in the long term.	In vivo	[153]
			H2O2-induced oxidant damage in Primary Cortical Neurons			In vitro
Tannic acid	A natural polyphenol	Acute TBI	Rats	PGC-1α/Nrf2/HO-1 signaling pathway	Pretreatment with tannin acid 30 min before, and 6 and 18 h after injury improved behavioral deficits, counteracting TBI-induced oxidative stress and mitochondrial damage probably by activating PGC-1α/Nrf-2/HO-1 signaling pathway.	In vivo	[155]
Allyl isothiocyanate	A organosulfur compound	Acute TBI	Mice	Nrf2 pathway	Allyl isothiocyanate treatment ameliorated TBI damage and neurological deficit, enhancing the expression of neuronal plasticity markers and reducing oxidative stress through Nrf2 upregulation.	In vivo	[157]
Lupeol	A triterpenoid	Acute TBI	Mice	Nrf2	Lupeol exerted neuroprotective effects and ameliorated memory and behavioral deficits, TBI-induced reducing glial cell activation, oxidative stress, and apoptosis likely through increasing Nrf2 levels in the brain.	In vivo	[158]
Huperzine-A	A sesquiterpene alkaloid	Acute and chronic TBI	Mice	Nrf2	Huperzine-A induces neuroprotective effects in a TBI mouse model, reducing the oxidative stress response via the Nrf2 pathway.	In vivo	[160]
Rutaecarpine	An alkaloid	Acute TBI	Mice	PGK1/Keap1/Nrf2 pathway	Rutaecarpine protected against neuronal apoptosis and oxidative stress induced by TBI, by activating the PGK1/Keap1/Nrf2 pathway.	In vivo	[162]
			H2O2-induced oxidant damage PC12			In vitro
Evodiamine	A quinazoline alkaloidal	Acute TBI	Mice	PGK1/Keap1/Nrf2 pathway	Evodiamine protected against neuronal apoptosis and oxidative stress induced by TBI, by activating the PGK1/Keap1/Nrf2 pathway.	In vivo	[163]
			H2O2-induced PC12			In vitro
Aucubin	An iridoid glycoside	Acute TBI	H2O2-induced oxidant damage in primary cortical neurons	Nrf2-ARE signaling pathway	Aubucin, by activating the Nrf2 pathway, attenuated TBI-induced oxidative stress and neuronal apoptosis, improving neurological outcomes, and behavioral and cognitive deficits.	In vitro	[165]
			Mouse TBI and Nrf2-KO mice			In vivo

Traumatic brain injury: TBI; nuclear factor E2-related factor 2: Nrf2; heme oxygenase-1: HO-1; NADPH Quinone Dehydrogenase 1: NQO1; Nrf2-knockout: Nrf2-KO; antioxidant response elements: ARE; peroxisome proliferator–activated receptor gamma co-activator 1 alpha: PGC-1α; peroxiredoxin 2: Prx2; sirtuin 1: SIRT1; Phosphoinositide 3-kinases: PI3Ks; apoptosis signal-regulating kinase 1: ASK1; Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1: Keap1; oxygen and glucose deprivation/reoxygenation: OGD/R.