Oxidative Medicine and Cellular Longevity

Review Article

Effects of Polyphenols on Oxidative Stress, Inflammation, and Interconnected Pathways during Spinal Cord Injury

Table 1

Some preclinical studies on the effects of polyphenols in targeting oxidative stress and close interconnected mediators following SCI.


Phytochemicals	Dose	Pharmacological mechanisms	Animal models	References

Mangiferin	20, 40 mg/kg (i.p.); until 30 days post-SCI	↓ MDA; TNF-α; IL-1β; NF-κB ↑ SOD; GPx; CAT	SD male rats; contusion-SCI; T10;	[19]
Mangiferin	10, 25, 50 mg/kg (i.p.); until 30 days post-SCI	↓ MDA; NF-κB; TNF-α; IL-1β; IL-6; caspase-3; caspase-9 ↑ CAT; SOD; GSH	SD rats; contusion-SCI; T8-T10;	[256]
Quercetin	0.2 mg/kg (i.p.); 1 h post-SCI	↓ iNOS; p38MAPK; MDA; SOD	SD male rats; contusion-SCI; T10;	[61]
	0.25 μmol/kg (i.p.); 1 h post-SCI	↓ MPO	Wistar male rats; compression-SCI; T6-T7; 70 g force; 5 s	[72]
	10, 100 mg/kg (i.p.); first 72 h post-SCI	↓ MDA; NO	Wistar male rats; compression-SCI; T7-T9; 70 g force 1 min	[73]
	20 mg/kg (i.p.); twice daily until 7 days post-SCI	↓ MDA; MPO; NO; IL-1β; IL-6; TNF-α; caspase-3 ↑ SOD; GSH	Wistar albino rats; contusion-SCI; T7-T10;	[75]
	7.5 mg/kg (i.p.); twice daily until 10 days post-SCI	↓ TNF-α; IL-1β; p-STAT1; iNOS; NF-κB; IL-12 ↑ IL-4; IL-10; TGF-β	SD male rats; compression-SCI; T8	[77]
	100 mg/kg (i.p.); until 3 days post-SCI	↓ ROS; IL-1β; IL-18; TNF-α	SD female rats; compression-SCI; T10	[78]
EGCG	50 mg/kg (i.p.); immediately and 1 h post-SCI	↓ iNOS; MPO; COX-2; TNF-α; IL-1β; PARP	SD male rats	[89]
EGCG	30 mg/kg (i.p.); until 7 days post-SCI	↓ TNF-α; RhoA	Female BALB/c mice; contusion-SCI; T8-T9;	[93]
Protocatechuic acid	50 mg/kg (i.p.)	↓ TNF-α; IL-1β; COX-2; iNOS; MMP-9	SD male rats; contusion-SCI; T9-T10;	[94]
Caffeic acid phenethyl ester	10 μL; 1 μg/kg (i.t.); 1 h post-SCI	↓ MDA; SOD; TOA ↑ TAC	Wistar female mice; compression-SCI; T5-T12; 63 g force; 1 min	[109]
	10 μg/kg (i.p.); 30 min post-SCI	↓ IL-1β; TNF-α	Wistar albino male rats; compression-SCI; T8-T12; 1.37-1.72 N force; 1 min	[111]
	10 μmol/kg (i.p.); until 4 weeks post-SCI	↓ COX-2; NOS; IL-1β	Wistar female rat; hemitransection-SCI; T10	[112]
Honokiol	20 mg/kg (i.p.)	↓ MPO; iNOS; COX-2; IL-1β; IL-6; TNF-α	SD female rats; contusion-SCI; T10; 25 g/cm	[131]
Rutin	50, 100 mg/kg (i.p.); until 3 days post-SCI	↓ MDA; ROS; IL-1β; IL-18; TNF-α	SD female mice; compression-SCI; T9-T10	[161]
	30 mg/kg (i.p.); until 3 days post-SCI	↓ MDA; p38MAPK; IL-1β; IL-6; TNF-α; NF-κB; ↑ SOD; GSH; CAT	SD male rats; contusion-SCI; T8-T9;	[171]
	30 mg/kg (i.p.); until 3 days	↓ TNF-α; MDA; ROS; TGF-β1; Smad2 ↑ MPO	Rats; contusion-SCI T10-T11;	[174]
Hesperidin	100 mg/kg; 7 days pre-SCI until 7 days post-SCI	↓ IL-1β; TNF-α; NF-κB; PARP; ↑ SOD; CAT; Nrf2; HO-1; p-p38	SD female rats; compression-SCI; T9-T10; 20 g force; 1 min	[186]
Oxyresveratrol	10, 20 mg/kg (i.p.); until 4 weeks post-SCI	↓ MDA; IL-1β; IL-6; TNF-α; NF-κB; COX-2; iNOS; ↑ Nrf2; SOD; GPx; GSH	SD female rats; contusion-SCI; T10;	[206]
Polydatin	20, 40 mg/kg (i.p.); 30 min post-SCI	↓ MDA; NO; iNOS; IL-1β; IL-6; TNF-α; NF-κB; ↑ SOD; Nrf2; HO-1	SD male rats; contusion-SCI; T8;	[208, 209]
Resveratrol	100 mg/kg (i.p.); immediately post-SCI	↓ MDA; NO; XO; ↑ GSH	Wistar male rats; contusion-SCI; T7-T10;	[201]
	100 mg/kg (i.p.); until 2 weeks post-SCI	↓ Caspase-3; ↑ LC3; Beclin1; PI3K	SD rats; contusion-SCI; T9-T10	[211]
	10 mg/kg (i.p.)	↓ MDA; p38MAPK; ↑ SOD; CAT; GSH	Wistar male rats; Spinal cord ischemia-reperfusion injury	[214]
	1 and 10 mg/kg; 30 min pre-SCI	↓ NO; MDA	Rabbits, spinal cord ischemia-reperfusion injury	[215]
	400 mg/kg (p.o.); until 10 days post-SCI	↓ MDA; IL-6 ↑ TCA	SD male rats; transection-SCI T10-T12	[216]
	50, 100 mg/kg (i.p.); immediately post-SCI	↓ MDA; ↑ Na⁺, K⁺-ATPase activities	SD male and female rats; contusion-SCI; T8;	[217]
	200 mg/kg (i.p.); until 3 days post-SCI	↓ MDA; MPO; IL-1β; IL-10; TNF-α; ↑ SOD	SD rats; contusion-SCI; T10;	[285]
Curcumin	50, 100, 200 mg/kg (i.v.); until 7 days post-SCI	↓ p38MAPK; NF-κB	Female mice; contusion-SCI; T9-T10;	[229]
	100 mg/kg (i.p.)	↓ MDA; NO; TBARS	Long Evans female rats; contusion-SCI;	[231]
	200 mg/kg (i.p.); immediately post-SCI	↑ SOD; GPx; CAT	Wistar male rats; compression-SCI; T7; 70 g force; 1 min	[232]
	300 mg/kg (i.p.)	↓ MDA	Wistar albino female rats; contusion-SCI; T7-T9;	[233]
	200 mg/kg (i.p.); until 8 weeks post-SCI	↓ MDA; IL-6; IL-8; TNF-α; p-ERK; p-p38; p-JNK; p-STAT; GFAP; ↑ SOD	SD female rats; compression-SCI; T9-T10; 30 g force; 2 min	[234]
	30 mg/kg (i.p.); until 7 days post-SCI	↓ NMDA; iNOS	SD rats; ischemic SCI	[235]
	50 mg/kg (i.p.); until 7 days post-SCI	↓ IL-1β; NO; NF-κB; STAT3	BALB/c female mice; compression-SCI; T8-T9; 30 g force, 1 min	[236]
	40 mg/kg (i.p.); 30 min post-SCI	↓ MDA; iNOS	SD male rats; contusion-SCI; T9-T10;	[237]
	300, 100, 30 mg/kg (i.p.); until 7 days post-SCI	↓ TNF-α; IL-1β; NF-κB; TGF-β1; TGF-β2	SD male rats; compression-SCI; T8-T10; 50 g force; 1 min	[238]
	40 mg/kg (i.p.); 30 min post-SCI	↓ iNOS; ↑ Bcl-2, CISD2	C57BL/6JNarl mice; hemisection and contusion-SCI; T9-T10;	[239]
	100 mg/kg (i.p.); until 7 days post-SCI	↓ SOX9; NF-κB; GFAP; CD45; CD11b	SD female rats; compression-SCI; T8-T10; 50 g force; 1 min	[240]
	60, 6 mg/kg (i.p.); until 4 weeks post-SCI	↓ IL-4; IL-1β; IL-2; IL-6; IL-12; TNF-α; MIP-1α; NF-κB; GFAP	Wistar male rats; balloon compression-SCI; T8-T10	[241]
	40 mg/kg (i.p.); 30 min post-SCI	↓ GFAP; ↑ p-JAK2; p-STAT3	SD male rats; contusion-SCI; T8	[242]
	75, 150, 300 mg/kg (i.p.); 20 min and until 3 days post-SCI	↓ TNF-α; NF-κB	SD male rats; compression-SCI; T8-T10	[243]
	100 mg/kg (i.p.); 15 min post-SCI	↓ TNF-α; IL-1β; NF-κB; TLR4	SD male rats; compression-SCI T8-T9; 30 g force	[244]
	200 mg/kg (p.o.)	↓ MDA; ↑ SOD	Wistar albino male rats; contusion-SCI T7-T10;	[286]
	200 mg/kg (i.p.); until 7 days post-SCI	↓ MDA; ↑ SOD	SD male rats; contusion-SCI T8	[287]
	60 mg/kg (i.p.); 30 min and weekly for 3 weeks post-SCI	↓ Caspase-3; IL-6; IL-1β; TNF-α; p-mTOR; p-Akt; Iba1; GFAP ↑ LC3	SD male rats; contusion-SCI; T9-T11;	[288]
	200 mg/kg (i.p.); until 8 weeks post-SCI	↓ Caspase-3; Bax; GFAP; ↑ Bcl-2	SD male rats; contusion-SCI; T9-T10;	[289]
Apocynin	50 mg/kg (i.p.); twice daily until 3 days post-SCI	↓ MPO; MDA; TNF-α; IL-1β; IL-6; ↑ GSH; SOD	SD male rats; compression-SCI; T6-T7; 24 g force; 1 min	[268]
Baicalin	50, 100 mg/kg (p.o.)	↓ MDA; IL-1β; IL-6; TNF-α; NF-κB; ↑ SOD; GPx; CAT	SD male mice; compression-SCI; T7; 23.8 g force; 2 min	[270]
Baicalin	10, 30, 100 mg/kg (i.p.); immediately and 24 h post-SCI	↓ MDA; NF-κB; TNF-α; Bax; ↑ GSH; Bcl-2	SD male rats; contusion-SCI; T12; 50 g	[271]
Gastrodin	100, 200 mg/kg (i.p.); until 5 days post-SCI	↓ TBARS ↑ SOD; GSH; Nrf2; GCLc; GCLm	SD male rats; contusion-SCI; T10;	[272]
Mulberrin	15, 30 mg/kg (p.o.); until 4weeks post-SCI	↓ TBARS; ROS; IL-1β; IL-6; TNF-α; NF-κB; PARP; ↑ SOD; GSH; Nrf2; HO-1	SD male rats; compression-SCI; T10; 30 g force; 1 min	[273]
Salvianolic acid A	2.5, 5, 10 mg/kg (i.p.); until 7 days post-SCI	↑ Nrf2; HO-1	SD male rats; compression-SCI; T12; 50 g force; 5 min	[274]
Salvianolic acid B	1, 10, 50 mg/kg (i.p.) until 3 days post-SCI	↓ TNF-α; NF-κB; ↑ HO-1	SD male rats; compression-SCI; T12; 50 g force; 5 min	[275]
Gallic acid	50 mg/kg (i.p.); immediately, 6 h and 12 h, and then one day until 7 days post-SCI	↓ MMP-9; TNF-α; IL-1β; IL-6; COX-2; iNOS	SD rats; contusion-SCI; T9-T10;	[276]
Gallic acid	10 mg/kg (i.p.); until 10 days post-SCI	↓ COX-2; NF-κB	Wistar male rats; contusion-SCI; T9;	[277]
Kaempferol		↓ IL-18; IL-1β; ROS; p-p38MAPK; p-JNK; NF-κB	SD rat; hemicontusion-SCI	[278]
Luteolin and palmitoylethanolamide	1 mg/kg (i.p.); 1 and 6 hours post-SCI 27 and 2.7 μM	↓ nNOS; iNOS; COX-2	CD1 mice; compression-SCI; T5-T8; 24 g force; in vitro: spinal cord slices	[279]
Naringenin	50, 100 mg/kg (p.o.); 3 days pre-SCI until 7 days post-SCI	↓ TNF-α; IL8; IL-1β; IL-6	SD male rats; compression-SCI T9-T11	[280]
Oleuropein	20 mg/kg (i.p.); immediately and 1 h post-SCI	↓ MDA; Bax; ↑ Bcl-2; GSH	SD female rats; contusion-SCI; T9;	[281]
Oleuropein	250 μL at the dose of 20/40/100 μg/kg (i.p.); 1 h and 6 h post-SCI	↓ MPO; IL-1β; TNF-α; NF-κB; LPO; TBARS; ↑ GDNF	CD1 male mice; compression-SCI; T5-T8; 24 g; 1 min	[282]
Pycnogenol	100 mg/kg (i.p.); 15 min post-SCI	↓ Bax; caspase-3; MDA; ↑ Bcl-2; SOD; MMP	Wistar male rats; contusion-SCI; T10;	[283]
Silymarin	Injected 1–2 mm caudal and rostral to the epicenter; 5 min post-SCI	↓ ROS; NF-κB; COX-2; iNOS; IL-1β	SD rats; contusion-SCI; T9-T10;	[284]
Carnosol	5 mg/kg (i.p.); 1 h post-SCI	↓ COX-2; NF-κB; IL-1β; IL-6; TNF-α; ↑ TAC; GSH; GPx; GST; SOD; CAT; p-Akt; Nrf2	SD female rats; contusion-SCI; T7-T10;	[290]
Tetrahydrocurcumin	80 mg/kg (i.p.); until 2 weeks post-SCI	↓ MDA; TNF-α; IL-6; IL-1β; NF-κB; ↑ SOD; GSH; GPx; p-Akt; FoxO-4	SD male rats; compression-SCI; T8; 30 g force; 2 min	[291]

Akt: tyrosine kinase B; Bax: Bcl-2-associated X protein; Bcl: B cell lymphoma; caspases: cysteine-dependent aspartate-directed proteases; CAT: catalase; COX: cyclooxygenase; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinases; FoxO-4: forkhead box O4; GCLc: catalytic subunit of glutamate-cysteine ligase; GCLm: modifying subunit of glutamate-cysteine ligase; GFAP: glial fibrillary acidic protein; GSH: glutathione; GST: glutathione S-transferase; GPx: glutathione peroxidase; HO-1: heme oxygenase-1; Iba1: ionized calcium-binding adaptor molecule 1; IL: interleukin; iNOS: inducible nitric oxide synthase; i.p.: intraperitoneal; i.t.: intrathecal; i.v.: intravenous; JAKs: Janus kinases; JNK: c-Jun N-terminal kinase; LC3: light chain 3; LPO: lipid peroxidation; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MIP-1α: macrophage inflammatory protein 1-alpha; MPO: myeloperoxidase; mTOR: mammalian target of rapamycin; NADPH oxidase: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappa B; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; PARP: poly(ADP-ribose) polymerase; p.o.: oral administration; ROS: reactive oxygen species; SCI: spinal cord injury; SD: Sprague Dawley; SOD: superoxide dismutase; SOX9: SRY-box transcription factor 9; STATs: signal transducer and activator of transcription proteins; T: thoracic; TAC: total antioxidant capacity; TBARS: thiobarbituric acid reactive substance; TLR4: transmembrane lipopolysaccharide receptor; TNF-α: tumor necrosis factor-alpha; XO: xanthine oxidase.