Additional Table 4.

Summary of various flavonoids on glymphatic/neurological activity and the visual system

Type(s) of flavonoid	Exp. Type	Model/Species	Dosage and Admin. Route	Exp. Protocols	Main findings	Citation
Baicalin	in vivo	C57BL/6J mice	° 0.5 mL of 10, 30, or 100 mg/kg ° Oral	° Administered once daily for 2 consecutive days post-brain injury	° 30 and 100 kg/mg groups: ↓ Brain inflammation, infarction, and overexpression of AQP4 protein levels post-stroke	Lee et al. (2019)
	in vivo	Sprague-Dawley rats	° 4 mL/kg of 2.5 mg/mL or 12.5 mg/mL ° IP	° SAH induced via endovascular perforation ° Baicalin administered 2 and 12 h post-SAH	↓ EBI, MMP-9, AQP4 levels in both dosages ↑ Nrf2/NQO1/HO-1 antioxidative signaling pathway ↑ BBB integrity improved post-SAH	Zhang et al. (2020)
Pinocembrin	in vivo	Sprague-Dawley rats	° 3, 10, or 30 mg/kg ° IV	° Cerebral ischemia induced by MCAO ° Injection at 0, 8, 16 h post-MCAO	↓ Cerebral edema ↑ Preservation of ultrastructure of the neurovascular unit ↓ Elevated levels of cytokines, AQP4, MMP-9, and inflammatory mediators	Gao et al. (2010)
Qctn, taxifolin, kaempferol	in vitro	RGC-5 cells	° 25 μM Qctn ° 100 μM taxifolin or 15 μM kaempferol	° 30 min post-flavonoid treatment, oxidative stress via GSH depletion (10 mM glutamate + 500 μM BSO), 0.5 mM t-BOOH, or 650 μM H2O2	° ~85% apoptosis in all 3 oxidative stress methods ° Qctn prevented cell death in all three methods ° Taxifolin prevented cell death in all but H2O2 treatment ° Kaempferol only effective against cell death by GSH depletion	Maher and Hanneken (2005)
Qctn	in vivo	Wistar rats	° 25 and 50 mg/kg ° Oral	° 6 mon treatment ° Diabetes induced via IP injection of streptozotocin (45 mg/kg)	↓ TNF-α and IL-1β levels post-Qctn, greater in 50 kg/mg dosage ↓ AQP4 overexpression in Müller cell endfeet and caspase-3	Kumar et al. (2014)
	in vivo	Wistar rats	° 2 μL of 10 μM ° Intravitreal	° Glaucoma model via cauterization of scleral veins OD ° IOP measured before and weekly post-surgery for 4 wk ° Qctn injection once weekly for 4 wk	° RGC function restored to 72% of normal eye ↑ Frequency and amplitude of mIPSCs in Off-type glaucomatous RGCs ↑ Frequency only of GABAergic mIPSCs in On-type RGCs ° Inhibited frequency only of glutamatergic mEPSCs in On-and Off-type RGCs	Zhou et al. (2019)
	in vivo	Wistar rats	° 2 μL of 10 μM ° Intravitreal	° AC injection of 5 μL paramagnetic polystyrene microbeads to induce COHTN OD ° IOP measured pre-COHTN, 1 and 3 d, end of 1, 2, 3, 4 wk post-COHTN	↓ Loss of RGC function as early as 3 days post-COHTN ↓ RGC apoptosis	Gao et al. (2017)
	in vitro	Sprague-Dawley rat RGCs	° 1, 10, 20, 50 or 100 μM	° Qctn added for 24, 48, or 72 h ° 200 μM COCl2 to induce hypoxia	↑ RGC survival at 10, 20, 50 μM ° High toxicity at 100 μM ° Optimum level of RGC viability: 20 μM at 48 h
Fisetin	in vivo, in vitro	DBA/2J, C57BL/6J mice	° 5, 10, 20, or 30 mg/kg	° Visual function assessed via PERG, VEPs, and tonometry ° Immunocytochemistry, ELISA, and Western blot used to determine expression levels of TNF-α, IL-1β, IL-6, NK-κB	↓ IOP ↑ Restoration of RGC function ↑ RGC viability ↓ Retinal microglial activation ↓ Inflammatory cytokine activations by inhibiting the NF-κB signaling pathway	Li et al. (2019)

AC: Anterior chamber, AQP4: aquaporin-4, BBB: blood brain barrier, BSO: buthionine sulfoximine, COHTN: chronic ocular hypertension, EBI: early brain injury, ELISA: enzyme-linked immunosorbent assay, GSH: glutathione, IL: interleukin, IOP: intraocular pressure, IP: intraperitoneal, IV: intravenous, MCAO: middle cerebral artery occlusion, mEPSC: miniature excitatory postsynaptic currents, mIPSC: miniature inhibitory postsynaptic currents, MMP-9: matrix metalloproteinase-9, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, OD: oculus dexter, PERG: pattern electroretinogram, Qctn: quercetin, RGC: retinal ganglion cells, SAH: subarachnoid hemorrhage, t-BOOH: t-butyl peroxide, TNF-α: tumor necrosis factor alpha, VEP: visual evoked potentials.