Additional Table 1.

Summary of inhibitory and facilitating agents on AQP4 activity and neurological effects

Inhibitor/Facilitator	Compounds of interest	Exp. Type	Model/Species	Dosage and Admin. Route	Exp. Protocols	Main findings	Citation
Inhibitor	AER-270	in vivo	C57BL/6J mice	0.8 mg/kg in 6 mL water IP	-	↓ Cerebral edema by 2.5× ↑ Survival by 3.3× in water intoxication models	Farr et al. (2019)
	AER-271	in vivo	C57BL/6J mice	10 mg/kg in 0.2 mL Tris IP	-	↓ Cerebral edema by 2.6× ↑ Neurological outcomes in ischemic stroke models
		in vivo	Sprague- Dawley rats	various dosages, IV and EJV	48 h infusion 30 min post- injection	° Minimum effective dosage to reduce cerebral edema is 4 mg/kg loading with 0.03 mg/kg/h infusion
		in vivo	Sprague- Dawley rats	5 mg/kg IP with 0.08 mg/kg/h SQ	24 h infusion	↓ Cerebral edema, neuronal death, and neuroinflammation 3 h post-cardiac arrest	Wallisch et al. (2019)
	AAZ	in vivo	Wistar/ST rats	10 mg/kg IP	Injection 3 or 12 h post- TBI/cerebral edema	↑ Survival rate from 53% to 75% in 3 h post-TBI group but no significant decrease in cerebral edema ↓ Cerebral edema with 100% survival in 12 h post- TBI group	Katada et al. (2012)
		in vivo	C57BL/6J mice	15 mg/kg in DMSO IP	Injection 30 min post-TBI	° Limited AQP4 reorganization ° No significant effect on astrocyte activation ↓ Post-TBI cerebral edema	Glober et al. (2019)
		in vitro	Sprague- Dawley rat astrocytes, Human astrocytes	0.2 mg/mL in DMSO	-	° AAZ prevented AQP4 aggregation and redistribution post-OGD
		in vitro	C8D1A astrocyte mTBI model	20 μM	Added 15 min before injury	↑ Viability of astrocytic cells post-TBI with AAZ pre-treatment	Sturdivant et al. (2016)
	AAZ, MZA	in vitro rat AQP4, Human AQP1	Recombinant	-	-	° AAZ: ↓ water permeability through AQP4 but not AQP1 channels by 46.7%, recovered to 88.6% water permeability ° MZA: no significant results of water conduction through AQP1 or AQP4	Tanimura et al. (2009)
	Carbonic anhydrase inhibitors TGN-020	in vitro	Xenopus oocytes	-	Oocyte functional assay used	° AAZ showed 80%, EZA 68%, 4- acetamidobenzsulfonamide 23% AQP4 inhibition	Huber et al. (2007)
	TGN-020	in vivo	C57BL/6J mice	200 mg/kg in 0.1 mL saline IP	Injection 15 min pre-ischemia	↓ Cerebral edema volume in pretreated TGN-020 brain ischemia mice models	Igarashi et al. (2011)
		in vivo	Wistar rats	5.0 mg/kg in DMSO IP	Injection immediately post-ON crush	↑ RGC loss by changes in glutamate synthetase levels ↑ Extracellular glutamate levels post-crush	Nishikawa et al. (2016)
		in vivo	Wistar rats	2 μL of 10 ng/μL in PBS IV	Injection 2 wk post-diabetes induction	↓ Swelling of Müller cells in diabetes-induced rats that showed increase in VEGF	Kida et al. (2017)
		in vivo	Wistar rats	2 μL of 10 ng/μL in PBS IV	Injection 8 wk post-diabetes induction	↓ Swelling of Müller cells ↓ Thickening of retina diabetes-induced rats	Oosuka et al. (2020)
	Compounds structurally similar to AQP4 inhibitors	in vitro in silico	X. laevis oocytes, rat AQP4b	5 μL of 200 μM	Compounds used had unrelated biological properties	° Thiadiazole, sumatriptan, and rizatriptan showed highest AQP4 inhibitory activity ° Suggests heteroaromatic groups may be favored over aliphatic groups, hydrogen bonds essential to inhibit AQP4	Huber et al. (2009)
Facilitator	TGN-073	in vivo	C57BL/6J mice	20 or 200 mg/kg in 0.2 mL saline IP	30 min before study	↑ Water flux turnover of interstitial fluid managed by AQP4 system	Huber et al. (2018)

AQP1: Aquaporin-1; AQP4: aquaporin-4; AAZ: acetazolamide; EJV: external jugular vein; EZA: 6-ethoxybenzothiazole-2-sulfonamide; IP: intraperitoneal; IV: intravitreal; MZA: methazolamide; OGD: oxygen glucose deprivation; ON: optic nerve; RGC: retinal ganglion cells; SQ: subcutaneous; TBI: traumatic brain injury; VEGF: vascular endothelial growth factor.