Aquaporin-4 and spinal cord injury

Table 1 Studies of aquaporin-4 expression following spinal cord injury

Ref.	Species	Model	Device	Parameters	Level	AQP4 RNA	AQP4 protein	AQP4 IHC	Water content	Behavioral outcome
Nesic et al[53]	Sprague dawley male rats	Contusion	IH Impactor	200 kdyn	T10	↑ AQP4 at 28 d post SCI	↑ AQP4 at 28 d post SCI	↑ AQP4 at 28 d and 5 m post SCI		↑ CNP in animals with increased AQP4
Nesic et al[36]	Sprague dawley male rats	Contusion	IH Impactor	150 kdyn,	T13		↓ AQP4 at 12 h, 24 h, 3 d and 7 d post SCI	↑ AQP4 at 5 m post SCI	↑ levels at lesion site at 3 d
				1 s dwell			↑ AQP4 at 14 d, 35 d, 40 d, 56 d, 3.5 m and 9 m post SCI	Astrocytes lacking AQP4 at dpi 14	↑ levels at all levels at 2 and 5 mo
Nesic et al[47]	Human				C5/6, C2, C8			↑ AQP4 in spared white matter
								↓ AQP4 in lesion epicenter
								(1-2 yr post SCI)
	Sprague dawley male rats	Contusion	IH Impactor	150 kdyn,	T10		↑ AQP4 at 2 and 11 m post SCI	↑ AQP4-/GFAP+ astrocytes at 14 d post SCI	↑ levels at 3 d, 2 and 5 m	BBB outcome coorelated with severity of injury
				1 s dwell			↓ AQP4 in severe SCI at 21 d	↑ AQP4 labeling in AQP4+ astrocytes post SCI
							↓ AQP4 in moderate SCI at 1, 7 and 14 d	↑ AQP4 at 1, 2, 3 and 5 m post SCI
							no change in moderate/mild SCI at 21 d
Leonard et al[79]	Rabbits	Compression	Balloon compression	8 atm pressure,	T10			↑ AQP4 at 5 h, 24 h, 3 d and 14 d post SCI	↑ levels at 5 h, 24 h and 3 d	↓ Tarlov score and sensory pin prick in SCI animals
				5 min hold

AQP4: Aquaporin-4; IH: Infinite Horizons; BBB: Basso, Beattie, Bresnahan; CNP: Chronic neuropathic pain; GFAP: Glial fibrillary acidic protein; SCI: Spinal cord injury.

Table 2 Studies utilizing therapeutic interventions to alter aquaporin-4 expression after spinal cord injury

Ref.	Species	Model	Device	Parameters	Level	Treatment	Timing/ duration	AQP4 RNA	AQP4 protein	AQP4 IHC	Water content	Behavioral outcome
Vitellaro-Zuccarello et al[73]	Sprague dawley male rats	Contusion	UTS Impactor	1 N, 1 s dwell	T9	rhEPO, 5000 UI/kg	Once, 30 min post injury			↑ AQP4 in untreated at 7 d and 28 d		↑ in rhEPO treated (BBB)
										↑ AQP4 in rhEPO at 7 d and 28 d
Guptarak et al[72]	Sprague dawley male rats	Contusion	IH Impactor	150 kdyn, 1 s dwell	T10	TMX, 1 mg	Once/day, 14 or 28 d post injury (acute), days 42-56 post injury (delayed)		↑ AQP4 in untreated and 35 d	↑ AQP4 in untreated and 35 d		↑ in TMX treated at 14 d and 28 d (acute treatment) no BBB recovery in animals treated from day 42-56 (delayed treatment)
									↑ AQP4 in TMX treated at 35 d	↑ AQP4 in TMX treated at 35 d
Wu et al[61]	C57B/L6 male mice	Contusion	Weight drop	5 g weight, 10 mm drop	T10	Melatonin, 50 mg/kg	Once, post injury		↑ AQP4 in untreated at 48 h		↑ levels in untreated at 48 h
									↓ AQP4 in melatonin treated at 48 h		↓ levels in melatonin treated at 48 h
Jing et al[63]	C57B/L6 male mice	Contusion	IH Impactor	50 kdyn	T10	Melatonin, 10 mg/kg	Twice/day, 2 wk post injury		↑ AQP4 in untreated at 7 d		↑ levels in untreated at 7 d	↑ in melatonin treated at 7, 10 and 14 d (BMS)
									↓ AQP4 in melatonin treated at 7 d		↓ levels in melatonin treated at 7 d
Zu et al[69]	Sprague dawley male rats	Contusion	Striking bar	150 gcf, 5 cm drop	T8	Curcumin, 40 mg/kg	Once, 30 min post injury	↑ AQP4 in untreated at 72 h	↑ AQP4 in untreated at 72 h	↑ AQP4 in untreated at 72 h	↑ levels in untreated at 72 h	no difference in BBB scores with treatment
								↓ AQP4 in curcumin treated at 72 h	↓ AQP4 in curcumin treated at 72 h	↓ AQP4 in curcumin treated at 72 h	↓ levels in curcumin treated at 72 h
Hu et al[24]	Sprague dawley female rats	Contusion	NYU weight drop device	10 g weight, 25 mm drop	T10	Myelotomy, 3.5 mm long, 1-1.5 mm deep	Once, 24 h after injury		↑ AQP4 in untreated at 2, 4 and 6 d		↑ levels in untreated at 4 and 6 d, not at 2 d	↑ in myelotomy treated at 14, 21, 28, 35 and 42 d
									↓ AQP4 in myelotomy treated at 4 and 6 d		↓ levels in myelotomy treated at 4 and 6 d	(BBB and inclinded plane test)
Mao et al[89]	CD1 male mice	Compression	Vascular clip	10 g force, 1 min hold	T9	SFN, 5 mg/kg	Once, 1 h post injury	↓ AQP4 in untreated at 48 h	↓ AQP4 in untreated at 48 h	↓ AQP4 in untreated at 48 h	↑ levels in untreated at 48 h
								↑ AQP4 in SFN treated at 48 h	↑ AQP4 in SFN treated at 48 h	↑ AQP4 in SFN treated at 48 h	↓ levels in SFN treated at 48 h
Fan et al[83]	Sprague dawley male rats	Compression	Weight application	5 g weight, 5 min hold	T12	AG, 150 mg/kg	Once, 24 h post injury		↑ AQP4 in untreated at 24 h and 48 h	↑ AQP4 in untreated at 48h	↑ levels in untreated at 12, 24 and 48 h	↑ in AG treated (BBB)
									↓ AQP4 in AG treated at 24 h and 48 h	↓ AQP4 in AG treated at 48 h	↓ levels in AG treated 12, 24 and 48 h
Wang et al[82]	Sprague dawley male rats	Compression	Weight application	50 g weight, 5 min hold	T12	2ME2, 2.5 mg/kg	Once, post injury		↑ AQP4 in untreated at 6, 12 and 24 h
									↓ AQP4 in 2ME2 treated at 12 h
Ge et al[84]	Sprague dawley male rats	Compression	Vascular clip	30 g force, 1 min hold	T12	EGCG, 100 mg/kg	1 ×/day, 3 d		↑ AQP4 in untreated at 12, 24, 48 and 72 h	↑ AQP4 in untreated at 24 and 72 h	↑ levels in untreated at 12, 24, 48 and 72 h
									↓ AQP4 in EGCG treated at 24, 48 and 72 h	↓ AQP4 in EGCG treated at 24 and 72 h	↓ levels in EGCG treated at 24, 48 and 72 h
Liu et al[58]	Sprague dawley male rats	Compression	Aneurysm clip	5 min hold	T12	Melatonin, 100 mg/kg	1 ×/day, 3 d		↑ AQP4 in untreated at 12, 24, 48 and 72 h	↑ AQP4 in untreated at 24 and 72 h	↑ levels in untreated at 12, 24, 48 and 72 h
									↓ AQP4 in melatonin treated at 24, 48 and 72 h	↓ AQP4 in melatonin treated at 24 and 72 h	↓ levels in melatonin treated at 24, 48 and 72 h

RhEPO: Erythropoietin; TMX: Tamoxifen; AQP4: Aquaporin-4; BBB: Basso, Beattie, Bresnahan; BMS: Basso mouse locomotor scale; NYU: New York University; SFN: Sulforaphane; AG: Aminoguanidine; 2ME2: 2-Methoxyestradiol; EGCG: Epigallocatechin gallate.

Table 3 Studies utilizing aquaporin-4 null mice

Ref.	Species	Model	Device	Parameters	Level	AQP4 IHC	Water content	Behavioral outcome
Kimura et al[98]	CD1 AQP4 -/- female mice, AQP4 +/+	Contusion	IH Impactor	60 kdyn	T10		↑ levels in -/- compared to +/+	↓ in -/- compared to +/+ (BMS, foot print analysis, bladder function)
Saadoun et al[95]	CD1 and BL/6 AQP4 -/-, AQP +/+	Compression	Dumont 5 forcepts	1 mm separation, 2 min hold	T6	↑ AQP4 in +/+ SCI at 2 d	↓ levels in -/- compared to +/+	↑ in -/- compared to +/+ (BMS, foot print analysis)
Wu et al[68]	CD1 AQP4 -/-, AQP4 +/+	Transection	Louisville Impactor System Apparatus	0.8 mm depth, right hemisection	C4	↓ AQP4 in +/+ SCI at 2 d and 7 d	↑ levels in both -/- and +/+ at 3 d
						↑ AQP4 in +/+ SCI at 42 d	↑ levels in -/- compared to +/+ at 3 d

AQP4: Aquaporin-4; IH: Infinite horizons; BMS: Basso mouse locomotor scale; SCI: Spinal cord injury.