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Table 2 Experimental stroke studies using AT2 receptor agonists

From: Therapeutic potential of the renin angiotensin system in ischaemic stroke

Animals
Gender
Strain
Weight
Stroke model Treatment profile
AT2R agonist
Administration
Dose
Time point
In vivo measures and methods Treatment outcome Proposed underlying mechanism Reference
Male
Wistar rats
280–320 g
tMCAO
90 min or 3 h
24 h or 7 day recovery
C2 1
i.p bolus
0.03 mg/kg
Post treatment
BP: telemetry method
NS: Bederson score
BHT: Beam walk, paw grasp, rotarod test, grip strength
Infarct volume: TTC
Haemoglobin content
Did not affect BP
Improved NS
Improved functional outcome
Decreased infarct volume
Decreased haemorrhage
Pro-angiogenic
Via Akt/eNOS/NO pathway
Upregulation of p-Akt, IL-10, BDNF and eNOS protein expression. Plus, nitrative stress markers nitrotyrosine and iNOS protein expression were downregulated in the ipsilateral hemisphere
The results were further correlated to a decrease in AT1R and an upregulation of AT2R cerebral expression
Alhusban et al. [60]
Male
Wistar rats
250–310 g
tMCAO or pMCAO
Filament model
Up to 21 days recovery
C21
i.p bolus
0.3 mg/kg/day
Post treatment
NS: 7 point score
Infarct volume: Nissl staining
For pMCAO treated rats
Improved NS
Decreased infarct volume
Pro-angiogenic
Increased VEGF expression due to Akt/mTOR signalling pathway activation
Mateos et al. [61]
Male
Sprague–Dawley rats
250–275 g
tMCAO
ET-1 model
3 day recovery
C21
i.c.v or i.p infusion
0.0075 μg/μl/h i.c.v
0.03 or 0.1 mg/kg i.p
Pre and post treatment
BP: tail cuff method
CBF: laser-Doppler
Infarct volume: TTC
NS: Bederson and Garcia scores
Did not affect BP
Did not affect CBF
Improved NS
Decreased infarct volume
Anti-inflammatory
Decrease in gene expression for inflammatory markers iNOS, CCR2 and its ligand CCL2 in ipsilateral cerebral cortex
Joseph et al. [62]
Male
SHR
270–320 g
tMCAO
ET-1 model
3 day recovery
CGP42112
i.c.v infusion
0.1–10 ng/kg/min
Pre and post treatment
BP: tail cuff method
Infarct volume: ballistic light method
BHT: ledged beam test
Did not affect BP
Improved motor function
Decreased infarct volume
Anti-oxidant
Decreased superoxide production in infarcted cortical regions, associated to an increase in brain AT2R expression
McCarthy et al. [63]
Male
SHR
Weight not specified
tMCAO
ET-1 model
3 day recovery
CGP42112
i.c.v injection
3 μg/kg
Post treatment
BP: tail cuff method
Infarct volume: ballistic light method
BHT: ledged beam test
Did not affect BP
Improved motor function
Decreased infarct volume
Anti-apoptotic
Decreased cleaved caspase-3 positive apoptotic cells and increased neuronal survival (NeuN positive cells) in ipsilateral hemisphere. Plus, increased activated microglia (OX42 marker) in ipsilateral core
McCarthy et al. [64]
Male
SHR
330–350 g
tMCAO
ET-1 model
3 day recovery
C21
i.c.v infusion and injection
3 μg/kg
Pre and post treatment
BP: tail cuff method
Infarct volume: ballistic light method
BHT: ledged beam test
Did not affect BP
Improved motor function
Decreased infarct volume
Anti-apoptotic and vasodilatory
Increased neuronal survival (NeuN positive cells) and activated microglia which are potentially BDNF positive
Myography studies in basilar arteries further suggested a vasodilatory effect induced by C21
McCarthy et al. [65]
Male
C57BL/6J
8–12 weeks
tMCAO
30 min
24 h recovery
CGP42112
i.p bolus
1 mg/kg
Post treatment
CBF: laser-Doppler
NS: Bederson score
BHT: hanging wire test
Infarct volume: thionin staining
Cerebral oedema
Did not affect cerebral oedema
Improved NS
Improved motor function
Improved CBF
Decreased infarct volume
Anti-apoptotic
C21 promotes cell viability in primary cortical neurons following oxygen glucose depravation challenge
Lee et al. [66]
Male
C57BL/6J WT and AT2R KO mice
25–30 g
pMCAO
dMCAO model
24 h recovery
C21
i.p bolus
10 µg/kg/day
Pre and post treatment
BP: tail cuff method
NS: 4 point score
CBF: laser speckle method
Infarct volume: MRI T2 scan
Cerebral oedema
Blood brain barrier (BBB) permeability: Evans blue dye
Did not affect BP
Improved NS
Improved CBF
Decreased infarct volume
Decreased oedema
Decreased BBB permeability
Ant-inflammatory
Decreased expression of MCP-1, TNF-α and SO
Also observed reduced BBB breakdown
Min et al. [67]
  1. Studies involved either transient middle cerebral artery (tMCAO) or permanent middle cerebral artery occlusion (pMCAO). Unless specified, tMCAO was performed via intraluminal filament model
  2. Akt protein kinase B, AT 1 R angiotensin II type I receptor, AT 2 R angiotensin II type II receptor, BBB blood brain barrier, BDNF brain derived neurotrophic factor, BHT behavioural testing, BP blood pressure, C21 compound 21, CBF cerebral blood flow, CCL2 chemokine (C–C motif) ligand 2, CCR2 C–C chemokine receptor type 2, COX-2 cyclooxygenase 2, dMCAO distal middle cerebral artery occlusion model, eNOS endothelial nitric oxide synthase, ET-1 endothelin-1, i.c.v intracerebroventricular, IL-10 interleukin 10, iNOS inducible nitric oxide synthase, i.p intraperitoneally, MCP-1 macrophage chemokine protein 1, MRI magnetic resonance imaging, mTOR mechanistic target of rapamycin, NeuN neuronal nuclei, NO nitric oxide, NS neurological score, OX-42 anti-CD11b/c antibody, p-Akt phosphorylated Akt, SHR spontaneously hypertensive rats, SO superoxide, TNF-α tumor necrosis factor alpha, TrkB tropomyosin receptor kinase B, TTC 2,3,5-triphenyltetrazolium chloride staining, VEGF vascular endothelial growth factor