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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