Hypertension. 2012 Dec;60(6):1531-7

Angiotensin II type 2 receptor stimulation initiated after stroke causes neuroprotection in conscious rats.

McCarthy CA, Vinh A, Broughton BR, Sobey CG, Callaway JK, Widdop RE.

Department of Pharmacology, Monash University, Clayton, Victoria, Australia. claudia.mccarthy@monash.edu

 

Abstract

We have demonstrated previously that pretreatment with an angiotensin II type 2 receptor (AT(2)R) agonist is neuroprotective against a subsequent stroke independent of any changes in blood pressure. Therefore, in the current study, we have examined the potential neuroprotective effect of AT(2)R stimulation initiated after stroke induction to mimic the clinical setting. Intracerebroventricular administration of the AT(2)R agonist CGP42112 was commenced 6 hours after an ischemic stroke had been induced in conscious spontaneously hypertensive rats. CGP42112 given over 4 doses in the same rats (3 µg/kg per dose centrally) at 6, 24, 48, and 72 hours after stroke induction reduced total infarct volume (32 ± 13 mm(3) versus vehicle, 170 ± 49 mm(3); P<0.05) and improved motor function. Furthermore, we have demonstrated that AT(2)R stimulation after stroke increased neuronal survival, decreased apoptosis, and caused an increase in the number of activated microglia in the core region of damage. The effects of CGP42112 were partially reversed with the coadministration of an AT(2)R antagonist, PD123319. Thus, the current study has shown for the first time that delayed central AT(2)R stimulation after a cerebral incident is neuroprotective in a conscious rat model of stroke.

PMID: 23090772

 

Supplement picture:

Administration of AT2R activators can elicit various neuroprotective actions associated with AT2R that are expressed in the brain.

Claudia McCarthy-3

Press release:

The angiotensin II type 2 receptor; an exciting novel target to reduce brain damage following stroke.

Stroke is Australia’s second single greatest killer after coronary heart disease and a leading cause of disability 1. These figures are likely to rise each year due to the aging population unless steps are taken to reduce the incidence rate 2. Despite this the only treatment that is currently available to reduce the extent of brain damage following stroke is thrombolysis, which has a limited application due to its narrow therapeutic window of approx 4-5hrs. In fact, only 1-5% of patients presenting with acute stroke are able to receive any form of active intervention, which illustrates the alarming lack of treatment options for stroke patients and a desperate need for novel therapies in this area.

With this in mind, Dr McCarthy is interested in understanding the relationship between the renin-angiotensin system and stroke outcome. This work stemmed from the observation that angiotensin receptor blockers (ARBs), a class of antihypertensive agents that are used prophylactically to prevent stroke, have additional protective effects within the brain. The neuroprotective actions of the ARBS are partly attributed to increased activation of a particular target site in the brain known as the angiotensin II type 2 receptor (AT2R). Our group is specifically interested in targeting the AT2R and have shown that when brain AT2R was activated prior to experimentally inducing a stroke the amount of injury was dramatically reduced3. Excitingly, we have now shown that the AT2R also exerts a protective influence even when activated 6 hours after stroke, which is of particular importance as this 6 hour window of opportunity will allow far more patients to receive benefit4.  Collectively, our work highlights the importance of the AT2R as a therapeutic target for stroke research and in the future will hopefully address the unmet need by providing a more effective strategy to treat acute stroke.

 

1. AIHW (2004). Heart, stroke and vascular diseases—Australian facts 2004.ed . Australia,  A.I.o.H.a.W.A.a.N.H.F.o.
2. Senes, S. (2006). How we manage stroke in Australia.ed. Welfare, A.I.o.H.a.
3. McCarthy, C.A., et al. (2009). Angiotensin AT2 receptor stimulation causes neuroprotection in a conscious rat model of stroke. Stroke, 40, 1482-1489.
4. McCarthy, C.A., et al. (2012). Angiotensin II type 2 receptor stimulation initiated after stroke causes neuroprotection in conscious rats. Hypertension, 60, 1531-1537.

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