Abstract
BackgroundIn this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents.Methods and ResultsSpontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury.ConclusionThese results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development.
Highlights
It is becoming increasingly evident that modulation of the reninangiotensin system (RAS) can be protective against the damaging effects of stroke
We have confirmed the neuroprotective effect of angiotensin II type 2 receptor (AT2R) stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development
Systolic Blood Pressure There was no significant difference in Systolic blood pressure (SBP) between any of the treatment groups indicating that C21 did not significantly alter SBP in either treatment protocol (Table 1)
Summary
It is becoming increasingly evident that modulation of the reninangiotensin system (RAS) can be protective against the damaging effects of stroke. Angiotensin II (Ang II) is the main effector hormone of the RAS that has the ability to interact with different receptor subtypes to elicit a range of physiological events. The most abundant of the Ang II receptors is the angiotensin II type 1 receptor (AT1R), responsible for most of the physiological and pathological events classically associated with Ang II [3]. The angiotensin II type 2 receptor (AT2R) is more sparsely expressed in adult tissue and is often silenced by the dominant AT1R. In certain disease settings, including stroke, AT2R expression is upregulated, suggesting that it may be involved in the body’s endogenous response to injury [4,5,6]. The neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
