Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach

Abstract

Significant neuroprotective effects of angiotensin II type 2 (AT) receptor (AT receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

Neuroprotection by post‐stroke administration of an oral formulation of angiotensin‐(1–7) in ischaemic stroke

“…To test for effects of orally active Ang‐(1–7) on cardiovascular function during baseline, adult Sprague–Dawley rats were implanted with telemetry recording devices (TA11PA‐C40; DSI, St Paul, MN, USA) in the abdominal aorta exactly as detailed in Bennion et al (), followed by 1 week of recovery. In a cross‐over study design with 2 days washout between each treatment administration, animals ( n = 8) were given a gavage of H 2 O or HPβCD–Ang‐(1–7) at one of two doses (125 or 250 μg kg −1 ) before undergoing telemetry recordings in baseline conditions for 6 h from morning to afternoon.…”

“…in the abdominal aorta exactly as detailed in Bennion et al (2018), followed by 1 week of recovery. In a cross-over study design with 2 days washout between each treatment administration, animals (n = 8)…”

The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

“…Further studies demonstrated that IP delivery of C21 after stroke induction, whether permanent or transient, improved outcome after stroke including in co-morbid animals with hypertension or advanced age [ 193 , 195 , [265] , [266] , [267] , [268] ] ( Table 2 ). Additionally, AT 2 R signalling with C21 has demonstrated further translational potential with promising results achieved with post-stroke oral delivery in female rats [ 269 ] or in a type 2 diabetes animal model [ 270 ], or with an intranasal delivery approach resulting in high levels detectable in the cortex and striatum, and improved outcome following stroke [ 271 ].…”

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

“…These findings resulted in considerable advances in utilizing brain RAS blockade or RAS modulation as a therapeutic strategy to treat diseases beyond neurogenic hypertension. This is specifically relevant in stroke and cerebrovascular diseases, Alzheimer's disease, cognitive dysfunction, Parkinson disease, aging, and others [107][108][109][110][111][112][113][114][115]. Numerous other new molecules or administration routes to target the brain RAS are currently under investigation.…”