Background:
Compound 21 (C21), a selective small-molecule angiotensin type 2 receptor (AT2R) agonist, has been proven in multiple preclinical studies to reduce infarct size and ameliorate neurological deficits, when administered after ischemic stroke via intracerebroventricular or intraperitoneal routes. However, C21 poorly penetrates the blood brain barrier (BBB). In this study, we used the novel and non-invasive approach of intranasal trans-olfactory (INTO) application, in order to bypass the BBB and deliver C21 directly into the brain. The therapeutic efficacy of INTO application of C21 was assessed in a model of transient middle cerebral artery occlusion (MCAO).
Methods:
(i) Male SD rats (12 weeks old) underwent ischemic stroke by endothelin-1-induced MCAO. They were randomly divided into two treatment groups, either receiving 0.9% saline or C21 (1.5 ug/kg) at 1.5, 4, 24 and 48 h post-stroke, using a rat intranasal catheter device (Impel Neuropharma, Seattle, WA) for INTO application. All rats underwent blinded neurological assessments at 4, 24 and 72 h after stroke, and immediately after the 72 h tests, were euthanized and cerebral infarct volumes were assessed by TTC staining. (ii) Male SD rats (12 weeks old) underwent implantation of a telemetry transducer (DSI, St. Paul, MN) into the abdominal aorta for measurement of blood pressure, heart rate and locomotor activity after INTO C21 (1.5 ug/kg) vs. 0.9% saline at baseline and post-ischemic stroke.
Results:
(i) Post-stroke INTO delivery of C21 (1.5 ug/kg) elicited a significant lowering of % cerebral infarct volume (25.4 ± 4.7; n=9) compared with saline-treated rats (48.4 ± 4.4; n=21) [p<0.05; two-way Mann-Whitney test]. The C21 (1.5 ug/kg)-treated rats also displayed highly significant improvements in Garcia and Bederson neurological scores (p<0.01; two-way Mann-Whitney test]. (ii) INTO delivery of C21 (1.5 ug/kg) either in naïve rats (n=7), or in rats post-stroke (n=4), did not significantly alter baseline blood pressure, heart rate and locomotor activity.
Conclusions:
Our results demonstrate, that INTO delivery of C21 exerts protective effects after ischemic stroke. These studies suggest INTO administration as potential future route of application of C21 to stroke patients.
Compound 21, the first orally active, selective agonist of the angiotensin type 2 receptor (AT2): implications for AT2 receptor research and therapeutic potential
