Abstract 10198: Endothelin B Receptor Agonist, IRL-1620 is an Effective Neurovascular Remodeling Agent in Diabetic Rats With Cerebral Ischemia
Endothelin B (ETB) receptor agonist, IRL-1620 administered at 2, 4, 6 hr post-cerebral ischemia, has been shown to significantly aid in neuroprotection and neurovascular remodeling in normal rats. The incidence of type 2 diabetes mellitus (diabetes) is on the rise and it can be expected that there will be an upsurge of associated diseases, such as ischemic stroke in patients with diabetes. The present study was conducted to determine the efficacy and neurovascular remodeling effect of IRL-1620 in normal (non-diabetic) and diabetic rats following cerebral ischemia induced by right middle cerebral artery (MCAO). The induction of diabetes was achieved through a high-fat diet and single low dose (45 mg/kg) of streptozotocin. IRL-1620 (5 μg/kg) was administered intravenously at 4, 6, and 8 hr after MCAO on day 0, 3 and 6 (total of 15 μg/kg in three divided doses on day 0, 3 and 6). A mortality of 46% was observed by day 7 in normal rats with MCAO when treated with vehicle, while it was 17% when treated with IRL-1620. In diabetic rats 90% mortality was observed by day 7 post-MCAO when treated with vehicle, while it was 45% when treated with IRL-1620. Functional outcome for the IRL-1620 group was significantly better in both non-diabetic and diabetic rats compared to the vehicle group. In both non-diabetic (80.81%; p=0.02) and diabetic (69.58%; p=0.04) rats a significant reduction in infarct volume was seen in the IRL-1620 group compared to the vehicle group. Significantly more blood vessels/30μm brain slice were observed in the IRL-1620 versus vehicle group. Immunofluorescence staining revealed a significant increase in ETB receptor expression for rats treated with IRL-1620, compared to vehicle. Co-localization of VEGF+ve and endothelial cells in diabetic rats was higher (p=0.0009) in the IRL-1620 group (15.5±1.1%) compared to the vehicle group (10.2±0.81%). In diabetic rats, the IRL-1620 group had significantly (p=0.0012) more neurons in the cortex compared to the vehicle group as well as the highest levels of neuronal replication. Administration of BQ-788, a specific ETB receptor antagonist, attenuated the effects of IRL-1620. It is concluded that IRL-1620 is an effective neurovascular remodeling agent and may be useful in the treatment of cerebral ischemia.
Author Disclosures: M. Husby: None. M.G. Leonard: None. A. Gulati: Ownership Interest; Modest; Patents Issued and pending.
- © 2015 by American Heart Association, Inc.