Azeliragon attenuates cerebral infarction aggravation in diabetic rats: Receptor for advanced glycation end-product as a novel therapeutic target

Diabetes mellitus contributes to neurological deterioration in acute ischemic stroke; nonetheless, rapid glucose control strategies have proven ineffective in clinical trials. We investigated whether targeting the receptor for advanced glycation end products (RAGE) could prevent infarction worsening in diabetic cerebral ischemia. To generate a diabetic model, streptozotocin (50 mg/kg) was intraperitoneally injected into male Sprague-Dawley rats (7-8 weeks old). A transient 30-min middle cerebral artery occlusion was performed at 34 days after diabetes induction. Azeliragon (10 mg/kg), a RAGE antagonist, was administered as a single intraperitoneal injection immediately after reperfusion. Total infarct volume, neurological severity, and mechanistic analyses were compared between vehicle and azeliragon groups. The 9.4 T animal magnetic resonance imaging analysis demonstrated that total infarct volume was significantly lower in the azeliragon group compared with the vehicle group (125.3 ± 26.2 mm³ vs. 240.5 ± 21.6 mm³; p = 0.003). Additionally, the modified neurological severity scores were significantly lower in the azeliragon group compared with the vehicle group (6.4 ± 1.7 vs. 11.1 ± 0.7; p = 0.012). The neuroprotective effect was consistently observed in a 4-day hyperglycemic model. Mechanistic analyses, including immunohistochemistry and Western blotting, revealed that azeliragon treatment significantly reduced the levels of Reactive Oxygen Species, apoptotic markers, and key inflammatory mediators. Specifically, the phosphorylated to total NF-κB p65 ratio was significantly lower (p = 0.030), along with the levels of tumor necrosis factor-α and interleukin-1β, in the azeliragon group compared with the vehicle group (p < 0.001 for each). Therefore, RAGE antagonism significantly reduced ischemic brain damage and neuroinflammation in diabetic cerebral ischemia, offering a promising therapeutic strategy.

Azeliragon; Cerebral infarction; Diabetes mellitus; Hyperglycemia; Receptor for advanced glycation end products; Treatment.