Blockade of receptor for advanced glycation end-products with azeliragon ameliorates streptozotocin-induced diabetic neuropathy

Treatment options for diabetic neuropathy are suboptimal, so development of a new therapeutic strategy is urgent. We focused on the role of receptor for advanced glycation end-products (RAGE) in diabetic neuropathy. We elaborated the effects of azeliragon (orally available small-molecule antagonist of RAGE) on streptozotocin (STZ)-induced mechanical hypersensitivity in mice. A reduction in mechanical nociceptive threshold observed 28 days after STZ treatment was improved by single administration of azeliragon (10 and 30 mg/kg) at 3 h, but this effect disappeared at 24 h. Conversely, repeat administration (three times; days 28, 30, and 32) of azeliragon (30 mg/kg) enhanced the antinociceptive effect significantly compared with that obtained upon single administration, and this effect persisted at least up to 24 h. The antinociceptive effect of azeliragon (30 mg/kg) was almost comparable with that of pregabalin (30 mg/kg). These drug treatments had no effect on blood glucose levels. Our findings suggest that RAGE might be an effective target for diabetic neuropathy treatment.