ABSTRACT
Title
NCX 1236, a novel gabapentin endowed of nitric oxide-releasing properties, reverses the development of mechanical allodynia in streptozotocin-treated diabetic mice
Authors
V. Borghi1, F. Impagnatiello1, P.A. Borea2, F. Vincenzi2, M. Targa2, E. Ongini1 and K. Varani2
1NicOx Research Institute, Bresso, Milan, Italy.
2University of Ferrara, Dept of Clinical and Experimental Medicine, Ferrara, Italy.
Abstract
NCX 1236 is a novel NO-donating gabapentin, shown to exert superior anti-allodynic activity compared to gabapentin in several models on neuropathic pain including streptozotocin (STZ)-induced painful diabetic neuropathy (PDN).
Here we addressed whether the repeated daily dosing of NCX 1236 or gabapentin also affects the development of mechanical allodynia following STZ (200 mg/kg, ip) administration. More specifically, mechanical allodynia was monitored using the Dynamic Plantar Aesthesiometer prior to and after 7, 14 and 21days daily oral dosing with vehicle, gabapentin (30mg/kg, po) or equimolar NCX 1236 (71mg/kg, po) 24h after the last treatment to assure the absence of residual gabapentin exposure at the time the measurements were recorded. The latter was also confirmed by monitoring plasma gabapentin exposure after NCX 1236 and gabapentin treatment using a UPLC/MS/MS method.
STZ increased plasma glucose levels within 24h post-injection and prompted the development of mechanical allodynia (threshold, 4.0±0.2 and 2.1±0.2 g, respectively in control and STZ-treated animals, p<0.05). Mechanical allodynia continued to decrease in animals receiving vehicle (threshold, 1.3±0.1g, at 21 days) or gabapentin (threshold, 1.8±0.3g, at 21 days). Conversely, NCX1236 resulted in a progressive reversal of the allodynic response which was evident 7 days after treatment (threshold, 3.2±0.2 g) and reached its maximum over the following weeks. Gabapentin and NCX1236 resulted in similar gabapentin plasma exposure following acute or repeated treatment schedule with an estimated Tmax of 30 min.
Data suggest that NCX 1236, differently from gabapentin, hampers the development and maintenance of STZ-induced mechanical allodynia in mice. It remains to be established whether these effects are retained in higher species and diabetic patients.
Here we addressed whether the repeated daily dosing of NCX 1236 or gabapentin also affects the development of mechanical allodynia following STZ (200 mg/kg, ip) administration. More specifically, mechanical allodynia was monitored using the Dynamic Plantar Aesthesiometer prior to and after 7, 14 and 21days daily oral dosing with vehicle, gabapentin (30mg/kg, po) or equimolar NCX 1236 (71mg/kg, po) 24h after the last treatment to assure the absence of residual gabapentin exposure at the time the measurements were recorded. The latter was also confirmed by monitoring plasma gabapentin exposure after NCX 1236 and gabapentin treatment using a UPLC/MS/MS method.
STZ increased plasma glucose levels within 24h post-injection and prompted the development of mechanical allodynia (threshold, 4.0±0.2 and 2.1±0.2 g, respectively in control and STZ-treated animals, p<0.05). Mechanical allodynia continued to decrease in animals receiving vehicle (threshold, 1.3±0.1g, at 21 days) or gabapentin (threshold, 1.8±0.3g, at 21 days). Conversely, NCX1236 resulted in a progressive reversal of the allodynic response which was evident 7 days after treatment (threshold, 3.2±0.2 g) and reached its maximum over the following weeks. Gabapentin and NCX1236 resulted in similar gabapentin plasma exposure following acute or repeated treatment schedule with an estimated Tmax of 30 min.
Data suggest that NCX 1236, differently from gabapentin, hampers the development and maintenance of STZ-induced mechanical allodynia in mice. It remains to be established whether these effects are retained in higher species and diabetic patients.