Linagliptin attenuates chronic post-ischemia pain: Possible anti-inflammatory and anti-oxidant mechanisms.

Complex regional pain syndrome (CRPS) is a debilitating neurologic disorder with an interlinked and yet incompletely defined pathogenesis. Treatment options remain a therapeutic challenge. Linagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors which are used for the treatment of diabetes mellitus. Apart from the improvement of glycemic control, accumulating evidence points to the beneficial effects of DPP-4 inhibitors in a wide array of conditions. Herein, the present study was outlined to investigate the antinociceptive effect of linagliptin in acute pain conditions, and in an animal model of CRPS. A prolonged hind paw ischemia reperfusion (I/R) injury to the left hind paw was done to induce chronic post-ischemia pain (CPIP) in rats. Allodynia and hyperalgesia were assessed in both ipsilateral and contralateral hind paws at different time points. At the end of the experiment, markers of oxidative stress and inflammatory cytokines were assayed in paw skin samples. The results showed that linagliptin had no effect on acute nociception. On the other hand, linagliptin treatment, for seven days, ameliorated hyperalgesia, mechanical and cold allodynia, and attenuated oxidative and inflammatory markers in CPIP rats. In conclusion, linagliptin was able to ameliorate aberrant pain behavior induced by prolonged hind paw ischemia. These effects can be attributed, at least partially, to the reduction of inflammatory cytokine levels and restore oxidant/antioxidant balance in the CPIP model. Hence, linagliptin pleiotropic effects open a new horizon to further investigate its role in the treatment of inflammatory and chronic painful conditions, especially in diabetic patients.