Diabetic neuropathy (DN) is the most challenging microvascular complication of diabetes and there is no suitable treatment for it, so the development of new agents to relieve DN is urgently needed. Since oxidative stress and
inflammation play an essential role in the development of DN, clearance of these factors are good strategies for the treatment of this disease. According to key role of cyclic
adenosine monophosphate (cAMP) in the regulation of oxidative stress and inflammatory pathways, it seems that
phosphodiesterase inhibitors (PDEIs) can be as novel
drug targets for improving DN through enhancement of cAMP level. The aim of this study was to evaluate the effects of
rolipram, a selective
PDE4 inhibitor, and
pentoxifylline, a general PDE inhibitor on experimental model of DN and also to determine the possible mechanisms involved in the effectiveness of these agents. We investigated the effects of
rolipram (1 mg/kg) and
pentoxifylline (100 mg/kg) and also combination of
rolipram (0.5 mg/kg) and
pentoxifylline (50 mg/kg), orally for five weeks in rats that became diabetic by STZ (55 mg/kg, i.p.).
After treatments, motor function was evaluated by open-field test, then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Next, oxidative stress
biomarkers and inflammatory factors were assessed by biochemical and ELISA methods, and RT-PCR analysis in DRG neurons.
Rolipram and/or
pentoxifylline treatment significantly attenuated DN - induced motor function deficiency by modulating distance moved and velocity.
Rolipram and/or
pentoxifylline treatment dramatically increased the cAMP level, as well as suppressed DN - induced oxidative stress which was associated with decrease in LPO and ROS and increase in TAC, total
thiol, CAT and SOD in DRG neurons. On the other hand, the level of inflammatory factors (TNF-α,
NF-kB and COX2) significantly decreased following
rolipram and/or
pentoxifylline administration. The maximum effectiveness was with
rolipram and/or
pentoxifylline combination on mentioned factors. These findings provide novel experimental evidence for further clinical investigations on
rolipram and
pentoxifylline combination for the treatment of DN.