Effect of Phosphodiesterase-3 Inhibition on Experimental Autoimmune Neuritis

Background: The phosphodiesterase-3 inhibitor cilostazol (CLZ) is widely prescribed as an antiplatelet agent in treatment for peripheral arterial disease. The immune modulating effect of CLZ has been unveiled in experimental autoimmune encephalomyelitis, the animal model for human multiple sclerosis; however, the effect of CLZ on immune-mediated peripheral nerve disease is unclear. Methods: Female Lewis rats were immunized with synthetic peptide from bovine P2 protein to induce experimental autoimmune neuritis (EAN). Ten or 30 mg/kg/day of CLZ was administered daily from 1 day post immunization (dpi) or after onset of paralysis. Immunohistochemistry and real-time PCR were studied on sequentially removed cauda equina (CE). Results: Motor paralysis developed at 11 dpi in all rats; however, subsequent paralysis was suppressed by 30 mg/kg/day of CLZ. CLZ administered after onset of paralysis suppressed motor disturbance compared with sham-treated EAN rats. Improvement of motor function roughly correlated with shrinkage of demyelination foci and inflammatory cell accumulation. Real-time PCR analysis for proinflammatory cytokine interferon (IFN)-gamma, anti-inflammatory cytokine interleukin (IL)-10, or cell adhesion molecule E-selectin (E-sel) mRNA expression revealed an upregulation of IL-10 message before motor paralysis onset and suppression of IFN and E-sel messages at the paralysis onset phase. Conclusions: CLZ treatment ameliorates EAN via IL-10 upregulation with reciprocal suppression of IFN and E-sel expression in peripheral nervous system.