Application of a phosphodiesterase-4 (PDE4) inhibitor to abort chronic toxoplasmosis and to mitigate consequential pathological changes

BackgroundProgression to a chronic state after an initial, mostly asymptomatic, acute phase is the normal fate of Toxoplasma infection in immunocompetent hosts. The inter-conversion between tachyzoite and bradyzoite life stages is a key to Toxoplasma survival and pathogenesis. Chronic toxoplasmosis is resistant to all commercially available medications. Reactivation of chronic stage has serious complications on immunocompromised hosts including encephalitis and death. Cyclic AMP, TNF-α and Th1 immune response have pivotal roles in establishing chronic disease. Rolipram, a PDE4 inhibitor, has regulatory roles on these factors. This is the first study to investigate a possible modulatory effect of rolipram on Toxoplasma infection in an experimental murine model. The ability, of this novel regimen to prevent or reverse Toxoplasma-induced pathology was evaluated.Materials and methodsToxoplasma-infected mice received rolipram (10 mg/kg) daily for three weeks. Life expectancy, serum ALT and histopathology of liver and brain were the parameters used to evaluate therapeutic and/or toxic impact of rolipram in comparison with infection and healthy control groups of mice.ResultsToxoplasma-induced pathology was never completely cleared by rolipram. However, a significant impact in aborting chronic state and in mitigating pathology was detected. The drug almost normalized Toxoplasma-induced high ALT levels reversing the hepatotoxic effect of the parasite.ConclusionThis study is the first to demonstrate relative merits of rolipram therapy to toxoplasmosis with illustration of its efficacy and toxicity. It reports a novel approach with potential future benefits using PDE inhibitors to abort resistant latent phases of biologically related infectious agents.