Roflumilast and cognition enhancement: A translational perspective

Cognitive impairment affiliated with neurological disorders has a severe impact on daily life functioning and the quality of life of patients. This is associated with a significant and long-lasting health, social and financial burden, not only for the patients, but also for families and the wider society. However, treatment for cognitive impairment is only available for the indication Alzheimer's disease (AD) and its prodromal stage Mild Cognitive Impairment (MCI), although with major adverse effects, i.e. gastrointestinal effects (drugs) or hemorrhages (antibodies). Roflumilast (selective phosphodiesterase type 4 (PDE4) inhibitor) has been approved as an anti-inflammatory drug for the treatment of chronic obstructive pulmonary disease (COPD), although still 5 % of the patients experience nausea or even vomiting at the approved dose of 500 µg. Nonclinical studies demonstrated that roflumilast appears a promising drug the treat cognitive impairment in healthy rodents and a wide variety of animal models of CNS disorders. These effects are attributed to pro-neuroplasticity and anti-inflammatory effects, which appeared dose dependent. Roflumilast has also been tested in clinical studies and showed cognition enhancement at low dosing (100-250 µg) in healthy adults, healthy elderly, MCI and schizophrenia. Currently, clinical trials are underway for testing the pro-cognitive effects in early AD, post stroke cognitive impairment and Fragile X. Overall, the data showed that roflumilast has beneficial effects on cognitive performance. These cognition-enhancing effects are found at doses that were well-tolerated. Based on this favorable therapeutic window, the repurposing of roflumilast for treating cognitive impairments in CNS diseases may offer an affordable treatment option for patients.