Multiple sclerosis (MS) is a chronic autoimmune disease (CNS) that results in central nervous system demyelination and cognitive impairment. Pathway analysis shows that cyclic adenosine monophosphate (cAMP) directs oligodendrocyte precursor cell (OPC) differentiation into mature myelinating oligodendrocytes, a prerequisite for remyelination. Phosphodiesterase 4 (PDE4) inhibitors suppress the breakdown of cAMP, thereby augmenting cAMP levels and facilitating OPC differentiation. We hypothesize that the PDE4 inhibitor roflumilast promotes in vivo remyelination in an animal model for remyelination.
The impact of roflumilast (5µM) on ex vivo remyelination was studied in lysolecithin-demyelinated mouse brain slices. In vivo, cuprizone-induced demyelinated 10-week-old male C57bl6 mice (6 weeks, 0.3% cuprizone w/w) were treated for seven days with subcutaneous roflumilast (1mg/kg or 3mg/kg) or vehicle injections upon withdrawal of the cuprizone. Immunohistochemistry for myelin basic protein (MBP) and transmission electron microscopy (TEM) were applied to study (re)myelination. Cognitive performance (e.g. spatial memory in the object location task (OLT)) was monitored during de- and remyelination processes.
Demyelinated brain slices showed an increase in remyelination upon roflumilast (5µM) treatment. In vivo, roflumilast (3mg/kg) treatment induced a significant increase in corpus callosum and dendate gyrus remyelination and an restored spatial memory. TEM analyses confirmed an increase in myelin sheath thickness on ultrastructural level in the corpus callosum of roflumilast treated mice. The improved remyelination and spatial memory performance following roflumilast treatment at a dosage 100-fold the regular cognition enhancing dose, prompt us to conclude that roflumilast boosts the endogenous repair mechanisms in cuprizone fed mice and thereby improves cognitive performances.