Dibutyryl Cyclic AMP Inhibits the Progression of Experimental Autoimmune Encephalomyelitis and Potentiates Recruitment of Endogenous Neural Stem Cells

Abstract

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Cyclic AMP and its analogs enhance regeneration of adult mammalian central nervous system (CNS). Endogenous neural stem cells (NSCs) play a pivotal role in CNS regeneration, producing new neuron and glial cells. Here, we examined the effect of dibutyryl cyclic AMP (dbcAMP) on experimental autoimmune encephalomyelitis (EAE) symptoms, endogenous remyelination, and recruitment of NSCs. EAE was induced by immunizing mice using myelin oligodendrocyte glycoprotein peptide and pertussis toxin. Proliferative cells within CNS were labeled using repetitive systemic injections of 5-bromo-2-deoxyuridine (BrdU) before EAE induction. Myelin staining was performed using Luxol fast blue. The number of nestin(+) and BrdU(+) cells in subventricular zone (SVZ) and olfactory bulb (OB) was evaluated using immunohistochemistry. dbcAMP suppressed EAE progression and decreased the extent of demyelinated plaques in the lumbar spinal cord. EAE induction reduced the number of proliferative cells in SVZ and increased their population in OB. EAE also increased the number of nestin(+) cells in OB. We also found that dbcAMP increased the recruitment of NSCs into the OB and brain parenchyma of EAE mice. Our results suggest dbcAMP as a potential therapy for inducing myelin repair in the context of demyelinating diseases like multiple sclerosis. Its positive effect seems to be mediated, at least partially, by endogenous neural stem cells and their increased recruitment.