Methods

Cell cultures of CNS resident cells are generated from murine neonatal brains or human induced pluripotent stem (iPS) cells and the mode of action of potential treatment candidates is analysed in vitro. The analysis of treatment effects on CNS resident cells includes assays such as calcium flux, activation and differentiation, cytokine and chemokine profiles, phagocytosis, toxicity, neurite growth, neurofilament immunoassay and the capacity to act as antigen-presenting cells. Promising treatment candidates will be used for further analysis in murine in vivo models.

EAE is an animal model of MS in which immune cell-mediated demyelination of the CNS occurs. EAE can be induced by active immunisation with CNS antigens, passive immunisation after adoptive transfer of myelin-specific T cells or by the use of transgenic models in which spontaneous induction of EAE occurs. In the murine model of MS, the clinical course and histopathology depend on the antigen and mouse strain used. The inflammation with focal confluent lesions is mostly confined to the spinal cord and shows extensive microglial activation and axonal damage as well as axonal loss. The EAE model is well suited for the analysis of axonal/neuronal protective treatment strategies.

The cuprizone model is a toxic animal model and belongs to the group of chemical-induced demyelination. Cuprizone is a copper chelator that is added to the postural feed and leads to demyelination processes in the CNS without peripheral involvement and with the blood-brain barrier largely intact. The pathophysiology is characterised by oligodendrocyte apoptosis, microglial activation and astrogliosis. Near complete demyelination is achieved after 5-6 weeks of Cuprizone intoxication and discontinuation of Cuprizone leads to spontaneous endogenous remyelination. It is a very good model to study the mode of action of therapeutics during de- and remyelination.