REMYELINATION IS ACCELERATED BY EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS: A NOVEL MODEL FOR THE ELUCIDATION OF IMMUNE-MEDIATED BRAIN REPAIR

Abstract

Introduction: Experimental autoimmune encephalomyelitis (EAE) and lysophosphatidylcholine (LPC)-induced demyelination are common rodent models of multiple sclerosis (MS). Clozapine and pioglitazone, two drugs used in the treatment of schizophrenia and type 2 diabetes, respectively, were tested in the LPC model to assess their potential to promote remyelination. The EAE and LPC models were then combined to study remyelination in a pro-inflammatory context. Methods: Female C57BL/6 mice received a bilateral injection of phosphate buffered saline (PBS) and LPC into the corpus callosum, followed by daily oral treatment with clozapine (10 mg/kg) or vehicle, or pioglitazone (15 mg/kg) or vehicle for 7 days. For the dual EAE and LPC model, mice were injected with myelin oligodendrocyte glycoprotein (MOG35-55) or complete Freund’s adjuvant (CFA; day 0) and pertussis toxin (PTX; days 0 and 2). LPC and PBS were then injected bilaterally into the corpus callosum on day 7. Results: Neither clozapine- nor pioglitazone-treated mice exhibited enhanced myelin repair after 7 days relative to vehicle-treated mice. In this dual model, EAE mice exhibited accelerated myelin repair following LPC injection relative to CFA/PTX mice. This was accompanied by increased innate immune cell activation, leukocyte infiltration and pro-inflammatory cytokine gene (IFN-gamma, IL-6 and TNF-alpha) expression in the brain parenchyma of EAE relative to CFA/PTX mice. Immune cell activation that increases the clearance of myelin debris and stimulates oligodendrocyte precursor cell differentiation and survival are proposed to mediate accelerated myelin repair in EAE mice following LPC injection. Conclusion: This dual model provides a method to identify immune-mediated processes that facilitate remyelination in MS.