A chronic cuprizone-induced demyelination model for the development of therapies in the progressive stage of Multiple Sclerosis

WIES MANCINI V.B.1, PASQUINI J.M.1, CORREALE J.D.2, PASQUINI L.A.1

Congreso; SAIC; 2016

Multiple Sclerosis (MS) is one of the most common causes of progressive disability affecting young people. Most patients initially present a relapsing-remitting course which, after 10 to 15-year evolution, becomes progressive in up to 50% of untreated patients, with clinical symptoms slowly but steadily deteriorating. In about 15% MS patients, disease progression is relentless from disease onset. A better understanding of relapsing-remitting MS disease mechanisms has led to the development of different disease-modifying therapies, reducing both severity and frequency of new relapses by modulating or suppressing the immune system. In contrast, therapeutic options available for progressive disease are comparatively disappointing and remain a challenge. A 0.2% cuprizone (CPZ) diet administered to 5 to 6-week mice is known to induce demyelination in the corpus callosum (acute model), while CPZ withdrawal triggers a spontaneous remyelination process. When this diet is maintained for 12 weeks (chronic model), remyelination fails, leading to progressive disability. The present work evaluates the use of the chronic model in the development of therapies targeting the progressive stages of MS. Our results show severe myelin damage in the corpus callosum (MBP, Olig 2 and Red oil staining), accompanied by the activation of astrocytes (GFAP), neural precursors (Nestin), and microglial cells (Iba1). Axons from chronic CPZ mice were more sparsely distributed, indicating neuronal loss. Unlike features observed in the acute model, our results in the chronic model show demyelination to reach the spinal cord, as evidenced by immunohistochemical (MBP and RIP) and electron microscopy analyses of myelin. These findings were concomitant with astroglial (GFAP) and microglial (Griffonia and ED1) activation. These findings hint at the possible use of the chronic CPZ model to develop therapeutic agents enabling remyelination and preventing neurodegeneration.