title: Adapted focal experimental autoimmune encephalomyelitis to allow MRI exploration of multiple sclerosis features.
abstract: We aimed to determine an optimal protocol for inducing a focal inflammatory lesion within the rat brain that could be large enough for an easier MRI monitoring while still relevant as a multiple sclerosis (MS) like lesion. We adapted a two-hit model based on pre-sensitization of the Lewis rat with myelin oligodendrocyte protein (MOG) followed by stereotaxic injection of pro-inflammatory cytokines (TNFα+IFNγ) within the internal capsule. We compared the following two strategies to increase focal lesion development for an easier MR translation: (1) a higher sensitization step (MOG50) or (2) a higher cytokine step with lower sensitization (MOG25). Control animals were administered only cytokines without MOG pre-sensitization. Animals were followed with T2, diffusion and T1 post gadolinium weighted images at 1, 3 and 7days following cytokine injection. Immunostaining was performed at the same time points for macrophages (ED1), myelin (MBP and Luxol Fast Blue) and blood brain barrier integrity (IgG). At day 1, the focal lesions depicted with T2-weighted images were very similar among groups and related to vasogenic edema (high apparent diffusion coefficient (ADC), gadolinium enhancement and IgG extravasation) induced by cytokines irrespective of the pre-sensitization step. Then, at day 3, MOG50 rats developed statistically larger T2 lesions than MOG25 and control rats that were correlated with inflammatory cell accumulation. At day 7, MOG50 rats also showed larger T2 lesions than MOG25 and control rats, together with loss of anisotropy that were correlated with demyelination. In contrast, MOG25 and control rats developed similar MR lesions decreasing over time and almost undetectable at day 7. We conclude that with a high pre-sensitization step, the focal lesion can be monitored by MRI whose signal reflects some features of a MS-like lesion, i.e. edema, inflammatory cell accumulation and later demyelination.
authors.affiliation: INSERM U.1049 Neuroinflammation, imagerie et thérapie de sclérose en plaques, F-33076 Bordeaux, France. thomas.tourdias@chu-bordeaux.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Tourdias
authors.forename: Bassem
authors.initials: B
authors.lastname: Hiba
authors.forename: Gerard
authors.initials: G
authors.lastname: Raffard
authors.forename: Marc
authors.initials: M
authors.lastname: Biran
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nishiguchi
authors.forename: Justine
authors.initials: J
authors.lastname: Aussudre
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Franconi
authors.forename: Bruno
authors.initials: B
authors.lastname: Brochet
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Petry
authors.forename: Vincent
authors.initials: V
authors.lastname: Dousset
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology*; D001921:Brain / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D016207:Cytokines