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Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) and progressively leads to physical disability and ...

Medical University Graz

Cortical demyelination is a common finding in patients with chronic multiple sclerosis (MS) and contributes to disease progression and overall disability. The exact pathomechanism that leads to cortical lesions is not clear. Research is limited by the fact that standard animal models of multiple sclerosis do not commonly affect the cortex, or if they do in some variants, the cortical demyelination is rather sparse and already remyelinated within a few days. In an attempt to overcome these limitations we implanted a tissue-compatible catheter into the cortex of Dark Agouti rats. After 14days the rats were immunized with 5μg myelin oligodendrocyte glycoprotein (MOG) in incomplete Freund's Adjuvant, which did not cause any clinical signs but animals developed a stable anti-MOG antibody titer. Then the animals received an injection of proinflammatory cytokines through the catheter. This led to a demyelination of cortical and subcortical areas starting from day 1 in a cone-like pattern spreading from the catheter area towards the subarachnoid space. On day 3 cortical demyelination already expanded to the contralateral hemisphere and reached its peak between days 9-15 after cytokine injection with a widespread demyelination of cortical and subcortical areas of both hemispheres. Clinically the animals showed only discrete signs of fatigue and recovered completely after day 15. Even on day 30 we still were able to detect demyelination in subpial and intracortical areas along with areas of partial and complete remyelination. Loss of cortical myelin was accompanied with marked microglia activation. A second injection of cytokines through the catheter on day 30 led to a second demyelination phase with the same symptoms, but again no detectable motor dysfunction. Suffering of the animals appeared minor compared to standard Experimental Autoimmune Encephalomyelitis and therefore, even long-term observation and repeated demyelination phases seem ethically acceptable.

Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats.

Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG-Abs) are commonly associated with clinical presentations as acute disseminated encephalomyelitis (ADEM) in both adults and children and anti-aquaporin 4 antibody-seronegative neuromyelitis optica spectrum disorder (NMOSD) and related syndromes such as optic neuritis, myelitis, and brainstem encephalitis. Most often, the presence of MOG-Abs is associated with a more benign clinical course and a good response to steroids. Here, we present a case report of a previously healthy 52-year-old female patient with fulminant demyelinating encephalitis, leading to death within a week after the first presenting symptoms from a massive brain edema irresponsive to high-dose intravenous steroids as well as osmotic therapy. The final diagnosis was only made postmortem after serum anti-MOG-Abs results were available. Histopathological analysis of the brain revealed extensive, predominantly cortical demyelinating lesions in the frontal, temporal, and parietal lobes with intracortical, leukocortical, and subpial plaques, associated with pronounced perivenous deposition of activated complement complex as well as features of acute MS characterized by destructive lesions.

Article	Year
Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats. Experimental neurology\| PubMed ID: 28457906	2017
A Fulminant Case of Demyelinating Encephalitis With Extensive Cortical Involvement Associated With Anti-MOG Antibodies. Frontiers in neurology\| PubMed ID: 32117004	2020

Michaela Tanja Haindl

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