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Evaluation of glial fibrillary acidic protein and aquaporin-4 in an opticospinal animal model of demyelination

Background: Neuromyelitis optica (NMO) is a human inflammatory/demyelinating disease of the central nervous system characterized by optic neuritis and longitudinally extensive transverse myelitis. The astrocyte water channel aquaporin-4 (AQP4) plays a major role in the physiopathology of NMO, and, in particular, circulating autoantibodies against AQP4 are present in 50 to 70% of NMO patients. While animal models of experimental autoimmune encephalomyelitis (EAE) showing opticospinal demyelination have been developed, the involvement of astrocytes and AQP4 in these models is poorly documented. Objective: Because of the reported lesion topography and the immune reaction, we chose the Brown Norway (BN) MOG-induced rat model to report clinical, MRI, neuropathological and immunological evaluations with a special focus on astrocyte AQP4 expression. Methods: Soluble recombinant mouse MOG (1-118) was used in association with incomplete Freund’s adjuvant to induce a model of opticospinal demyelination in BN rats. Clinical, MRI and immunological assessments were performed during the disease process with a special focus on glial fibrillary acidic protein (GFAP), a specific marker of astrocytes, and AQP4 expression. Results: During the disease stage, we observed that GFAP and AQP4 expression was significantly decreased in the demyelinated optic nerves whereas it was increased in the spinal cord and the periventricular area. These changes occurred in locations corresponding to T2-hypersignal abnormalities on MRI scan. No significant immunoreactivity was detected in the sera of the affected animals against linear and conformational epitopes of AQP4. The disability score in rats was correlated with the demyelination and inflammation in optic nerves and spinal cords but also with the glial scar in spinal cord characterized by astrogliosis and overexpression of AQP4. Conclusions: In this opticospinal model of demyelination, reactivity against GFAP and AQP4 was significantly but differently modified in each of the following: spinal cord, periventricular area and optic nerve. This model could provide a better understanding of the role of astrocytes and AQP4 in demyelination and may help to differentiate the mechanisms involved in the opticospinal demyelinating diseases in humans.

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