Previous experimental NMO models have been useful to clarify the pathomechanisms of NMO, such as the pathogenicity of NMO-IgG in vitro [5] and that the NMO-IgG epitope is localized at the extracellular domains of membrane AQP4 [2, 5]. but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed Fargesin both in EAE rats receiving hIgGNMO and E5415A in a dose Fargesin dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50?% than those receiving low-dose E5415A Fargesin or hIgGNMO less than 3?%. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the Rabbit Polyclonal to SLC39A7 lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO. Conclusions In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive Fargesin tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages. (350/350) Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0259-2) contains supplementary material, which is available to authorized users. Keywords: Animal model, Aquaporin 4, Astrocyte, Baculovirus display method, Neuromyelitis optica, Neutrophil Introduction Neuromyelitis optica (NMO), an autoimmune disease of the central nervous system (CNS), is clinically characterized by severe optic neuritis and longitudinally extensive transverse myelitis (LETM) [1]. About 70C90?% of the patients are seropositive for disease-specific autoantibodies [2, 3], such as NMO-IgG, which targets aquaporin-4 (AQP4) [4, 5], the water channel mainly localized to astrocytic foot processes [6]. NMO is characterized by a higher age of onset, female predominance [7], and greater autoimmune background than multiple sclerosis (MS) [8]. Clinical, MRI, and laboratory findings specific to NMO have been reported [7, 9C13]. The characteristic childhood-onset symptom of NMO is mainly optic neuritis, while that in elderly patients is myelitis [14], suggesting that the age of onset is associated with the localization of the lesion in NMO. The reason for the preferential involvement of optic neuritis and myelitis in NMO remains unclear. In addition to the optic nerve and spinal cord, there have been several reports on NMO lesions localized at circumventricular or periaqueductal areas, such as the area postrema [15] and hypothalamus [16], where AQP4 expression is enriched in the central nervous system [16]. However, the reason for the absence of NMO lesions in cerebral or cerebellar gray matter is still unknown. In a study of the cerebrospinal fluid (CSF), marked elevation of glial fibrillary acidic protein (GFAP) was evident in NMO, but not in MS, indicating that massive astrocyte lysis is a key to NMO pathology [9]. Moreover, pathological studies in autopsied NMO cases demonstrated extensive loss of astrocytic proteins, AQP4 and GFAP, especially in peri-vascular lesions with deposition of immunoglobulins and activated complement [17] and abundant infiltration of granulocytes and microglia [18]. In contrast, in these perivascular active lesions, myelin sheaths and axons are relatively preserved, suggesting a primary astrocytopathy [17]. We have reported that this vasculocentric AQP4 loss in the absence of myelin loss is a specific pathological feature in NMO, which has been reported both in early active lesions of autopsied NMO cases and a rodent model of NMO [17, 19]. Furthermore, in autopsied NMO cases, most of NMO cases tend to have extensive necrotic changes, and in the chronic phase in particular, the lesions show tissue softening and cavity formation [17, 18]. Experimental NMO models are needed for elucidating the underlying pathomechanisms and for testing candidate therapeutic drugs. Previous experimental NMO models have been useful to clarify the pathomechanisms of NMO, such as the pathogenicity of NMO-IgG in vitro [5] and that the NMO-IgG epitope is localized at the extracellular domains of membrane AQP4 [2, 5]. NMO-like lesion could not be.