A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations
Abstract Background Optic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a no...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02623-7 |
| _version_ | 1811197961579790336 |
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| author | Yuko Morita Takahide Itokazu Toru Nakanishi Shin-ichiro Hiraga Toshihide Yamashita |
| author_facet | Yuko Morita Takahide Itokazu Toru Nakanishi Shin-ichiro Hiraga Toshihide Yamashita |
| author_sort | Yuko Morita |
| collection | DOAJ |
| description | Abstract Background Optic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a novel therapeutic strategy, elucidating the underlying pathological mechanism using a clinically relevant experimental ON model is necessary. However, previous ON animal models have only resulted in mild lesions with limited functional impairment. In the present study, we attempted to establish a feasible ON model with severe pathological and functional manifestations using a high-affinity anti-AQP4 antibody. Subsequently, we aimed to address whether our model is suitable for potential drug evaluation by testing the effect of minocycline, a well-known microglia/macrophage inhibitor. Methods AQP4-immunoglobulin G (IgG)-related ON in rats was induced by direct injection of a high-affinity anti-AQP4 monoclonal antibody, E5415A. Thereafter, the pathological and functional characterizations were performed, and the therapeutic potential of minocycline was investigated. Results We established an experimental ON model that reproduces the histological characteristics of ON in seropositive NMO, such as loss of AQP4/glial fibrillary acidic protein immunoreactivity, immune cell infiltration, and extensive axonal damage. We also observed that our rat model exhibited severe visual dysfunction. The histological analysis showed prominent accumulation of macrophages/activated microglia in the lesion site in the acute phase. Thus, we investigated the possible effect of the pharmacological inhibition of macrophages/microglia activation by minocycline and revealed that it effectively ameliorated axonal damage and functional outcome. Conclusions We established an AQP4-IgG-induced ON rat model with severe functional impairments that reproduce the histological characteristics of patients with NMO. Using this model, we revealed that minocycline treatment ameliorates functional and pathological outcomes, highlighting the usefulness of our model for evaluating potential therapeutic drugs for ON in NMO. |
| first_indexed | 2024-04-12T01:23:17Z |
| format | Article |
| id | doaj.art-79d94aad56e045b99bf659e92f817a42 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-12T01:23:17Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-79d94aad56e045b99bf659e92f817a422022-12-22T03:53:44ZengBMCJournal of Neuroinflammation1742-20942022-10-0119111210.1186/s12974-022-02623-7A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestationsYuko Morita0Takahide Itokazu1Toru Nakanishi2Shin-ichiro Hiraga3Toshihide Yamashita4Department of Molecular Neuroscience, Graduate School of Medicine, Osaka UniversityDepartment of Molecular Neuroscience, Graduate School of Medicine, Osaka UniversityDepartment of Molecular Neuroscience, Graduate School of Medicine, Osaka UniversityDepartment of Molecular Neuroscience, Graduate School of Medicine, Osaka UniversityDepartment of Molecular Neuroscience, Graduate School of Medicine, Osaka UniversityAbstract Background Optic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a novel therapeutic strategy, elucidating the underlying pathological mechanism using a clinically relevant experimental ON model is necessary. However, previous ON animal models have only resulted in mild lesions with limited functional impairment. In the present study, we attempted to establish a feasible ON model with severe pathological and functional manifestations using a high-affinity anti-AQP4 antibody. Subsequently, we aimed to address whether our model is suitable for potential drug evaluation by testing the effect of minocycline, a well-known microglia/macrophage inhibitor. Methods AQP4-immunoglobulin G (IgG)-related ON in rats was induced by direct injection of a high-affinity anti-AQP4 monoclonal antibody, E5415A. Thereafter, the pathological and functional characterizations were performed, and the therapeutic potential of minocycline was investigated. Results We established an experimental ON model that reproduces the histological characteristics of ON in seropositive NMO, such as loss of AQP4/glial fibrillary acidic protein immunoreactivity, immune cell infiltration, and extensive axonal damage. We also observed that our rat model exhibited severe visual dysfunction. The histological analysis showed prominent accumulation of macrophages/activated microglia in the lesion site in the acute phase. Thus, we investigated the possible effect of the pharmacological inhibition of macrophages/microglia activation by minocycline and revealed that it effectively ameliorated axonal damage and functional outcome. Conclusions We established an AQP4-IgG-induced ON rat model with severe functional impairments that reproduce the histological characteristics of patients with NMO. Using this model, we revealed that minocycline treatment ameliorates functional and pathological outcomes, highlighting the usefulness of our model for evaluating potential therapeutic drugs for ON in NMO.https://doi.org/10.1186/s12974-022-02623-7Neuromyelitis opticaAxonal degenerationNeuroinflammationMacrophages/microglia activationMinocyclineOptic neuritis |
| spellingShingle | Yuko Morita Takahide Itokazu Toru Nakanishi Shin-ichiro Hiraga Toshihide Yamashita A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations Journal of Neuroinflammation Neuromyelitis optica Axonal degeneration Neuroinflammation Macrophages/microglia activation Minocycline Optic neuritis |
| title | A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations |
| title_full | A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations |
| title_fullStr | A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations |
| title_full_unstemmed | A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations |
| title_short | A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations |
| title_sort | novel aquaporin 4 associated optic neuritis rat model with severe pathological and functional manifestations |
| topic | Neuromyelitis optica Axonal degeneration Neuroinflammation Macrophages/microglia activation Minocycline Optic neuritis |
| url | https://doi.org/10.1186/s12974-022-02623-7 |
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