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Article: Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

TitleMemantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders
Authors
KeywordsAquaporin-4
Autoimmunity
Memantine
Neuroinflammation
Neuromyelitis optica
Issue Date2020
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/
Citation
Journal of Neuroinflammation, 2020, v. 17, p. article no. 236 How to Cite?
AbstractBackground: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation play important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.
Persistent Identifierhttp://hdl.handle.net/10722/285291
ISSN
2018 Impact Factor: 5.7
2015 SCImago Journal Rankings: 2.538
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorYick, LW-
dc.contributor.authorTang, CH-
dc.contributor.authorMA, OKF-
dc.contributor.authorKwan, SC-
dc.contributor.authorChan, KH-
dc.date.accessioned2020-08-18T03:52:05Z-
dc.date.available2020-08-18T03:52:05Z-
dc.date.issued2020-
dc.identifier.citationJournal of Neuroinflammation, 2020, v. 17, p. article no. 236-
dc.identifier.issn1742-2094-
dc.identifier.urihttp://hdl.handle.net/10722/285291-
dc.description.abstractBackground: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation play important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/-
dc.relation.ispartofJournal of Neuroinflammation-
dc.rightsJournal of Neuroinflammation. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAquaporin-4-
dc.subjectAutoimmunity-
dc.subjectMemantine-
dc.subjectNeuroinflammation-
dc.subjectNeuromyelitis optica-
dc.titleMemantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders-
dc.typeArticle-
dc.identifier.emailYick, LW: lwyick@hku.hk-
dc.identifier.emailTang, CH: dchtang@hku.hk-
dc.identifier.emailKwan, SC: jsckwan@hku.hk-
dc.identifier.emailChan, KH: koonho@hku.hk-
dc.identifier.authorityChan, KH=rp00537-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12974-020-01913-2-
dc.identifier.pmid32782018-
dc.identifier.pmcidPMC7418436-
dc.identifier.scopuseid_2-s2.0-85089359879-
dc.identifier.hkuros313026-
dc.identifier.volume17-
dc.identifier.spagearticle no. 236-
dc.identifier.epagearticle no. 236-
dc.publisher.placeUnited Kingdom-

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