Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury

Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role i...

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Bibliographic Details
Published in:Molecular neurobiology Vol. 60; no. 12; pp. 7222 - 7237
Main Authors: Basavarajappa, Devaraj, Gupta, Vivek, Chitranshi, Nitin, Viswanathan, Deepa, Gupta, Veer, Vander Wall, Roshana, Palanivel, Viswanthram, Mirzaei, Mehdi, You, Yuyi, Klistorner, Alexander, Graham, Stuart L.
Format: Journal Article
Language:English
Published: New York Springer US 01.12.2023
Springer Nature B.V
Subjects:
Animals
Anti-Inflammatory Agents - metabolism
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Biomedical and Life Sciences
Biomedicine
Cell activation
Cell Biology
Cell death
Central nervous system
Excitotoxicity
Glaucoma
Glaucoma - metabolism
Glial cells
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Immunomodulation
Inflammasomes
Inflammation
Mice
Molecular modelling
Multiple sclerosis
N-Methyl-D-aspartic acid receptors
N-Methylaspartate - metabolism
Neurobiology
Neurodegeneration
Neuroinflammatory Diseases
Neurology
Neurosciences
Neurotoxicity
NF-κB protein
Nitric-oxide synthase
Oral administration
Receptors, N-Methyl-D-Aspartate - metabolism
Retina
Retina - metabolism
Retinal ganglion cells
Sphingosine 1-phosphate
Sphingosine 1-phosphate receptors
Structure-function relationships
Up-regulation
Glaucoma
Excitotoxicity
Sphingosine-1-phosphate
NMDA
Neuroinflammation
Inflammasome
Glia
Siponimod
ISSN:0893-7648, 1559-1182, 1559-1182
Online Access:Get full text
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Summary:Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina. Siponimod is an immunomodulatory drug for multiple sclerosis and is a selective modulator of S1PR subtypes 1 and 5 and has been shown to have beneficial effects on the central nervous system (CNS) in degenerative conditions. Our previous study showed that mice administered orally with siponimod protected inner retinal structure and function against acute NMDA excitotoxicity. To elucidate the molecular mechanisms behind these protective effects, we investigated the inflammatory pathways affected by siponimod treatment in NMDA excitotoxicity model. NMDA excitotoxicity resulted in the activation of glial cells coupled with upregulation of the inflammatory NF-kB pathway and increased expression of TNFα, IL1-β, and IL-6. Siponimod treatment significantly reduced glial activation and suppressed the pro-inflammatory pathways. Furthermore, NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) were significantly diminished with siponimod treatment. Our data demonstrated that siponimod induces anti-inflammatory effects via suppression of glial activation and inflammatory singling pathways that could protect the retina against acute excitotoxicity conditions. These findings provide insights into the anti-inflammatory effects of siponimod in the CNS and suggest a potential therapeutic strategy for neuroinflammatory conditions.
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ISSN:0893-7648
1559-1182
1559-1182
DOI:10.1007/s12035-023-03535-0