siponimod and Glaucoma

Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1/2 activation and attenuated the apoptotic signaling via suppression of c-Jun/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt/Erk1/2 activation, c-Jun/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c-Jun/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.

Topics: Animals; Apoptosis; Disease Models, Animal; Glaucoma; Mice; Neurodegenerative Diseases; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-akt; Retinal Ganglion Cells; Signal Transduction; Sphingosine 1 Phosphate Receptor Modulators

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.

Topics: Animals; Anti-Inflammatory Agents; Glaucoma; Mice; N-Methylaspartate; Neuroinflammatory Diseases; Receptors, N-Methyl-D-Aspartate; Retina