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Siponimod exerts neuroprotective effects on the retina and higher visual pathway through neuronal S1PR1 in experimental glaucoma

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Neural Regeneration Research 2023年第4期18卷 840-848页

作者： Devaraj Basavarajappa Vivek Gupta Nitin Chitranshi Roshana Vander Wall rashi rajput Kanishka Pushpitha Samridhi Sharma Mehdi Mirzaei Alexander Klistorner Stuart L.Graham Department of Clinical Medicine Faculty of MedicineHealth and Human SciencesMacquarie UniversityNorth RydeSydneyNSWAustralia

Sphingosine-1-phosphate receptor(S1PR)signaling regulates diverse pathophysiological processes in the central nervous *** role of S1PR signaling in neurodegenerative conditions is still largely *** is a specific modulator of S1P1 and S1P5 receptors,an immunosuppressant drug for managing secondary progressive multiple *** investigated its neuroprotective properties in vivo on the retina and the brain in an optic nerve injury model induced by a chronic increase in intraocular pressure or acute N-methyl-D-aspartate ***-specific deletion of sphingosine-1-phosphate receptor(S1PR1)was carried out by expressing ***-Cre recombinase under Syn1 promoter in S1PR1mice to define the role of S1PR1 in *** retinal electrophysiological responses,along with histological and immunofluorescence analysis of the retina and optic nerve tissues,indicated significant neuroprotective effects of siponimod when administered orally via diet in chronic and acute optic nerve injury ***,siponimod treatment showed significant protection against trans-neuronal degenerative changes in the higher visual center of the brain induced by optic nerve *** treatment also reduced microglial activation and reactive gliosis along the visual *** results showed that siponimod markedly upregulated neuroprotective Akt and Erk1/2 activation in the retina and the ***-specific deletion of S1PR1 enhanced retinal and dorsolateral geniculate nucleus degenerative changes in a chronic optic nerve injury condition and attenuated protective effects of *** summary,our data demonstrated that S1PR1signaling plays a vital role in the retinal ganglion cell and dorsolateral geniculate nucleus neuronal survival in experimental glaucoma,and siponimod exerts direct neuroprotective effects through S1PR1 in neurons in the central nervous system independent of its peripheral immuno-modulatory *** findings s

关键词： glaucoma intraocular pressure neurodegeneration neuroprotection optic nerve injury retinal ganglion cells siponimod sphingosine-1-phosphate

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