Basavarajappa Devaraj, Gupta Vivek, Chitranshi Nitin, Wall Roshana Vander, Rajput Rashi, Pushpitha Kanishka, Sharma Samridhi, Mirzaei Mehdi, Klistorner Alexander, Graham Stuart L
Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Sydney, NSW, Australia.
Neural Regen Res. 2023 Apr;18(4):840-848. doi: 10.4103/1673-5374.344952.
Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR signaling in neurodegenerative conditions is still largely unidentified. Siponimod is a specific modulator of S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis. We 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 excitotoxicity. Neuronal-specific deletion of sphingosine-1-phosphate receptor (S1PR1) was carried out by expressing AAV-PHP.eB-Cre recombinase under Syn1 promoter in S1PR1 mice to define the role of S1PR1 in neurons. Inner 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 models. Further, siponimod treatment showed significant protection against trans-neuronal degenerative changes in the higher visual center of the brain induced by optic nerve injury. Siponimod treatment also reduced microglial activation and reactive gliosis along the visual pathway. Our results showed that siponimod markedly upregulated neuroprotective Akt and Erk1/2 activation in the retina and the brain. Neuronal-specific deletion of S1PR1 enhanced retinal and dorsolateral geniculate nucleus degenerative changes in a chronic optic nerve injury condition and attenuated protective effects of siponimod. In summary, our data demonstrated that S1PR1 signaling 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 effects. Our findings suggest that neuronal S1PR1 is a neuroprotective therapeutic target and its modulation by siponimod has positive implications in glaucoma conditions.
鞘氨醇-1-磷酸受体（S1PR）信号传导调节中枢神经系统中的多种病理生理过程。S1PR信号传导在神经退行性疾病中的作用仍 largely 未明。西尼莫德是S1P1和S1P5受体的特异性调节剂，是一种用于治疗继发进展型多发性硬化症的免疫抑制药物。我们在由眼内压慢性升高或急性N-甲基-D-天冬氨酸兴奋性毒性诱导的视神经损伤模型中，研究了其在体内对视网膜和大脑的神经保护特性。通过在S1PR1小鼠的Syn1启动子下表达AAV-PHP.eB-Cre重组酶来进行鞘氨醇-1-磷酸受体（S1PR1）的神经元特异性缺失，以确定S1PR1在神经元中的作用。视网膜内层电生理反应，以及视网膜和视神经组织的组织学和免疫荧光分析表明，在慢性和急性视神经损伤模型中通过饮食口服西尼莫德时具有显著的神经保护作用。此外，西尼莫德治疗对由视神经损伤引起的大脑高级视觉中枢的跨神经元退行性变化显示出显著的保护作用。西尼莫德治疗还减少了视觉通路中的小胶质细胞激活和反应性胶质增生。我们的结果表明，西尼莫德显著上调了视网膜和大脑中神经保护性Akt和Erk1/2的激活。在慢性视神经损伤条件下，S1PR1的神经元特异性缺失增强了视网膜和背外侧膝状核的退行性变化，并减弱了西尼莫德的保护作用。总之，我们的数据表明，S1PR1信号传导在实验性青光眼中的视网膜神经节细胞和背外侧膝状核神经元存活中起着至关重要的作用，并且西尼莫德通过中枢神经系统神经元中的S1PR1发挥直接神经保护作用，而与其外周免疫调节作用无关。我们的研究结果表明，神经元S1PR1是一个神经保护治疗靶点，其通过西尼莫德调节在青光眼病症中具有积极意义。
