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

Neural Regeneration Research, Journal Year: 2022, Volume and Issue: 18(4), P. 840 - 840

Published: May 9, 2022

Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR neurodegenerative conditions is still largely unidentified. Siponimod a specific modulator S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis. We investigated its neuroprotective properties vivo on retina brain optic nerve injury model induced by chronic increase intraocular pressure or acute N-methyl-D-aspartate excitotoxicity. Neuronal-specific deletion sphingosine-1-phosphate (S1PR1) was carried out expressing AAV-PHP.eB-Cre recombinase under Syn1 promoter S1PR1flox/flox mice to define S1PR1 neurons. Inner retinal electrophysiological responses, along with histological immunofluorescence analysis tissues, indicated significant effects siponimod when administered orally via diet models. Further, treatment showed protection against trans-neuronal degenerative changes higher visual center injury. also reduced microglial activation reactive gliosis pathway. Our results that markedly upregulated Akt Erk1/2 brain. enhanced dorsolateral geniculate nucleus condition attenuated protective siponimod. In summary, our data demonstrated plays vital ganglion cell neuronal survival experimental glaucoma, exerts direct through neurons system independent peripheral immuno-modulatory effects. findings suggest therapeutic target modulation has positive implications glaucoma conditions.

Language: Английский

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A Novel Mouse Model of TGFβ2-Induced Ocular Hypertension Using Lentiviral Gene Delivery

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 6883 - 6883

Published: June 21, 2022

Glaucoma is a multifactorial disease leading to irreversible blindness. Primary open-angle glaucoma (POAG) the most common form and associated with elevation of intraocular pressure (IOP). Reduced aqueous humor (AH) outflow due trabecular meshwork (TM) dysfunction responsible for IOP in POAG. Extracellular matrix (ECM) accumulation, actin cytoskeletal reorganization, stiffening TM are increased resistance. Transforming growth factor (TGF) β2, profibrotic cytokine, known play an important role development ocular hypertension (OHT) An appropriate mouse model critical understanding underlying molecular mechanism TGFβ2-induced OHT. To achieve this, can be targeted recombinant viral vectors express gene interest. Lentiviruses (LV) their tropism towards stable transgene expression low immunogenicity. We, therefore, developed novel using LV transfer active human TGFβ2 TM. We vector-encoding hTGFβ2C226,228S under control cytomegalovirus (CMV) promoter. Adult C57BL/6J mice were injected intravitreally expressing null or hTGFβ2C226,228S. observed significant increase 3 weeks post-injection compared eyes average delta change 3.3 mmHg. stayed elevated up 7 post-injection, which correlated drop AH facility (40.36%). Increased was both anterior segment samples mice. The morphological assessment region via hematoxylin eosin (H&E) staining direct ophthalmoscopy examination revealed no visible signs inflammation other abnormalities eyes. Furthermore, transduction primary cells LV_hTGFβ2C226,228S exhibited alterations cytoskeleton structures, including formation F-actin stress fibers crossed-linked networks (CLANs), signature arrangements stiffer fibrotic-like Our study demonstrated sustained lentiviral delivery that induces

Language: Английский

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Autophagy in the eye: from physiology to pathophysiology

Autophagy Reports, Journal Year: 2023, Volume and Issue: 2(1)

Published: March 1, 2023

Autophagy is a catabolic self-degradative pathway that promotes the degradation and recycling of intracellular material through lysosomal compartment. Although first believed to function in conditions nutritional stress, autophagy emerging as critical cellular pathway, involved variety physiological pathophysiological processes. dysregulation associated with an increasing number diseases, including ocular diseases. On one hand, mutations autophagy-related genes have been linked cataracts, glaucoma, corneal dystrophy; on other alterations pathways are common finding essentially all diseases eye. Moreover, LC3-associated phagocytosis, form non-canonical autophagy, promoting visual cycle function. This review collects latest understanding context We will discuss respective roles physiology and/or pathophysiology each tissues, its diurnal/circadian variation, well involvement

Language: Английский

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N,N-Dimethyl-3β-hydroxycholenamide attenuates neuronal death and retinal inflammation in retinal ischemia/reperfusion injury by inhibiting Ninjurin 1

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: April 7, 2023

Retinal ischemia-reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although molecular mechanism underlying ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part mortality of ganglion cells.Single-cell RNA sequencing (scRNA-seq), docking, and transfection assay were used explore effectiveness pathogenesis N,N-dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR DMHCA-treated microglia after oxygen glucose deprivation/reoxygenation (OGD/R).DMHCA could suppress inflammatory gene expression attenuate neuronal lesions, restoring structure vivo. Using scRNA-seq on retina mice, we provided novel insights into immunity demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as promising treatment target for RIR. Moreover, Ninj1, which was increased OGD/R-treated microglia, downregulated group. DMHCA suppressed activation nuclear factor kappa B (NF-κB) pathways induced OGD/R, undermined NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed anti-inflammatory anti-apoptotic function DMHCA. Molecular docking indicated that had low binding energy - 6.6 kcal/mol, suggesting highly stable binding.Ninj1 may play pivotal role microglia-mediated inflammation, while be potential strategy against injury.

Language: Английский

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Rapamycin suppresses neuroinflammation and protects retinal ganglion cell loss after optic nerve crush

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 119, P. 110171 - 110171

Published: April 14, 2023

Language: Английский

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