Ana Carolina de Pádua Alpino Pereira, Saulo Augusto Alves da Cruz, Luiza Dos Santos Heringer, Greice Nascimento Pires, Daniel Areias da Silva Raquita, Jéssica Dos Santos Tavares, Pedro Souto Rodrigues, Ana Beatriz Miranda de Sá, Cintia Monteiro de Barros, Sérgio Henrique Seabra, Henrique Rocha Mendonça, Renato Augusto DaMatta, Sheila Espírito-Santo
{"title":"The protective effect of Fingolimod upon visual behavior in a demyelination animal model is associated with synaptopathy prevention.","authors":"Ana Carolina de Pádua Alpino Pereira, Saulo Augusto Alves da Cruz, Luiza Dos Santos Heringer, Greice Nascimento Pires, Daniel Areias da Silva Raquita, Jéssica Dos Santos Tavares, Pedro Souto Rodrigues, Ana Beatriz Miranda de Sá, Cintia Monteiro de Barros, Sérgio Henrique Seabra, Henrique Rocha Mendonça, Renato Augusto DaMatta, Sheila Espírito-Santo","doi":"10.1016/j.neuro.2025.03.004","DOIUrl":null,"url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that causes motor, cognitive, and sensory dysfunctions, with visual disorder being one of the most prevalent. Synaptopathy has been recognized as one of the predominant pathogenic components of MS. We previous characterized inhibition of synaptopathy in the visual thalamus using the cuprizone-induced demyelination MS animal model. However, investigations about potential treatments to prevent synaptopathy have received little attention. Fingolimod is one of the most widely used and effective immunomodulators for controlling inflammatory relapses in MS, but few studies in MS animal models have tested its effect on synaptopathy. Given that none of these investigations used the cuprizone-induced demyelination model, our study investigated the preventive effect of Fingolimod on cuprizone-induced synaptopathy. Using Western blotting for synaptophysin, PSD-95, and gephyrin, as well as ultrastructural analysis, we demonstrated that daily intraperitoneal injections of Fingolimod (1mg/Kg) protect against the increase of inhibitory synapses in cuprizone-treated mice. Fingolimod also prevented reduction of ARC immunolabeling, a sensor of neuronal activity, in cuprizone animals. Finally, through the visual Cliff test, Fingolimod was able to protect cuprizone animals against visual dysfunction. On the other hand, through immunostaining for CNPase, GFAP and IBA-1 we observed that Fingolimod failed to prevent demyelination and glial reactivity in the cuprizone animals. Taken together, the data indicate the potential of preventive treatment with Fingolimod against synaptopathy and visual dysfunction associated with inflammatory demyelination.</p>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":" ","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurotoxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuro.2025.03.004","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that causes motor, cognitive, and sensory dysfunctions, with visual disorder being one of the most prevalent. Synaptopathy has been recognized as one of the predominant pathogenic components of MS. We previous characterized inhibition of synaptopathy in the visual thalamus using the cuprizone-induced demyelination MS animal model. However, investigations about potential treatments to prevent synaptopathy have received little attention. Fingolimod is one of the most widely used and effective immunomodulators for controlling inflammatory relapses in MS, but few studies in MS animal models have tested its effect on synaptopathy. Given that none of these investigations used the cuprizone-induced demyelination model, our study investigated the preventive effect of Fingolimod on cuprizone-induced synaptopathy. Using Western blotting for synaptophysin, PSD-95, and gephyrin, as well as ultrastructural analysis, we demonstrated that daily intraperitoneal injections of Fingolimod (1mg/Kg) protect against the increase of inhibitory synapses in cuprizone-treated mice. Fingolimod also prevented reduction of ARC immunolabeling, a sensor of neuronal activity, in cuprizone animals. Finally, through the visual Cliff test, Fingolimod was able to protect cuprizone animals against visual dysfunction. On the other hand, through immunostaining for CNPase, GFAP and IBA-1 we observed that Fingolimod failed to prevent demyelination and glial reactivity in the cuprizone animals. Taken together, the data indicate the potential of preventive treatment with Fingolimod against synaptopathy and visual dysfunction associated with inflammatory demyelination.
期刊介绍:
NeuroToxicology specializes in publishing the best peer-reviewed original research papers dealing with the effects of toxic substances on the nervous system of humans and experimental animals of all ages. The Journal emphasizes papers dealing with the neurotoxic effects of environmentally significant chemical hazards, manufactured drugs and naturally occurring compounds.