Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models

• Published in: Neurobiology of disease 2024-08, Vol.198, p.106552-106552, Article 106552
• Main Authors: Birmpili, Dafni, Charmarké-Askar, Imane, Spenlé, Caroline, Riché, Stéphanie, Pham-Van, Lucas Dinh, Kuntzel, Thomas, Xhurxhi, Thanos, Riou, Aurélien, Bonnet, Dominique, Bagnard, Dominique
• Format: Article
• Language: English
• Subjects: Apelin-13; Experimental autoimmune encephalomyelitis; Fluoropeptide; Life Sciences; Multiple sclerosis; Neurobiology; Neurons and Cognition; Pharmaceutical sciences; Pharmacology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2024.106552

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function. •Apelin RNA and protein levels are decreased in the CNS of both EAE mice and MS patients.•Apelin 13 supplementation via a fluorinated apelin peptide is capable of crossing the BBB and ameliorates EAE score.•The fluorinated apelin peptide preserves neurons in vitro and mediates the function of microglia and macrophages.