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Exosomal TNF-α mediates voltage-gated Na+ channel 1.6 overexpression and contributes to brain tumor-induced neuronal hyperexcitability.
Sanchez Trivino, Cesar Adolfo; Spelat, Renza; Spada, Federica; D'Angelo, Camilla; Manini, Ivana; Rolle, Irene Giulia; Ius, Tamara; Parisse, Pietro; Menini, Anna; Cesselli, Daniela; Skrap, Miran; Cesca, Fabrizia; Torre, Vincent.
Afiliación
  • Sanchez Trivino CA; International School for Advanced Studies (SISSA), Trieste, Italy.
  • Spelat R; International School for Advanced Studies (SISSA), Trieste, Italy.
  • Spada F; Institute of Materials (IOM-CNR), Area Science Park, Basovizza, Trieste, Italy.
  • D'Angelo C; International School for Advanced Studies (SISSA), Trieste, Italy.
  • Manini I; Department of Life Sciences, University of Trieste, Trieste, Italy.
  • Rolle IG; International School for Advanced Studies (SISSA), Trieste, Italy.
  • Ius T; Department of Medicine, University of Udine, Udine, Italy.
  • Parisse P; Institute of Pathology and.
  • Menini A; Department of Medicine, University of Udine, Udine, Italy.
  • Cesselli D; Neurosurgery Unit, Department of Neurosciences, Santa Maria della Misericordia University Hospital, Udine, Italy.
  • Skrap M; Institute of Materials (IOM-CNR), Area Science Park, Basovizza, Trieste, Italy.
  • Cesca F; International School for Advanced Studies (SISSA), Trieste, Italy.
  • Torre V; Department of Medicine, University of Udine, Udine, Italy.
J Clin Invest ; 134(18)2024 Aug 01.
Article en En | MEDLINE | ID: mdl-39088270
ABSTRACT
Patients affected by glioma frequently experience epileptic discharges; however, the causes of brain tumor-related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 hours with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10-15 mV. Voltage clamp recordings demonstrated that the activation of the Na+ current shifted toward more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability, we focused on exosomal cytokines. Western blot and ELISAs showed that TNF-α was present inside glioma-derived exosomes. Remarkably, incubation with TNF-α fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. Real-time PCR revealed that both exosomes and TNF-α induced overexpression of the voltage-gated Na+ channel Nav1.6, a low-threshold Na+ channel responsible for hyperexcitability. When neurons were preincubated with infliximab, a specific TNF-α inhibitor, the hyperexcitability induced by exosomes and TNF-α was drastically reduced. We propose that infliximab, an FDA-approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients with BTRE.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Factor de Necrosis Tumoral alfa / Exosomas / Canal de Sodio Activado por Voltaje NAV1.6 / Glioma / Neuronas Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Factor de Necrosis Tumoral alfa / Exosomas / Canal de Sodio Activado por Voltaje NAV1.6 / Glioma / Neuronas Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos