%0 Journal Article
%T Exosomal TNF-α mediates voltage-gated Na+ channels 1.6 overexpression and contributes to brain-tumor induced neuronal hyperexcitability.
%A Sanchez Trivino CA
%A Spelat R
%A Spada F
%A D'Angelo C
%A Manini I
%A Rolle IG
%A Ius T
%A Parisse P
%A Menini A
%A Cesselli D
%A Skrap M
%A Cesca F
%A Torre V
%J J Clin Invest
%V 0
%N 0
%D 2024 Aug 1
%M 39088270
%F 19.456
%R 10.1172/JCI166271
%X Patients affected by glioma frequently suffer of 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 h 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 towards more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability we focused on exosomal cytokines. Western Blot and ELISA assays show that TNF-α is 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. RT-PCR revealed that both exosomes and TNF-α induced over-expression 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 were drastically reduced. We propose that Infliximab, an FDA approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients suffering of BTRE.