Neurobiological Correlates of Alpha-Tocopherol Antiepileptogenic Effects and MicroRNA Expression Modulation in a Rat Model of Kainate-Induced Seizures.
Patrizia Ambrogini, Maria Cristina Albertini, Michele Betti, Claudia Galati, Davide Lattanzi, David Savelli, Michael Di Palma, Stefania Saccomanno, Desirée Bartolini, Pierangelo Torquato, Gabriele Ruffolo, Fabiola Olivieri, Francesco Galli, Eleonora Palma, Andrea Minelli, Riccardo Cuppini
Author Information
Patrizia Ambrogini: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy. patrizia.ambrogini@uniurb.it. ORCID
Maria Cristina Albertini: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Michele Betti: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Claudia Galati: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Davide Lattanzi: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
David Savelli: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Michael Di Palma: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Stefania Saccomanno: Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy.
Desirée Bartolini: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Pierangelo Torquato: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Gabriele Ruffolo: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
Fabiola Olivieri: Department of Molecular and Clinical Sciences, Marche Polytechnic University, Ancona, Italy.
Francesco Galli: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Eleonora Palma: Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
Andrea Minelli: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Riccardo Cuppini: Department of Biomolecular Sciences, Section of Physiology, University of Urbino Carlo Bo, I-61029, Urbino, Italy.
Seizure-triggered maladaptive neural plasticity and neuroinflammation occur during the latent period as a key underlying event in epilepsy chronicization. Previously, we showed that α-tocopherol (α-T) reduces hippocampal neuroglial activation and neurodegeneration in the rat model of kainic acid (KA)-induced status epilepticus (SE). These findings allowed us to postulate an antiepileptogenic potential for α-T in hippocampal excitotoxicity, in line with clinical evidence showing that α-T improves seizure control in drug-resistant patients. To explore neurobiological correlates of the α-T antiepileptogenic role, rats were injected with such vitamin during the latent period starting right after KA-induced SE, and the effects on circuitry excitability, neuroinflammation, neuronal death, and microRNA (miRNA) expression were investigated in the hippocampus. Results show that in α-T-treated epileptic rats, (1) the number of population spikes elicited by pyramidal neurons, as well as the latency to the onset of epileptiform-like network activity recover to control levels; (2) neuronal death is almost prevented; (3) down-regulation of claudin, a blood-brain barrier protein, is fully reversed; (4) neuroinflammation processes are quenched (as indicated by the decrease of TNF-α, IL-1β, GFAP, IBA-1, and increase of IL-6); (5) miR-146a, miR-124, and miR-126 expression is coherently modulated in hippocampus and serum by α-T. These findings support the potential of a timely intervention with α-T in clinical management of SE to reduce epileptogenesis, thus preventing chronic epilepsy development. In addition, we suggest that the analysis of miRNA levels in serum could provide clinicians with a tool to evaluate disease evolution and the efficacy of α-T therapy in SE.
