Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy

• Published in: Annals of neurology 2016-12, Vol.80 (6), p.896-908
• Main Authors: Bar-Klein, Guy, Klee, Rebecca, Brandt, Claudia, Bankstahl, Marion, Bascuñana, Pablo, Töllner, Kathrin, Dalipaj, Hotjensa, Bankstahl, Jens P., Friedman, Alon, Löscher, Wolfgang
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - diagnostic imaging; Convulsions & seizures; Disease Models, Animal; Electrocorticography; Epilepsy; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - prevention & control; Female; Inflammation - diagnostic imaging; Inflammation - prevention & control; Isoflurane - pharmacology; Kainic Acid; Magnetic Resonance Imaging; Male; Neuroimaging; Neurons - pathology; Paraoxon; Positron-Emission Tomography; Rats; Rodents
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24804

Objective Acquired epilepsy is a devastating long‐term risk of various brain insults, including trauma, stroke, infections, and status epilepticus (SE). There is no preventive treatment for patients at risk. Attributable to the complex alterations involved in epileptogenesis, it is likely that multitargeted approaches are required for epilepsy prevention. We report novel preclinical findings with isoflurane, which exerts various nonanesthetic effects that may be relevant for antiepileptogenesis. Methods The effects of isoflurane were investigated in two rat models of SE‐induced epilepsy: intrahippocampal kainate and systemic administration of paraoxon. Isoflurane was either administered during (kainate) or after (paraoxon) induction of SE. Magnetic resonance imaging was used to assess blood–brain barrier (BBB) dysfunction. Positron emission tomography was used to visualize neuroinflammation. Long‐term electrocorticographic recordings were used to monitor spontaneous recurrent seizures. Neuronal damage was assessed histologically. Results In the absence of isoflurane, spontaneous recurrent seizures were common in the majority of rats in both models. When isoflurane was administered during kainate injection, duration and severity of SE were not affected, but only few rats developed spontaneous recurrent seizures. A similar antiepileptogenic effect was found when paraoxon‐treated rats were exposed to isoflurane after SE. Moreover, in the latter model, isoflurane prevented BBB dysfunction and neurodegeneration, whereas isoflurane reduced neuroinflammation in the kainate model. Interpretation Given that isoflurane is a widely used volatile anesthetic, and is used for inhalational long‐term sedation in critically ill patients at risk to develop epilepsy, our findings hold a promising potential to be successfully translated into the clinic. Ann Neurol 2016;80:896–908