Metyrapone prevents brain damage induced by status epilepticus in the rat lithium-pilocarpine model Luis García-García a, b, * , Ahmed A. Shiha a , Rub  en Fern  andez de la Rosa a , Mercedes Delgado a ,  Agata Silv  an a , Pablo Bascu ~ nana c , Jens P. Bankstahl c , Francisca Gomez a, b , Miguel A. Pozo a, d, e a Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII nº 1, 28040 Madrid, Spain b Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram on y Cajal s/n, 28040 Madrid, Spain c Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany d Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ram on y Cajal s/n, 28040 Madrid, Spain e Instituto Tecnol ogico PET, C/ Manuel Bartolom e Cossío nº 10, 28040 Madrid, Spain article info Article history: Received 19 December 2016 Received in revised form 27 April 2017 Accepted 6 May 2017 Available online xxx Keywords: Seizure Glucocorticoids Metyrapone Lithium-pilocarpine model [18F]FDG PET [18F]GE180 abstract The status epilepticus (SE) induced by lithium-pilocarpine is a well characterized rodent model of the human temporal lobe epilepsy (TLE) which is accompanied by severe brain damage. Stress and gluco- corticoids markedly contribute to exacerbate neuronal damage induced by seizures but the underlying mechanisms are poorly understood. Herein we sought to investigate whether a single administration of metyrapone (150 mg/kg, i.p.), an 11b-hydroxylase inhibitor, enzyme involved in the peripheral and central synthesis of corticosteroids, had neuroprotective properties in this model. Two experiments were carried out. In exp. 1, metyrapone was administered 3 h before pilocarpine injection whereas in exp. 2, metyrapone administration took place at the onset of the SE. In both experiments, 3 days after the insult, brain metabolism was assessed by in vivo 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography (PET). Brains were processed for analyses of markers of hippocampal integrity (Nissl staining), neurodegeneration (Fluoro-Jade C), astrogliosis (glial fibrillary acidic protein (GFAP) immu- nohistochemistry) and, for a marker of activated microglia by in vitro autoradiography with the TSPO (18 kDa translocator protein) radioligand [ 18 F]GE180. The SE resulted in a consistent hypometabolism in hippocampus, cortex and striatum and neuronal damage, hippocampal neurodegeneration, neuronal death and gliosis. Interestingly, metyrapone had neuroprotective effects when administered before, but not after the insult. In summary, we conclude that metyrapone administration prior but not after the SE protected from brain damage induced by SE in the lithium-pilocarpine model. Therefore, it seems that the effect of metyrapone is preventive in nature and likely related to its antiseizure properties. © 2017 Elsevier Ltd. All rights reserved. 1. Introduction Epilepsy is a neurological disorder that approximately affects to 50 million patients worldwide. Among the different forms of epi- lepsy, the temporal lobe epilepsy (TLE) is the most prevalent in adults. Furthermore, it is often accompanied by high rates of resistance to pharmacological treatment (Tellez-Zenteno and Hernandez-Ronquillo, 2012). In rodents, the status epilepticus (SE) triggered by the cholin- ergic agonist pilocarpine (and its variant by previous administra- tion of lithium) has proven its usefulness as a model to study the pathophysiology and progression of the disease, as well as to test potential antiepileptic treatments. This model resembles the behavioral, electrographic and neuropathological features of hu- man TLE, where seizure foci are located in limbic regions such as the hippocampus and amygdala (Turski et al., 1989). Pilocarpine rapidly elicits a SE followed by a prolonged silent period and later gives rise to spontaneous recurrent seizures which is accompanied by a general brain hypometabolism as measured by in vivo 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomog- raphy ([ 18 F]FDG PET). Hypometabolism appears shortly after the SE * Corresponding author. Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII nº 1, 28040 Madrid, Spain. E-mail address: lgarciag@ucm.es (L. García-García). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2017.05.007 0028-3908/© 2017 Elsevier Ltd. All rights reserved. Neuropharmacology xxx (2017) 1e13 Please cite this article in press as: García-García, L., et al., Metyrapone prevents brain damage induced by status epilepticus in the rat lithium- pilocarpine model, Neuropharmacology (2017), http://dx.doi.org/10.1016/j.neuropharm.2017.05.007