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Intracerebral administration of the potassium channel blocker 4-aminopyridine (4-AP) triggers neuronal depolarization and intense acute seizure activity followed by neuronal damage. We have recently shown that, in the lithium-pilocarpine rat model of status epilepticus (SE), a single administration of metyrapone, an inhibitor of the 11β-hydroxylase enzyme, had protective properties of preventive nature against signs of brain damage and neuroinflammation. Herein, our aim was to investigate to which extent, pretreatment with metyrapone (150 mg/kg, i.p.) was also able to prevent eventual changes in the acute brain metabolism and short-term neuronal damage induced by intrahippocampal injection of 4-AP (7 μg/5 μl). To this end, regional brain metabolism was assessed by 2-deoxy-2-[18F]fluoro- d -glucose ([18F]FDG) positron emission tomography (PET) during the ictal period. Three days later, markers of neuronal death and hippocampal integrity and apoptosis (Nissl staining, NeuN and active caspase-3 immunohistochemistry), neurodegeneration (Fluoro-Jade C labeling), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and microglia-mediated neuroinflammation (in vitro [18F]GE180 autoradiography) were evaluated. 4-AP administration acutely triggered marked brain hypermetabolism within and around the site of injection as well as short-term signs of brain damage and inflammation. Most important, metyrapone pretreatment was able to reduce ictal hypermetabolism as well as all the markers of brain damage except microglia-mediated neuroinflammation. Overall, our study corroborates the neuroprotective effects of metyrapone against multiple signs of brain damage caused by seizures triggered by 4-AP. Ultimately, our data add up to the consistent protective effect of metyrapone pretreatment reported in other models of neurological disorders of different etiology.

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 glucocorticoids 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 11β-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-[18F]fluoro- d -glucose ([18F]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) immunohistochemistry) and, for a marker of activated microglia by in vitro autoradiography with the TSPO (18 kDa translocator protein) radioligand [18F]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.