1. Metyrapone prevents acute glucose hypermetabolism and short-term brain damage induced by intrahippocampal administration of 4-aminopyridine in rats
- Author
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Miguel A. Pozo, Pablo Bascuñana, Francisca Gomez, Jens P. Bankstahl, Ágata Silván, Luis García-García, Mercedes Delgado, and Rubén Fernández de la Rosa
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Antimetabolites ,Status epilepticus ,Brain damage ,Hippocampus ,Neuroprotection ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,Potassium Channel Blockers ,Animals ,Medicine ,4-Aminopyridine ,Hypoxia, Brain ,Neuroinflammation ,Injections, Intraventricular ,Glial fibrillary acidic protein ,biology ,Metyrapone ,business.industry ,Cell Biology ,medicine.disease ,Rats ,Astrogliosis ,Glucose ,Neuroprotective Agents ,030104 developmental biology ,Endocrinology ,nervous system ,Positron-Emission Tomography ,biology.protein ,Hypermetabolism ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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.
- Published
- 2018