Levetiracetam: Antiepileptic Properties and Protective Effects on Mitochondrial Dysfunction in Experimental Status Epilepticus

• Published in: Epilepsia (Copenhagen) Vol. 47; no. 3; pp. 469 - 478
• Main Authors: Gibbs, Julie E., Walker, Matthew C., Cock, Hannah R.
• Format: Journal Article
• Language: English
• Published: 350 Main Street , Malden , MA 02148 , USA and 9600 Garsington Road , Oxford , OX4 2XG , England Blackwell Publishing Inc 01-03-2006; Blackwell
• Subjects: Aconitate Hydratase - metabolism; Animals; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Chromatography, High Pressure Liquid; Citrate (si)-Synthase - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Electroencephalography - drug effects; Electroencephalography - statistics & numerical data; Epilepsy - drug therapy; Epilepsy - prevention & control; Glutathione; Glutathione - analysis; Glutathione - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus - chemistry; Hippocampus - drug effects; Hippocampus - metabolism; Levetiracetam; Male; Medical sciences; Mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - prevention & control; Nervous system (semeiology, syndromes); Neurology; Neurons - chemistry; Neurons - metabolism; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; Perforant Pathway - metabolism; Perforant Pathway - physiology; Perforant pathway stimulation; Pharmacology. Drug treatments; Piracetam - analogs & derivatives; Piracetam - pharmacology; Piracetam - therapeutic use; Rats; Rats, Sprague-Dawley; Status epilepticus; Status Epilepticus - diagnosis; Status Epilepticus - etiology; Status Epilepticus - prevention & control; Nervous system diseases; Psychotropic; Epilepsy; Anticonvulsant; Cerebral disorder; Prevention; Mitochondria; Subintrant crisis; Dysfunction; Nootropic agent; Central nervous system disease; Perforant pathway; Status epilepticus; Levetiracetam; Levetiracetam-Status epilepticus-Perforant pathway stimulation-Mitochondria-Glutathione
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2006.00454.x

Purpose: To assess the anticonvulsant activity of the novel antiepileptic drug, levetiracetam (LEV) in a model of self‐sustaining limbic status epilepticus, and to measure the consequence of LEV treatment on the pattern of mitochondrial dysfunction known to occur after status epilepticus (SE).
Methods: The rat perforant pathway was stimulated for 2 h to induce self‐sustaining status epilepticus (SSSE). Stimulated rats were assigned to one of three treatment groups, receiving intraperitoneal injections of saline, 200 mg/kg LEV, or 1,000 mg/kg LEV, 15 min into SSSE and at 3 times over the next 44‐h period. All animals received diazepam after 3‐h SSSE to terminate seizures. Forty‐four hours later, the hippocampi were extracted and prepared for electrochemical high‐performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, α‐ketoglutarate dehydrogenase, citrate synthase, complex I, and complex II/III). These parameters were compared between treatment groups and with sham‐operated rats.
Results: LEV administration did not terminate seizures or have any significant effect on spike frequency, although rats that received 1,000 mg/kg LEV did exhibit improved behavioral seizure parameters. Significant biochemical changes occurred in saline‐treated stimulated rats compared with shams: with reductions in glutathione, α‐ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities. Complex II/III activities were unchanged throughout. Rats that received 1,000 mg/kg LEV had significantly improved biochemical parameters, in many instances, comparable to sham control levels.
Conclusions: Despite continuing seizures, administration of LEV (1,000 mg/kg) protects against mitochondrial dysfunction, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects.