title: Prostaglandin E(2)  potentiates methylmalonate-induced seizures.
abstract: OBJECTIVE
  Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurologic dysfunction, including seizures. It is known that metabolic crises in affected patients are precipitated by infections. Although growing evidence supports that inflammation facilitates seizures, it is not known whether inflammatory mediators facilitate MMA-induced seizures. Therefore, in this study we investigate the involvement of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in MMA-induced seizures.
  
  
  METHODS
  Adult male Wistar rats were implanted with electrodes over the parietal cortex for electroencephalography (EEG) recording and a cannula in the right lateral ventricle. Animals were injected with PGE(2) (100 ng/2 μl, i.c.v.) or phosphate-buffered saline (PBS) (2 μl, i.c.v.), 15 min before MMA (2.5 μmol/2.5 μl, i.c.v.) or NaCl (2.5 μmol/2.5 μl, i.c.v.). The anticonvulsant effect of celecoxib (0.2; 2 or 20 mg/kg, p.o., 60 min before MMA) on MMA-induced seizures, and whether PGE(2) (10 or 100 ng/2 μl, i.c.v.) prevented the anticonvulsant effect of celecoxib (2 mg/kg, p.o.) were also investigated.
  
  
  RESULTS
  PGE(2) decreased the latency to MMA-induced jerks and generalized seizures, and increased the amplitude of generalized seizure EEG recordings. The selective COX-2 inhibitor celecoxib at the dose 2 mg/kg, but not at the dose 20 mg/kg, completely prevented MMA-induced seizures. The protective effect of celecoxib (2 mg/kg) against MMA-induced seizures was prevented by PGE(2).
  
  
  CONCLUSIONS
  These results support a role for PGE(2) in the seizures elicited by MMA, which is in agreement with the view that infections may precipitate and exacerbate neurologic dysfunction in patients with MMA acidemic.
authors.affiliation: Department of Physiology and Pharmacology, Center of Health Sciences, Federal University of Santa Maria, Santa Maria, RS, Brasil.
authors.forename: Mirian Graciela Silva Stiebbe
authors.initials: MG
authors.lastname: Salvadori
authors.forename: Cristina Ruedell Reschke
authors.initials: CR
authors.lastname: Banderó
authors.forename: Ana Cláudia
authors.initials: AC
authors.lastname: Jesse
authors.forename: Anajara Teixeira
authors.initials: AT
authors.lastname: Gomes
authors.forename: Leonardo Magno
authors.initials: LM
authors.lastname: Rambo
authors.forename: Lívia Maronesi
authors.initials: LM
authors.lastname: Bueno
authors.forename: Vanessa Trindade
authors.initials: VT
authors.lastname: Bortoluzzi
authors.forename: Mauro Schneider
authors.initials: MS
authors.lastname: Oliveira
authors.forename: Carlos Fernando
authors.initials: CF
authors.lastname: Mello
mesh_terms: D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004569:Electroencephalography; D008297:Male; D008764:Methylmalonic Acid; D010296:Parietal Lobe / Q000187:drug effects / Q000503:physiopathology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D008764:Methylmalonic Acid; D000068579:Celecoxib; D015232:Dinoprostone