title: Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures.
abstract: OBJECTIVE
  Statins are selective inhibitors of 3-hydroxyl-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway for cholesterol biosynthesis. Increasing evidence indicates that statins, particularly atorvastatin, are neuroprotective in several conditions, including stroke, cerebral ischemia, traumatic brain injury, and excitotoxic amino acid exposure. However, only a few studies have investigated whether statins modulate seizure activity. In the current study we investigated whether atorvastatin or simvastatin alters the seizures induced by pentylenetetrazol (PTZ), a classical convulsant.
  
  
  METHODS
  Adult male Wistar rats were treated with atorvastatin or simvastatin for 7 days (10 mg/kg/day). Seizure activity was induced by PTZ (60 mg/kg, i.p.), and evaluated by behavioral and electrographic methods. Cholesterol levels were determined by a standard spectrophotometric method. Blood-brain barrier (BBB) permeability was assessed by the fluorescein method. Atorvastatin levels in the plasma and cerebral cortex were determined by high-performance liquid chromatography tandem mass spectrometry.
  
  
  RESULTS
  We found that oral atorvastatin treatment increased the latency to PTZ-induced generalized seizures. In contrast, when the 7-day atorvastatin treatment was withheld for 1 day (i.e., atorvastatin withdrawal), PTZ-induced seizures were facilitated, as evidenced by a decrease in the latency to clonic and generalized tonic-clonic seizures induced by PTZ. In contrast, simvastatin treatment for 7 days (10 mg/kg/day, p.o.), with or without withdrawal, did not alter PTZ-induced seizures. Interestingly, the effects of atorvastatin treatment and withdrawal were not accompanied by changes in plasma or cerebral cortex cholesterol levels or in the BBB permeability. Atorvastatin levels in the plasma and cerebral cortex after 7 days of treatment were above the half maximal inhibitory concentration for inhibition of HMG-CoA reductase, whereas atorvastatin was not detectable in the plasma or cerebral cortex following a 24 h washout period (atorvastatin withdrawal).
  
  
  CONCLUSIONS
  We conclude that atorvastatin treatment and withdrawal have differential effects on pentylenetetrazol-induced seizures, which are not related to changes in plasma or cerebral cortex cholesterol levels or in BBB permeability. Additional studies are necessary to evaluate the molecular mechanisms underlying our findings as well as its clinical implications.
authors: Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil.
authors: Vinícius Rafael
authors: VR
authors: Funck
authors: Clarissa Vasconcelos
authors: CV
authors: de Oliveira
authors: Letícia Meier
authors: LM
authors: Pereira
authors: Leonardo Magno
authors: LM
authors: Rambo
authors: Leandro Rodrigo
authors: LR
authors: Ribeiro
authors: Luiz Fernando Freire
authors: LF
authors: Royes
authors: Juliano
authors: J
authors: Ferreira
authors: Gustavo Petri
authors: GP
authors: Guerra
authors: Ana Flávia
authors: AF
authors: Furian
authors: Maurício Schneider
authors: MS
authors: Oliveira
authors: Carlos Augusto
authors: CA
authors: Mallmann
authors: Carlos Fernando
authors: CF
authors: de Mello
authors: Mauro Schneider
authors: MS
authors: Oliveira
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D000069059:Atorvastatin; D001812:Blood-Brain Barrier / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry; D002784:Cholesterol / Q000097:blood; D003292:Convulsants / Q000494:pharmacology*; D004569:Electroencephalography; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D008297:Male; D010433:Pentylenetetrazole / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D006538:Heptanoic Acids; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D010433:Pentylenetetrazole