Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures

Authors

  • Vinícius Rafael Funck,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
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  • Clarissa Vasconcelos de Oliveira,

    1. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Letícia Meier Pereira,

    1. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Leonardo Magno Rambo,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
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  • Leandro Rodrigo Ribeiro,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
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  • Luiz Fernando Freire Royes,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
    2. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Juliano Ferreira,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
    2. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Gustavo Petri Guerra,

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
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  • Ana Flávia Furian,

    1. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Maurício Schneider Oliveira,

    1. Postgraduate Program in Veterinary Medicine, Federal University of Santa Maria, Santa Maria, Brazil;
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  • Carlos Augusto Mallmann,

    1. Postgraduate Program in Veterinary Medicine, Federal University of Santa Maria, Santa Maria, Brazil;
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  • Carlos Fernando de Mello,

    1. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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  • Mauro Schneider Oliveira

    1. Postgraduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil
    2. Postgraduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
    3. Federal University of Pampa at Itaqui, Itaqui, Brazil
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Address correspondence to Mauro S. Oliveira, Universidade Federal do Pampa, Campus Itaqui, Rua Luiz Joaquim de Sá Britto, s/n, Itaqui 97650-000, RS, Brasil. E-mail: oliveira.ms@gmail.com

Summary

Purpose:  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.

Key Findings:  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).

Significance:  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.

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