Acute creatine administration improves mitochondrial membrane potential and protects against pentylenetetrazol-induced seizures.
A growing body of evidence indicates that creatine (Cr) exerts beneficial effects on a variety of pathologies where energy metabolism and oxidative stress play an etiological role. However, the benefits of Cr treatment for epileptics are still shrouded in controversy. In the present study, we found that acute Cr treatment (300 mg/kg, p.o.) prevented the increase in electroencephalographic wave amplitude typically elicited by PTZ (30, 45 or 60 mg/kg, i.p.). Cr treatment also increased the latency periods of first myoclonic jerks, lengthened the latency periods of the generalized tonic-clonic seizures and reduced the time spent in the generalized tonic-clonic seizures induced by PTZ (60 mg/kg). Administration of PTZ (all doses) decreased Na(+), K(+)-ATPase activity as well as adenosine triphosphate (ATP) and adenosine diphosphate levels in the cerebral cortex, but Cr treatment prevented these effects. Cr administration also prevented increases in xanthine oxidase activity, adenosine monophosphate levels, adenosine levels, inosine levels and uric acid levels that normally occur after PTZ treatment (60 mg/kg, i.p.). We also showed that Cr treatment increased the total Cr (Cr + PCr) content, creatine kinase activity and the mitochondrial membrane potential (ΔΨ) in the cerebral cortex. In addition, Cr prevented PTZ-induced mitochondrial dysfunction characterized by decreasing ΔΨ, increasing thiobarbituric acid-reactive substance levels and increasing protein carbonylation. These experimental findings reinforce the idea that mitochondrial dysfunction plays a critical role in models of epileptic seizures and suggest that buffering brain energy levels through Cr treatment may be a promising therapeutic approach for the treatment of this neurological disease.
Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brazil.
Leonardo Magno
LM
Rambo
Leandro Rodrigo
LR
Ribeiro
Iuri Domingues
ID
Della-Pace
Daniel Neis
DN
Stamm
Rogério
R
da Rosa Gerbatin
Marina
M
Prigol
Simone
S
Pinton
Cristina Wayne
CW
Nogueira
Ana Flávia
AF
Furian
Mauro Schneider
MS
Oliveira
Michele Rechia
MR
Fighera
Luiz Fernando Freire
LF
Royes
D000818:Animals; D003401:Creatine / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010433:Pentylenetetrazole / Q000009:adverse effects; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*
D003401:Creatine; D010433:Pentylenetetrazole