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Acute creatine administration improves mitochondrial membrane potential and protects against pentylenetetrazol-induced seizures

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Abstract

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.

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Acknowledgments

The authors thank Dr. Guilherme Bresciani for critical reading of the manuscript. This work was supported by FAPERGS/CNPq (Grant: #11/2082-4). L.F.F. Royes, M.R. Fighera and L.M. Rambo are the recipients of CNPq fellowships (Grant: #141164/2010-7). I. Della-Pace is the recipient of CAPES fellowships. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. In addition, we would like to state that all authors have observed and approved the study and that no part of the submitted work has been published or is under consideration for publication elsewhere. Moreover, the present work was supported by government funding and has no financial or other relationships that might lead to a conflict of interest. We also would like to declare that all experiments were carried out according to the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) revised 1996 and that the University Ethics Committee approved the respective protocols.

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Correspondence to Luiz Fernando Freire Royes.

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Rambo, L.M., Ribeiro, L.R., Della-Pace, I.D. et al. Acute creatine administration improves mitochondrial membrane potential and protects against pentylenetetrazol-induced seizures. Amino Acids 44, 857–868 (2013). https://doi.org/10.1007/s00726-012-1408-6

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