The Journal of Biological Physics and Chemistry


Volume 4, Number 1, p. 2532

T. Barbakadze1, E. Zhuravliova1, N. Narmania1, T. Sanikidze2, T. Kekelidze 3,and D. Mikeladze1

1 Institute of Physiology, Georgian Academy of Sciences, Tbilisi, Georgia
2 Tbilisi State Medical University, Tbilisi, Georgia
3 Tbilisi State University, Tbilisi, Georgia

Effects of guanidine analogues of creatine on the formation of reactive oxygen species and viability of primary neuronal/glial cells

Guanidine analogues of creatine (Cr) such as guanidinosuccinic acid (GSA) and guanidinopropionic acid (GPA) have been suggested as being important with respect to the etiology of uraemic encephalopathy causing epileptic and cognitive symptomatologies. We investigated the effects of creatine, GSA, and GPA on the viability of primary neuronal/glial culture cells, the redox state of the mitochondrial respiratory chain components and the production of reactive oxygen species (ROS). Using apoptosis-inducing systems, near infrared spectroscopy (NIR) and electron paramagnetic resonance (EPR), we found that GSA, like glutamate, induces apoptosis, and increases the production of nitric oxide (NO) in the neuronal/glial cells. Glutamate, but not GSA caused short-term elevation of the redox state of cytochrome oxidase, reflecting an initial Ca2+ response by mitochondria. Cr decreased the glutamate and GSA-induced cell death of neuronal/glial cells in a dose-dependent manner. Neuroprotective effects of creatine were eliminated by the NO synthase (NOS) inhibitor N6-nitro-L-arginine methyl ester (L-NAME), indicating that the production of NO is necessary for the protective action of this compound. Furthermore, Cr increased the onset and duration of the glutamate-induced initial responses of cytochrome oxidase, suggesting that Cr maintains membrane potential during the uptake of Ca2+. GPA, as well as the NOS inhibitor, L-NAME, eliminates the effect of creatine on cytochrome oxidase. On the other hand, Cr induces the production of a superoxide anion, which is accompanied by elevation of the redox state of the cytochrome oxidase. We conclude that Cr, by intensifying the ATP/PCr turnover predominantly in glial cells, can increase the activity of F1F0-ATPase and raise the mitochondrial membrane potential, which in turn activates mitochondrial NOS and produces ROS via cytochrome oxidase.

Keywords: apoptosis, creatine, guanidinopropionic acid, guanidinosuccinic acid, neuronal/glial cells

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