Creatine prevents the inhibition of energy metabolism and lipid peroxidation in rats subjected to GAA administration

Abstract

Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder, biochemically characterized by the tissue accumulation of guanidinoacetate (GAA). Affected patients present epilepsy and mental retardation whose etiopathogeny is unclear. Previous reports have shown that GAA alters brain energy metabolism and that creatine, which is depleted in patients with GAMT deficiency, can act as a neuroprotector; as such, in the present study we investigated the effect of creatine administration on some of the altered parameters of energy metabolism (complex II, Na(+),K(+)-ATPase and creatine kinase) and lipid peroxidation caused by intrastriatal administration of GAA in adult rats. Animals were pretreated for 7 days with daily intraperitonial administrations of creatine. Subsequently, these animals were divided into two groups: Group 1 (sham group), rats that suffered surgery and received saline; and group 2 (GAA-treated). Thirty min after GAA or saline, the animals were sacrificed and the striatum dissected out. Results showed that the administration of creatine was able to reverse the activities of complex II, Na(+),K(+)-ATPase and creatine kinase, as well as, the levels of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation. These findings indicate that the energy metabolism deficit caused by GAA may be prevented by creatine, which probably acts as an antioxidant since it was able to prevent lipid peroxidation. These data may contribute, at least in part, to a better understanding of the mechanisms related to the energy deficit and oxidative stress observed in GAMT deficiency.

Inborn errors of creatine metabolism and epilepsy

“…In the striatum of rats, GAA probably interferes with energetic metabolism at the level of complex II, ATPase and creatine kinase activities through lipid peroxidation causing oxidative stress (Zugno et al., 2006; Zugno et al, 2007). Creatine prevents the neurotoxicity of GAA in rat striatum (Kolling & Wyse, 2010). Moreover, GAA (but not creatine) has a specific mimetic effect on GABA A receptors (Neu et al., 2002).…”

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

“…Arginine is a substrate for the enzyme arginine-glycine amidinotransferase (AGAT), which forms guanidinoacetate (GAA) and ornithine from glycine and arginine (Schulze and Battini 2008). GAA enhances oxidative stress in the rat brain (Zugno et al 2008) and these changes have been hypothesized to contribute to the central nervous system (CNS) pathophysiology in guanidinoacetate:methyltransferase (GAMT) deficiency (Amayreh et al 2014;Grioni et al 2014;Kolling and Wyse 2010). It has been suggested that elevated plasma GAA contributes to neuropathology in ARG1 deficiency (Amayreh et al 2014).…”

Homocysteine induces energy imbalance in rat skeletal muscle: Is creatine a protector?

“…Creatine solution (50 mg/kg of body weight) was injected intraperitoneally, once a day, from the 6th to the 28th days of age . Control animals received saline solution in the same volumes as those applied to Hcy‐treated and creatine‐treated rats.…”