5-Oxoproline Reduces Non-Enzymatic Antioxidant Defenses in vitro in Rat Brain

Abstract

5-Oxoproline (pyroglutamic acid) accumulates in glutathione synthetase deficiency, an inborn metabolic defect of the gamma-glutamyl cycle. This disorder is clinically characterized by hemolytic anemia, metabolic acidosis and severe neurological disorders. Considering that the mechanisms of brain damage in this disease are poorly known, in the present study we investigated whether oxidative stress is elicited by 5-oxoproline. The in vitro effect of (0.5-3.0 mM) 5-oxoproline was studied on various parameters of oxidative stress, such as total radical-trapping antioxidant potential, total antioxidant reactivity, chemiluminescence, thiobarbituric acid-reactive substances, sulfhydryl content, carbonyl content, and 2',7'-dichlorofluorescein fluorescence, as well as on the activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex and cerebellum of 14-day-old rats. Total radical-trapping antioxidant potential and total antioxidant reactivity were significantly reduced in both cerebral structures. Carbonyl content and 2',7'-dichlorofluorescein fluorescence were significantly enhanced, while sulfhydryl content was significantly diminished. In contrast, chemiluminescence and thiobarbituric acid-reactive substances were not affected by 5-oxoproline. The activities of catalase, superoxide dismutase and glutathione peroxidase were also not altered by 5-oxoproline. These results indicate that 5-oxoproline causes protein oxidation and reactive species production and decrease the non-enzymatic antioxidant defenses in rat brain, but does not cause lipid peroxidation. Taken together, it may be presumed that 5-oxoproline elicits oxidative stress that may represent a pathophysiological mechanism in the disorder in which this metabolite accumulates.

Altered Metabolites in the Plasma of Autism Spectrum Disorder: A Capillary Electrophoresis Time-of-Flight Mass Spectroscopy Study

“…This cycle is necessary for the synthesis and breakdown of glutathione, and also for the intracellular transport of free amino acids [49]. Although the pathological role of 5-oxoproline in the human brain is not clarified, it has been presumed from animal studies that 5-oxoproline elicits oxidative stress, which may represent a pathophysiological mechanism in the neuro-pathological disorder in which this metabolite accumulates [50], [51]. Direct contribution of 5-oxoproline down-regulation in ASD pathology is not clear, but like taurine and arginine, 5-oxoproline might be a putative biomarker for ASD that has oxidative stress alterations.…”

Treating oxidative stress in heart failure: past, present and future

“…Of particular interest is OPLAH, a cytoplasmic enzyme of the GSH cycle whose only function is the conversion of 5‐oxoproline, a degradation product of GSH, into glutamate ( Figure ). Interestingly, studies have demonstrated that excessive 5‐oxoproline accumulation can lead to the induction of intracellular oxidative stress . Therefore, OPLAH plays a pivotal role not only in the γ‐glutamyl cycle, by producing glutamate for de novo GSH synthesis, but also as an antioxidant by scavenging 5‐oxoproline.…”

Analysis of glutamine, glutamate, pyroglutamate, and GABA in cerebrospinal fluid using ion pairing HPLC with positive electrospray LC/MS/MS

“…The brain lacks a urea cycle, and the efflux of glutamine from brain to blood constitutes the most important mechanism for excreting excess ammonia (Bak et al, 2006). Pyroglutamate is derived metabolically from glutamate and in high concentrations has been shown to be neurotoxic and promote excitotoxicity (Pederzolli et al, 2007). The concentrations of metabolites of the gamma glutamyl cycle including glutamine, glutamate, GABA and pyroglutamate are important biomarkers for disease states and drug effect.…”