Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain

Seminotti, Bianca; Knebel, Lisiane Aurélio; Fernandes, Carolina Gonçalves; Amaral, Alexandre Umpierrez; Rosa, Marcelo Prado Amaral; Eichler, Paula; Leipnitz, Guilhian

doi:10.1016/j.lfs.2011.06.013

Cited by 13 publications

(3 citation statements)

References 42 publications

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“…Considering that oxidative stress has been considered an important underlying pathomechanism of common neurodegenerative disorders (Berg and Youdim, 2006; Mancuso et al, 2006; Stoy et al, 2005) and of some inborn errors of metabolism (Busanello et al, 2011; Ribas et al, 2011; Seminotti et al, 2011), in the present work we investigated the effects of MCAC on a large spectrum of relevant parameters of redox homeostasis in cerebral cortex from young rats. We used cerebral cortex in this investigation because brain abnormalities are seen in this structure in MCAD deficient patients.…”

Section: Discussionmentioning

confidence: 99%

Disruption of redox homeostasis in cerebral cortex of developing rats by acylcarnitines accumulating in medium‐chain acyl‐CoA dehydrogenase deficiency

Tonin

Grings

Knebel

et al. 2012

Intl J of Devlp Neuroscience

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Medium-chain fatty acids and acylcarnitines accumulate in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most frequent fatty acid oxidation defect clinically characterized by episodic crises with vomiting, seizures and coma. Considering that the pathophysiology of the neurological symptoms observed in MCADD is poorly known and, to our knowledge, there is no report on the involvement of acylcarnitines in the brain damage presented by the affected patients, the objective of the present study was to investigate the in vitro effects of hexanoylcarnitine (HC), octanoylcarnitine, decanoylcarnitine (DC) and cis-4-decenoylcarnitine (cDC) at concentrations varying from 0.01 to 1.0mM on important oxidative stress parameters in cerebral cortex of young rats. HC, DC and cDC significantly induced lipid peroxidation, as determined by increased thiobarbituric acid-reactive substances (TBA-RS) values. In addition, carbonyl formation was significantly augmented and sulfhydryl content diminished by DC, reflecting induction of protein oxidative damage. HC, DC and cDC also decreased glutathione (GSH) levels, the most important brain antioxidant defense. Furthermore, DC-induced elevation of TBA-RS values and decrease of GSH levels were prevented by the free radical scavengers melatonin and α-tocopherol, indicating the involvement of reactive oxygen species in these effects. We also found that l-carnitine itself did not induce lipid and protein oxidative damage, neither reduced the antioxidant defenses. Our present data show that the major medium-chain acylcarnitines accumulating in MCADD elicit oxidative stress in rat brain. It is therefore presumed that these compounds may be involved to a certain extent in the pathogenesis of the neurologic dysfunction of MCADD.

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Section: Discussionmentioning

confidence: 99%

Disruption of redox homeostasis in cerebral cortex of developing rats by acylcarnitines accumulating in medium‐chain acyl‐CoA dehydrogenase deficiency

Tonin

Grings

Knebel

et al. 2012

Intl J of Devlp Neuroscience

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“…The pathophysiology of nonketotic hyperglycinemia is complex. In addition to end-product deficiency of 5,10-methylenetetrahydrofolate [7][8][9], glycine toxicity both directly [10][11][12][13][14] and through excess glycine simulation at the allosteric site of the NR1/NR2 NMDA receptor [15][16][17] is hypothesized to be a major factor.…”

Section: Introductionmentioning

confidence: 99%

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

Shelkowitz

Saneto

Al-Hertani

et al. 2022

Orphanet J Rare Dis

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Background Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. Aim We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. Methods Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). Results Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. Conclusion KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

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“…In the experimental study, administration of glycine to animals in contrast to the expected renal cytoprotection was associated with an increase in acute ischemic-reperfusion renal injury as a result of NMDA activation (Arora et al 2014). It has been demonstrated that NMDA activation is associated with increased intracellular calcium, impairment of nitric oxide synthesis, and increased production of reactive oxygen species, and is the one of the key causes in pathogenesis of heart failure (Kang et al 2009;Seminotti et al 2011;Martins-Pinge et al 2013;Stern and Potapenko 2013;Moura et al 2014). The role of NMDA activation in the pathogenesis of ischemic/reperfusion injury has been confirmed by the cytoprotective effect of the NMDA inhibition, especially, in pre-and postconditioning of the isolated rat heart (Weinberg et al 2016;Govoruskina et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Sex-related differences in plasma amino acids of patients with ST-elevation myocardial infarction and glycine as risk marker of acute heart failure with preserved ejection fraction

et al. 2022

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Nowadays, the problem of preventing acute heart failure (AHF) in patients with ST-elevation myocardial infarction (STEMI) and preserved left-ventricular ejection fraction (pLVEF) is still not completely resolved, especially in late-presented patients. The purpose of study was: (1) assessment of free plasma amino acid (PAA) alterations in STEMI patients [not receiving reperfusion therapy (RT)], depending on sex and LVEF; (2) analysis of development of late/persistent AHF more than 48 h after admission (pAHF) in STEMI patients with pLVEF depending on PAA levels. This prospective cohort study included 92 STEMI patients (33 women and 59 men), not receiving RT. The free PAA were investigated by ion-exchange liquid-column chromatography. The women had significantly higher PAA levels than men in general cohort and cohort with pLVEF (n = 69). There were associations between female sex and pAHF in general cohort (OR 3.7, p = 0.004) and cohort with pLVEF (OR 11.4, p = 0.0001) by logistic regression. The association between pAHF and glycine level [OR 2.5, p < 0.0001; AUC 0.84, p < 0.0001; 86.7% sensitivity and 77.8% specificity for > 2.6 mg/dL] was revealed in cohort with pLVEF (including female and male). Glycine remained a predictor of pAHF with pLVEF by multivariable logistic regression adjusting for comorbidities, demographic and clinical variables. Higher rate of pAHF in female than in male STEMI patients with pLVEF is associated with higher plasma glycine in women. The glycine level may be genetically determinated by female sex. The plasma glycine > 2.6 mg/dL is a predictor of pAHF in STEMI with pLVEF (including female and male).

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Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain

Cited by 13 publications

References 42 publications

Disruption of redox homeostasis in cerebral cortex of developing rats by acylcarnitines accumulating in medium‐chain acyl‐CoA dehydrogenase deficiency

Disruption of redox homeostasis in cerebral cortex of developing rats by acylcarnitines accumulating in medium‐chain acyl‐CoA dehydrogenase deficiency

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

Sex-related differences in plasma amino acids of patients with ST-elevation myocardial infarction and glycine as risk marker of acute heart failure with preserved ejection fraction

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