Proline induces oxidative stress in cerebral cortex of rats

Delwing, Débora; Bavaresco, Caren Serra; Wannmacher, Clóvis Milton Duval; Wajner, Moaçir; Dutra-Filho, Carlos Severo; Wyse, Ângela T. S.

doi:10.1016/s0736-5748(02)00109-0

Cited by 58 publications

(27 citation statements)

References 23 publications

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“…Recently, more insight into the deleterious effect of elevated proline level in brain has been gained with reports showing that proline decreases Na þ , K þ -ATPase and acetylcholinesterase activities and elicits oxidative stress in rat brains. [28][29][30] The present study emphasizes the importance of intermediate phenotypes (ie plasma proline level) to reveal the determinism of genetically complex diseases such as psychotic disorders. Moreover, the finding of an association between hyperprolinemia and schizoaffective disorder but not with schizophrenia is potentially important to delineate the etiological boundaries of these clinical entities.…”

Section: Discussionmentioning

confidence: 93%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P ¼ 0.02, Odds ratio ¼ 4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an An increased frequency of several psychotic disorders, such as children-onset schizophrenia, 1 schizophrenia, 2 and bipolar disorder, 3 has been observed in patients with the 22q11 deletion syndromes (22q11DS), 4 which include the DiGeorge syndrome (MIM 188400) and the velo-cardio-facial syndrome (MIM 192430). This has led to the hypothesis that sequence variations of one or several genes located within the 3 Mb region commonly deleted in most of the 22q11DS patients 5 might confer susceptibility for psychoses in the general population. In a previous study, we had identified in two schizophrenic relatives (diagnosed according to DSM III criteria) a 350 kb heterozygous deletion within the DiGeorge critical region (DGCR) removing entirely the proline dehydrogenase (PRODH) gene. This deletion was associated in patients with moderate hyperprolinemia. In addition, two heterozygous PRODH missense mutations (L441P and L289M) were detected in three of 63 schizophrenic patients but not in 68 controls, and these mutations were also associated with moderate hyperprolinemia. 6 Interestingly, we subsequently found the same PRODH deletion and the L441P substitution at the homozygous state in children suffering from a severe form of type I hyperprolinemia, a condition characterized by high plasma proline levels, seizures and mental retardation. 7 T...

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Section: Discussionmentioning

confidence: 93%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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“…It is well established that some of these compounds are inhibitors of mitochondrial energy metabolism, whereas others elicit free radical production (Streck et al, 2003aStreck et al, 2003c;Delwing et al, 2003a;Delwing et al, 2003b). Considering that Na + , K + -ATPase consumes approximately 50% of ATP generated in CNS, it may be presumed that ATP decrease can indirectly inactivate this activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Na⁺, K⁺‐ATPase activity in rat striatum by the metabolites accumulated in Lesch–Nyhan disease

Bavaresco

Zugno

Tagliari

et al. 2004

Intl J of Devlp Neuroscience

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In the present study, we investigated the in vitro effect of hypoxanthine, xanthine and uric acid, metabolites accumulating in tissue of patients with Lesch-Nyhan disease, on Na(+), K(+)-ATPase activity in striatum of neonate rats. Results showed that all compounds significantly inhibited Na(+), K(+)-ATPase activity. We also studied the kinetics of the inhibition of Na(+), K(+)-ATPase activity caused by hypoxanthine. The apparent K(m) and V(max) of Na(+), K(+)-ATPase activity for ATP as the substrate and hypoxanthine as the inhibitor were 0.97 mM and 0.69 nmol inorganic phosphate (Pi) released per min per mg of protein, respectively. K(i)-value was 1.9 microM, and the inhibition was of the non-competitive type. We also observed that the inhibitory effects of hypoxanthine, xanthine and uric acid probably occur through the same mechanism, suggesting a common binding site for these oxypurines on Na(+), K(+)-ATPase. Therefore, it is conceivable that inhibition of brain Na(+), K(+)-ATPase activity may be involved at least in part in the neuronal dysfunction characteristic of patients with Lesch-Nyhan disease.

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“…Proline is a nonessential amino acid, which may have a role in brain function; as a modulator/precursor of neuronal glutaminergic activity [Murphy and Scambler, 2005] and the regulation of cortical acetylcholinesterase function [Delwing et al, 2003]. Hyperprolinemia type I is an autosomal recessive condition resulting in the deficiency of proline dehydrogenase and increased plasma proline levels (plasma proline levels 3-10-fold above normal) [Phang et al, 2001].…”

Section: Prodhmentioning

confidence: 99%

Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome

Prasad

Howley

Murphy

2008

Dev Disabil Res Revs

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There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population.

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Proline induces oxidative stress in cerebral cortex of rats

Cited by 58 publications

References 23 publications

Hyperprolinemia is a risk factor for schizoaffective disorder

Hyperprolinemia is a risk factor for schizoaffective disorder

Inhibition of Na⁺, K⁺‐ATPase activity in rat striatum by the metabolites accumulated in Lesch–Nyhan disease

Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome

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Proline induces oxidative stress in cerebral cortex of rats

Cited by 58 publications

References 23 publications

Hyperprolinemia is a risk factor for schizoaffective disorder

Hyperprolinemia is a risk factor for schizoaffective disorder

Inhibition of Na+, K+‐ATPase activity in rat striatum by the metabolites accumulated in Lesch–Nyhan disease

Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome

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Inhibition of Na⁺, K⁺‐ATPase activity in rat striatum by the metabolites accumulated in Lesch–Nyhan disease