DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia.

Phenylketonuria (PKU) is a disease caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in an accumulation of phenylalanine (Phe) in the brain tissue, cerebrospinal fluid, and other tissues of PKU patients. Considering that high levels of Phe are associated with neurological dysfunction and that the mechanisms underlying the neurotoxicity in PKU remain poorly understood, the main objective of this study was to investigate the in vivo and in vitro effects of Phe on DNA damage, as determined by the alkaline comet assay. The results showed that, compared to control group, the levels of DNA migration were significantly greater after acute administration of Phe, p-chlorophenylalanine (p-Cl-Phe, an inhibitor of PAH), or a combination thereof in cerebral cortex and blood, indicating DNA damage. These treatments also provoked increase of carbonyl content. Additionally, when Phe or p-Cl-Phe was present in the incubation medium, we observed an increase in the frequency and index of DNA damage in the cerebral cortex and blood, without affecting lactate dehydrogenase (LDH) release. Our in vitro and in vivo findings indicate that DNA damage occurs in the cerebral cortex and blood of rats receiving Phe, suggesting that this mechanism could be, at least in part, responsible for the neurological dysfunction in PKU patients.

Anti-nociceptive and anti-edematogenic effects of glibenclamide in a model of acute gouty attack in rats.

OBJECTIVE AND DESIGN: We investigated the effect of glibenclamide on inflammatory parameters in a model of acute gouty attack in rats. TREATMENT: Intra-articular injection of 50 µl of monosodium urate (MSU) crystals (1.25 mg/site) was used to induce gout-related inflammation. The effects of glibenclamide (1-10 mg/kg, s.c.) or dexamethasone (8 mg/kg, s.c., positive control) were assessed on several inflammation parameters. METHODS: Spontaneous nociception assessment, edema measurement, total and differential leucocyte counts, interleukin (IL)-1ß release, prostaglandin E2 production and determination of blood glucose levels were analyzed. Peritoneal macrophages were incubated with MSU and levels of IL-1ß were measured. Statistical significance was assessed by one- or two-way analysis of variance. RESULTS: Glibenclamide (3 mg/kg) or dexamethasone (8 mg/kg) prevented nociception and edema induced by MSU injection in rats. Glibenclamide did not affect leukocyte infiltration, IL-1ß release and PGE2 production, but only reduced IL-1ß production by MSU-stimulated macrophages at very high concentration (200 µM). Dexamethasone significantly reduced leukocyte infiltration, IL-1ß release and PGE2 production. Glibenclamide reduced whereas dexamethasone increased blood glucose levels of MSU-injected rats. CONCLUSIONS: Glibenclamide reduced nociception and edema, but not leukocyte infiltration, IL-1ß release and PGE2 production. However, its substantial effect on nociception and edema suggests that glibenclamide can be an interesting option as an adjuvant treatment for pain induced by acute attacks of gout.

Plasmatic vitamin C in nontreated hepatitis C patients is negatively associated with aspartate aminotransferase.

OBJECTIVES: To evaluate the possible relationship between aminotransferases levels and markers of oxidative stress in chronic hepatitis C patients. DESIGN AND METHODS: Patients without treatment for hepatitis were divided in to group I (15-39 U/L); group II (41-76 U/L) and group III (81-311 U/L) of activity alanine aminotransferase (ALT). Blood markers of oxidative stress [catalase (CAT), glutathione peroxidase (GPx), thiobarbituric acid-reactive species (TBARS), nonprotein and protein thiol (NP-SH and P-SH) groups and vitamin C] were determined. RESULTS: P-SH and NP-SH levels, TBARS, GPx and CAT were not different between groups. Vitamin C was significantly decreased in groups II (P=0.03) and III (P=0.001) when compared with group I and correlated negatively with aspartate aminotransferase (AST; r=-0.29, P=0.042). CONCLUSION: Vitamin C levels were negatively associated with AST, suggesting that vitamin C could be an additional indicator of hepatitis C severity.