Metabolomics as a tool to evaluate the toxicity of formulations containing amphotericin B, an antileishmanial drug.

Amphotericin B (AmB) is a drug of choice against life-threatening systemic fungal infections and an alternative therapy for the treatment of all forms of leishmaniasis. It is known that AmB and its conventional formulation cause renal damage; however, the lipid formulations can reduce these effects. The aim of the present study was to identify metabolic changes in mice treated with two different AmB formulations, a nanoemulsion (NE) (lipid system carrier) loaded with AmB and the conventional formulation (C-AmB). For this purpose, metabolic fingerprinting represents a valuable strategy to monitor, in a non-targeted manner, the changes that are at the base of the toxicity mechanism of AmB. Plasma samples of BALB-c mice were collected after treatment with 3 alternate doses of AmB at 1 mg kg-1 administered intravenously and analysed with CE, LC and GC coupled to MS. Blood urea nitrogen (BUN) and plasma creatinine levels were also analysed. Kidney tissue specimens were collected and evaluated. It was not observed that there were any alterations in BUN and creatinine levels as well as in histopathological analysis. Approximately 30 metabolites were identified as potentially related to early C-AmB-induced nephrotoxicity. Disturbances in the arachidonic acid, glycerophospholipid, acylcarnitine and polyunsaturated fatty acid (PUFA) pathways were observed in C-AmB-treated mice. In the AmB-loaded NE group, it was observed that there were fewer metabolic changes, including changes in the plasma levels of cortisol and pyranose. The candidate biomarkers revealed in this study could be useful in the detection of the onset and severity of kidney injury induced by AmB formulations.

Mild thiamine deficiency and chronic ethanol consumption modulate acetylcholinesterase activity change and spatial memory performance in a water maze task.

Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter.

Effect of coffee on chemical hepatocarcinogenesis in rats.

The aim of this study was to investigate the effect of daily coffee ingestion on hepatocarcinogenesis in rats submitted to the resistant hepatocyte (RH) model. During lactation, the dams were fed a control or a coffee-supplemented diet. After weaning, male pups followed the same dietary protocol and were submitted to the RH model. The animals were sacrificed at 110 days of life. Removal of the medial and left lateral lobes was used as mitogenic stimulus, and the liver regeneration was estimated. Morphometric analyses of preneoplastic lesions were carried out on liver histological sections submitted to the histochemical procedure of the glucose-6-phosphatase activity. The gamma-glutamyltranspeptidase (GGT) activity was analyzed in the homogenate of regenerated livers. Body weight, mass liver regeneration, and hepatic cell architecture were not affected by coffee ingestion. In the group of animals fed the coffee-supplemented diet, the number of persistent and remodeling nodules was reduced (85.5% and 70.5%, respectively). The hepatic area occupied by the persistent nodules was also reduced (92%). There was a reduction of 7.7% in the GGT activity in the group fed the coffee-supplemented diet, although not statistically significant. The results indicate that coffee modulates chemical hepatocarcinogenesis in rats.

Chronic ethanol intake and ageing effects on cortical and basal forebrain cholinergic parameters: morphometric and biochemical studies.

Abstract Twenty-eight Wistar rats treated orally with 20% ethanol solution, were divided into two groups: adult group (n = 19) and aged group (n = 9) consisting of animals aged 4 and 12 months, respectively, at the beginning of the treatment. Neurons from the basal nucleus region were counted and the percentage of choline acetyltransferase-immunoreactive cholinergic neurons was determined in adjacent sections. Acetylcholine release and choline-acetyltransferase activity in the cerebral cortex were assessed in the same animals. Nutritional parameters of the ethanol treated animals were monitored and found to be normal. Chronic exposure to ethanol did not result in global neuronal loss or loss of cholinergic neurons in the basal nucleus region. However, a greater expression of ChAT-immunoreactivity in the basal nucleus region and a tendency toward increased ChAT activity in the cerebral cortex of the control and treated aged animals, compared respectively to adult ones, were observed. These findings suggest adaptive changes of the aged rats in response to the possible cholinergic hypofunction, manifested as a decreased release of acetylcholine under stimulated conditions.