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Study of predictive biomarkers of manganese toxicity : control and prevention of neurotoxicity associated with parenteral nutrition
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Resumo(s)
Mn is an essential element supplemented to patients receiving parenteral
nutrition (PN), however repeated Mn supplementation may cause
neurotoxicity. To prevent Mn-induced neurotoxicity, we studied the
mechanism of Mn toxicity in brain, aiming to select biomarkers of
neurotoxicity, using 2 in vivo assays with Wistar rats sub-acutely exposed
to 4 or 8 doses of MnCl2 (25 mg/Kg). Treated rats showed an increase of
biomarkers of oxidative stress, F2-isoprostanes (F2-IsoPs) and F4-
neuroprostanes (F4-NPs), as well as biomarkers of neuroinflammation
prostaglandin E2 (PGE2), cortical glial fibrillary acidic protein
immunoreactivity (GFAP-ir) and tumor necrosis factor-α (TNF-α). On the
other hand, Mn decreased acetylcholinesterase (AChE) activity in rat´s
brain. The reversibility of the neurotoxic effects was evaluated with
several biomarkers and neurobehavioral assays, being cortical GFAP the
most persistent after Mn exposure. Whole blood (WB) and urine Mn were
used as biomarkers of Mn exposure, although urinary Mn appears to
reflect recent exposure, while WB Mn concentration closely correlates
with Mn accumulation. Thus, both biomarkers were selected to
biomonitor patients receiving Mn in PN.
Biomarkers related to energy metabolism, in particular tricarboxylic acid
(TCA) cycle organic acids and AChE activity in red blood cells (RBC) were
negatively correlated with brain cortical GFAP-ir and brain Mn levels. The
urinary TCA cycle organic acids and AChE activity in RBCs may be
predictive biomarkers to biomonitor PN patients. In addition, two antioxidants
tested in RBE4 cells exposed to Mn, evidence that 5-ASA has a
greater efficacy in protecting these cells from Mn-induced cytotoxicity,
compared with 4-PAS.
Descrição
Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2014
Palavras-chave
Teses de doutoramento - 2014