Study of predictive biomarkers of manganese toxicity : control and prevention of neurotoxicity associated with parenteral nutrition

• Author(s): Santos, Dinamene Marques dos
• Date: 2014
• Persistent ID: http://hdl.handle.net/10451/10779
• Origin: Repositório da Universidade de Lisboa
• Subject(s): Teses de doutoramento - 2014
• Document Type: Doctoral thesis
• Language: English
• Advisor(s): Santos, Ana Paula Marreilha dos, 1957-; Batoréu, Maria Camila Canteiro, 1948-
• Contributor(s): Repositório da Universidade de Lisboa

Description

Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2014

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.

Fundação para a Ciência e Tecnologia (FCT, SFRH/BD/64128/2009, Strategic Project Pest-OE/SAU/UI4013/2011)