Astrocyte-mediated excitotoxicity in manganism

• Grant number: 11/02295-2
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2011
• End date: June 30, 2013
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Alan Stewart Hazell
• Grantee: Alan Stewart Hazell
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Manganese neurotoxicity (MN) is a serious brain disorder resulting from chronic exposure to manganese in the mining and industrial sector, and in clinical cases involving total parenteral nutrition. Its long-term neuropathological consequences include the development of Alzheimer's type II astrocytosis and profound neuronal loss in the globus pallidus of the basal ganglia. The goal of this proposal is to elucidate and characterize the pathogenetic mechanisms that lead to cerebral damage in this disorder. The research proposal will address the following two hypotheses: 1) Focal increase in extracellular glutamate concentration due to loss of astrocytic glutamate transport function contributes to depolarization and neuronal cell death in MN, and 2) Loss of astrocytic glutamate transporter regulation occurs as a consequence of oxidative stress and alterations in metabotropic glutamate receptor (mGluR) activity in MN. Using a rat model of MN developed by us which recapitulates the pathophysiological changes observed in the human disorder, we will evaluate the involvement of astrocytic glutamate transporters in the pathogenetic sequence of events that leads to neuronal cell death in the globus pallidus in rats with MN, examine how these transporters determine regional vulnerability, the mechanisms by which alterations in the levels of these transporters occur in this disorder and potential therapeutic strategies using in vivo microdialysis, immunoblotting, immunohistochemistry, autoradiography, the calcium channel blocker nicardipine, the ²-lactam antibiotic ceftriaxone, the antioxidant N-acetylcysteine, and the Group II mGluR agonist DCG IV. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE MOURA, THATIANE C.; AFADLAL, SZEIFOUL; HAZELL, ALAN S.. Potential for stem cell treatment in manganism. NEUROCHEMISTRY INTERNATIONAL, v. 112, p. 134-145, JAN 2018. (11/02263-3, 11/02295-2, 13/07559-3)