Role of the ROS generating Nox enzymes in glutamate signaling and excitotoxicity in the hippocampus

• Research unit: COST
• Project number: C13.0142

Key words (English)

Nox nadph oxidases; reactive oxygen species; oxidative stress; excitotoxicity; signaling

Research programs (English)

COST-Action BM1203 - EU-ROS

Short description (English)

Neurodegenerative diseases are a key challenge for the 21st century and reactive oxygen species (ROS) are thought to contribute to their pathogenesis. One of the mechanisms driving oxidative stress in CNS disease is the increased activation of glutamate receptors leading to excitotoxicity, but how this leads to oxidative stress is poorly understood. Based on recent data, NADPH oxidases (NOX) are likely mediating excitotoxic ROS generation. Two - not mutually exclusive - mechanisms have been discussed: i) NOX-derived ROS may enhance glutamate release, and ii) NOX may generate ROS downstream from activation of glutamate receptors. We will study this question in organotypic hippocampal cultures from wild type and NOX-deficient mice. To test hypothesis 1, organotypic cultures will be exposed to hypoxia/reoxygenation and ROS generation and glutamate release will be investigated. To test hypothesis 2, organotypic cultures will be exposed to excitotoxic stimulation, and ROS generation, Ca2+ signaling, and neuronal damage will be assessed. We will also investigate our hypotheses using isoform-specific NOX inhibitors. Taken together, our results will not only provide a better understanding of excitotoxicity, but also contribute to the development of novel therapies. Our project fully integrates into the EUROS COST action. It addresses the cellular basis of ROS, investigates the role of ROS in human pathologies, and test new drugs that interfere with ROS-generating pathways.

Further information (English)

Full name of research-institution/enterprise: Université de Genève Faculté de médecine Département de pathologie et immunologie

Partners and International Organizations (English)

AT; BE; BG; HR; CZ; DK; EE; FI; FR; F.Y.R. of Macedonia; DE; EL; HU; IE; IL; IT; LT; LU; MT; NL; NO; PL; PT; RO; RS; SI; ES; SE; TR; UK; AU

Abstract (English)

Neurpdegenerative. diseases are a key challenge for the 21st Century and reactive oxygen species (ROS) are thought to contribute to their pathogenesis. One of the mechanisms driving oxidative sb-ess in CNS disease is the increased activation of glutamate receptors leading to excitotoxicity, but how this leads to oxidative stress is pooriy understood. Based on récent data, NADPH oxidases (NOX) are likely mediating excitotoxic ROS génération. Two - not mutually exclusive - mechanisms have been discussed: i) NOX-derived ROS may enhance glutamate release, and ii) NOX may generate ROS downstream from activation of glutamate receptors. We will study this question in organotypic hippocampal cultures frorn wild type and NOX-défiçient micè. To t^t hypothesis 1, organotypic cultures will bé exposed to hypoxia/re^ génération ànd âlutàrnate release will be investigated. To test hypothesis 2, organotypic cultures will be exposed to excitotoxic stimulation, and ROS génération, Ca2+ signaling, and neuronal damage will be assessed. We will alsb investigate our hypotiieses using isoform-specific NOX Inhibitors. Taken together, our results will not only provide a better understanding bf excitotoxicity, but also contiibute to the development of novel thérapies. Our project fully intégrâtes into the EUROS COST action. It addresses tiie cellular basis of ROS, investigates the rôle of ROS in human pathologies, and test new drugs that interfère with ROS-generating pathways;

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C13.0142