Glutamate acts on a wide variety of receptors, divided into three broad groups: the ionotropic AMPA/KA receptors, NMDA receptors, and the metabotropic receptors. Activation of glutamate receptors is known to induce a series of intracellular biochemical cascades. Among these, often calcium dependent processes, stimulation of nitric oxide (NO) formation by nitric oxide synthase (NOS), has attracted much attention. This NO cascade, seems to play a pivotal role in the development of ischemic brain damage. The most compelling are studies of mutant mice that do not express the neuronal isoform of NOS. Such knockout mice show reduced infarct volumes after middle cerebral artery occlusion compared to wild type mice and also less damage following transient global ischemia. Also, in rat striatal cultures NO plays a key role in a slow, delayed form of degeneration that takes place following brief exposure to the selective glutamate receptor agonist, NMDA.
The aim of this project is to identify processes by which NO causes neuronal degeneration.
Restricted blood supply to the brain, cerebral ischemia, leads to a decrease in oxygen and glucose delivery, that if severe induces brain damage. Cerebral ischemia is in humans encountered following stroke, sub arachnoid hemorrhage, head trauma or after cardiac arrest. These conditions lead to great suffering of the individual, and the socio-economic impact of ischemic brain damage is great. In Europe stroke represents the third cause of death afflicting 2000- 3000 individuals out of a population of 1 million inhabitans. Today there is no approved therapy against strok.
Experimental research may generate new treatment paradigms in the clinic setting. There is a substantial industrial interest in pursuing the development of drugs that diminish or prevent the devastating effects of cerebral ischemia. The goal of this project is to propose new therapeutic strategies for limitation of damage caused by stroke by identifying processes leading the cell death. The aim of the-project is to elucidate the mechanisms which act downstream from glutamate receptors and nitric oxide formation and which are involved in neurodegeneration. The working hypothesis is brief the following: Nitric oxide formed following ischemia will activate guanylate cyclase, which stimulates release of glutamate, thereby enhancing glutamate toxicity. The nitric oxide will also react with superoxide anions to form free radicals, which cause oxidative injury and DNA fragmentation. This activates gene programs including the tumor supressor gene p 53, a presumptive regulator of cell death. In this project four research groups participate, all active in the forefront of their respective areas of research.
The groups cover different areas of expertise and contribute to the project with complementary methodological approaches addressing the specific following questions: - Which metabotropic glutamate receptors modulate NO formation? - Are guanylate cyclase inhibitors neuroprotective? - What regulates nitric oxide synthase activity following ischemia? - Does NO cause nitration of key cellular proteins? - Does DNA damage correlate with NO formation? - Does NO stimulate NFkb expression? - Is NO formation related to p53, Bax or ICE expression? The projects comply with research areas 3.2.2 and 3.2.4 of the BIOMED 2 workprogramme. 03
Funding SchemeCSC - Cost-sharing contracts
W1P 9NL London