Mechanisms of Resistance to Neurotoxins
Abstract
Glutamic acid can kill nerve cells during stroke, ischemia, trauma and perhaps in neurodegenerative disease such as Parkinson's. Glutamate kills cells through ionotropic receptor mediated excitotoxicity or via an oxidative stress pathway called oxidative glutamate toxicity. Oxidative stress is also involved in the toxicity of some chemical warfare agents. A major goal of this proposal has been to identify reagents and conditions which protect nerve cells from neurotoxins and oxidative stress, and to determine when in the programmed cell death pathway the neuroprotective agent acts. Toward this end it was shown during the last year that the activation of dopamine D4 receptors protects nerve cells by blocking the activation of cGMP activated calcium channels which regulate calcium influx. Flavonoids, a group of compounds found in plants, were shown for the first time to protect cells by three distinct mechanisms depending upon their structure. These include inhibiting cGMP gated calcium influx, preventing the loss of the intracellular antioxidant glutathione, and by acting as an antioxidant per se. Finally, preliminary experiments were carried out to determine if agents which protect nerve cells from glutamate toxicity also protect from arsenite, cisplatin, and hydrogen peroxide toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA398170
Entities
People
- David R. Schubert
Organizations
- Salk Institute for Biological Studies