HIGH-THROUGHPUT SCREENING ASSAY FOR NEUROPROTECTIVE AGENTS

DESCRIPTION (provided by applicant): . N-methyl-D-aspartate receptor (NMDAR) plays an important role in memory and cognitive functions of the brain. However, this receptor is also involved in several neurodegenerative diseases. These disorders include but are not limited to ischemia, pain, Alzheimer, Parkinson, schizophrenia, epilepsy, and other neurodegenerative diseases. Indeed, inappropriate activation of NMDAR results in excessive calcium influx and can cause neuronal death. Thus, blockage of NMDARs by channel blockers or antagonists was hoped to be neuroprotective and suitable for the treatment of NMDA related disorders in the central nervous system. To date, several classes of neuroprotective compounds have been investigated in phase 3 clinical trials for brain injury and other central nervous system disorders. Most of the trials have yielded disappointing results and some showed toxicity, which resulted in their early termination. Thus, there is a great need for the discovery of new compounds that modulate NMDAR activity. Assembly of receptors with signal transduction proteins into large multiprotein complexes has emerged as a general mechanism of cellular signaling and processes such as phosphorylation and protein-protein interactions are considered major regulators of receptor function. NMDA receptor core has been reported to include 77 associated-scaffolding and regulatory proteins, which, as we are coming to understand, control receptor localization and current flow through the receptor and downstream signaling events. Pharmacological manipulation of the NMDAR complex with its associated protein and enzymes, as distinct to NMDAR alone, may provide new therapeutic drugs that can inhibit NMDAR without displaying the side effects of NMDAR antagonists. Taking these findings into consideration, we propose to develop a high- throughput assay for screening compounds that modulate phosphorylation and/or protein-protein interactions of the NMDAR subunits. N-methyl-D-aspartate receptor is an ion channel that plays an important role in memory and cognitive functions of the brain. However, over activation of this receptor is involved in several neurodegenerative diseases. Because of the disappointment of NMDAR antagonists as neuroprotectors in clinical trials, there is a real need for novel therapeutic drugs in this area. Pharmacological manipulation of the NMDAR complex with its associated proteins as distinct to NMDAR alone, may provide new therapeutic drugs that can inhibit NMDAR without displaying the side effects of NMDAR antagonists. Thus, our goal is to develop a High Throughput Assay for screening compounds that modulate the associated proteins of the NMDA receptor, facilitating thereby the generation of new drug therapies for "high-profile" diseases such as ischemia, pain, Alzheimer, Parkinson, schizophrenia, epilepsy, depression, migraine and other neurodegenerative diseases.