Research Project
6337853
DESCRIPTION: (Adapted from the Applicant's Abstract) Traumatic spinal cord injury (SCI) leads to permanent loss of motor function and control of function below the level of the injury. A significant portion of the loss is due to secondary factors rather than the initial trauma. These factors include increased extracellular concentrations of glutamate which have demonstrated excitotoxicity. Ionotropic glutamate antagonists, administered acutely after injury showed promise as neuroprotective agents which has not been borne out by clinical trials due to adverse side effects. Recently developed metabotropic glutamate receptor agonists also show neuroprotective characteristics in tissue culture studies and are expected to have a more favorable side effect profile. Preliminary studies of a clinically relevant model of SCI in rodents have adapted it for relatively rapid assay of neuroprotective effects. The present proposal will test 3 of the most promising metabotropic glutamate receptor agonists in this assay and compare them to a known ionotropic glutamate receptor antagonist for neuroprotective effects. Dose response curves at a single time point will be constructed. Then the most efficacious dose of each compound will be tested for therapeutic window after injury. PROPOSED COMMERCIAL APPLICATION: On average, 11,000 traumatic spinal cord injuries (SCI) are reported every year in the United States. Currently, there are no effective medications for the treatment of SCI. The development of effective pharmacotherapies that reduce the severity of injury following a traumatic event could as much as $400 billion on future direct and indirect SCI lifetime costs in the United States alone. The medications developed in this program would also be expected to be efficacious for the treatment of traumatic head injury, stroke and related disorders. STRENGTHS: This is a resubmitted Phase I proposal. The current application has +___________ retained the strengths of the original proposal and corrected the deficiencies noted in the first review. The preliminary studies demonstrate that the 3 drugs to be investigated have shown neuroprotective effects in several different neuronal culture excitotoxicity studies. The present proposal will produce dose response curves for all 3 drugs in comparison with vehicle and with a known neuroprotective ionotropic antagonist. The time of administration will be held at 5 minutes post-injury for all the studies. The use of the ionotropic antagonist for comparison is relevant and useful. A second set of experiments will use the most efficacious dose of each drug and vary the time of delivery post-injury to determine the therapeutic window for administration. The second set of studies do not use strict controls (i.e. administration of vehicle at each time point) but rather use a single group of untreated SCI rats as control. The investigator has justified this control approach by citing previous studies in the laboratory which show no effect of vehicle administration at differing time points. Assessment of neuroprotective capacity will be by determination of numbers of surviving ventral horn motor neurons at lesion site and at discrete distances fore and aft of the site of contusion. Animals will be sacrificed at 24 hours, a time point which has been determined to reflect accurately the level of damage 1 month after injury. Since loss of glia cells has also been associated with loss of function, the investigator will assess numbers of glia, both astrocytes and oligodendrocytes, if time permits. The proposal is well thought out, well written and logical in its flow of experiments. The investigator is well qualified to perform the work. The data from these studies could form the foundation for additional preclinical studies of loss of function in the rodent SCI model and later, human clinical studies. The background and preliminary studies sections suggest that metabotropic glutamate receptor agonists may hold the key to neuroprotection for traumatic injury, inadvertent surgical injury and perhaps neurodegenerative disorders. WEAKNESSES: There are few weaknesses in this application. The investigator +__________ states that the T8 incomplete SCI model induces a respiratory deficit, but this deficit is never explained, nor does it appear to be a measure that will be used to assess loss of function. Clearly, since the accidental mortality in this model is less than 10 percent, the deficit is not lethal. Is it possible to quantify and use this as an assessment of loss of function? Another minor point is that the volume of solution being injected to the injury site is not defined. It is presumed that a single volume will be used and the concentration of drug varied, but this is not spelled out.
