Accession Number:

ADA434977

Title:

Neuroprotection Profile of the High Affinity NMDA Receptor Antagonist Conantokin-G

Descriptive Note:

Doctoral thesis

Corporate Author:

UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD

Personal Author(s):

Report Date:

2002-01-01

Pagination or Media Count:

74.0

Abstract:

Conantokin-G Con-G or CGX-1007, a potent NR2B subunit selective NMDA receptor antagonist, was evaluated for its neuroprotective properties in experimental models of neuronal injury. In primary neuronal cultures Con-G was shown to decrease excitotoxic calcium responses to NMDA and provide 100 neuroprotection against hypoxiahypoglycemia 34 956M13-91, NMDA 77 956M42-141, glutamate 819 956M346-1937 or veratradine 2136 956M1508-3026 induced injury numbers in parentheses indicate EC50 and 95 confidence limits. Con-G 0.1-1 956M also provided up to 80 protection against staurosporine-induced apoptotic injury P0.01, n 12group, which was linked to the NR2B subunit. For in vivo brain injury studies, middle cerebral artery occlusion MCAo in the rat was used as a model of transient focal brain ischemia. In this model Con-G 0.01-2.0 nmoles, i.c.v. reduced brain infarction and improved both neurological and electroencephalographic EEG recovery as evaluated both 24 and 72 h post-injury. The maximal neuroprotective effect was measured with the highest dose of Con-G tested 2.0 nmol, i.c.v with an 89 reduction of core infarct volume P0.05, n 6-10group. Post-injury time course experiments demonstrated a therapeutic window out to at least 4 h from the start of the injury. These neuroprotective effects were also associated with a 50 reduction in the early expression i.e. 1-4 h of the c-fos gene P0.05, n 3-4group, a preservation of Bcl-2 immunoreactivity at 24 h P0.05, n 4, and with a reduction in DNA strand breaks in the ischemic hemisphere as evaluated 24 h post-injury P0.05, n 6group.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE