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) : Williams, Anthony J.


Full Text : http://www.dtic.mil/get-tr-doc/pdf?AD=ADA434977


Report Date : 2002


Pagination or Media Count : 74


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 hypoxia/hypoglycemia (34 &#956;M13-91), NMDA (77 &#956;M42-141), glutamate (819 &#956;M346-1937) or veratradine (2136 &#956;M1508-3026) induced injury (numbers in parentheses indicate EC50 and 95% confidence limits). Con-G (0.1-1 &#956;M) also provided up to 80% protection against staurosporine-induced apoptotic injury (P<0.01, n = 12/group), 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 (P<0.05, n = 6-10/group). 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 (P<0.05, n = 3-4/group), a preservation of Bcl-2 immunoreactivity at 24 h (P<0.05, n = 4), and with a reduction in DNA strand breaks in the ischemic hemisphere as evaluated 24 h post-injury (P<0.05, n = 6/group).


Descriptors :   *WOUNDS AND INJURIES , *RECEPTOR SITES(PHYSIOLOGY) , *PHARMACOLOGICAL ANTAGONISTS , *ELECTROENCEPHALOGRAPHY , *CEREBRAL CORTEX , TRANSIENTS , CALCIUM , BRAIN , RATS , GLUTAMIC ACID , EXPERIMENTAL DESIGN , THESES , REDUCTION , RESPONSE , HYPOXIA , NERVE CELLS , SALTS , ARTERIES , ISCHEMIA , HYPOGLYCEMIA , INFARCTION , OBSTRUCTION(PHYSIOLOGY) , APOPTOSIS.


Subject Categories : ANATOMY AND PHYSIOLOGY
      MEDICINE AND MEDICAL RESEARCH
      PHARMACOLOGY


Distribution Statement : APPROVED FOR PUBLIC RELEASE