JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Williams, A. J.
Right arrow Articles by Tortella, F. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Williams, A. J.
Right arrow Articles by Tortella, F. C.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL
Medline Plus Health Information
*Transient Ischemic Attack

Vol. 294, Issue 1, 378-386, July 2000

Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-D-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies1

Anthony J. Williams, Jitendra R. Dave, James B. Phillips, Yu Lin, R. Tyler McCabe and Frank C. Tortella

Department of Neuropharmacology and Molecular Biology, Walter Reed Army Institute of Research, Silver Spring, Maryland (A.J.W., J.R.D., J.B.P., Y.L., F.C.T.); and Cognetix, Inc., Salt Lake City, Utah (R.T.M.)

Conantokin-G (Con-G), a 17-amino-acid peptide derived from marine snails and a potent N-methyl-D-aspartate (NMDA) antagonist, was evaluated for its neuroprotective properties in vitro and in vivo. In primary cerebellar neurons, Con-G was shown to decrease excitotoxic calcium responses to NMDA and to exhibit differential neuroprotection potencies against hypoxia/hypoglycemia-, NMDA-, glutamate-, or veratridine-induced injury. Using the intraluminal filament method of middle cerebral artery occlusion as an in vivo rat model of transient focal brain ischemia, the neuroprotective dose-response effect of Con-G administration beginning 30 min postocclusion was evaluated after 2 h of ischemia and 22 h of reperfusion. In the core region of injury, an 89% reduction in brain infarction was measured with significant neurological and electroencephalographic recovery at the maximal dose tested (2 nmol), although mild sedation was noted. Lower doses of Con-G (0.001-0.5 nmol) were significantly neuroprotective without causing sedation. Postinjury time course experiments demonstrated a therapeutic window out to at least 4 to 8 h from the start of the injury, providing a 47% reduction in core injury. The neuroprotective effect of Con-G (0.5 nmol) was also evaluated after 72 h of injury, where a 54% reduction in core brain infarction was measured. Critically, in both recovery models (i.e., 24 and 72 h), the reduction in brain infarction was associated with significant improvements in neurological and electroencephalographic recovery. These data provide evidence for the potent and highly efficacious effect of Con-G as a neuroprotective agent, with an excellent therapeutic window for the potential intervention against ischemic/excitotoxic brain injury.

1 The views of the authors do not purport or reflect the position of the Department of the Army or the Department of Defense (para 4-3, AR 360-5). This work was supported in part by Cognetix, Inc. and funds from DOD/U.S. Army. Preliminary versions of this data were published in abstract form in Soc Neurosci Abstr (1998) 24(1):978 and FASEB Abstr (1999) 13(5):A1099.

0022-3565/00/2941-0378$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by U.S. Government


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
R. W. Teichert, E. C. Jimenez, V. Twede, M. Watkins, M. Hollmann, G. Bulaj, and B. M. Olivera
Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors
J. Biol. Chem., December 21, 2007; 282(51): 36905 - 36913.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
A. B. Alex, A. J. Baucum, and K. S. Wilcox
Effect of Conantokin G on NMDA Receptor-Mediated Spontaneous EPSCs in Cultured Cortical Neurons
J Neurophysiol, September 1, 2006; 96(3): 1084 - 1092.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. J. Williams, C. C. Bautista, R.-W. Chen, J. R. Dave, X.-C. M. Lu, F. C. Tortella, and J. A. Hartings
Evaluation of Gabapentin and Ethosuximide for Treatment of Acute Nonconvulsive Seizures following Ischemic Brain Injury in Rats
J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 947 - 955.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Z.-G. Jiang, X.-C. M. Lu, V. Nelson, X. Yang, W. Pan, R.-w. Chen, M. S. Lebowitz, B. Almassian, F. C. Tortella, R. O. Brady, et al.
A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia
PNAS, January 31, 2006; 103(5): 1581 - 1586.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. J. Williams, F. C. Tortella, X. M. Lu, J. E. Moreton, and J. A. Hartings
Antiepileptic Drug Treatment of Nonconvulsive Seizures Induced by Experimental Focal Brain Ischemia
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 220 - 227.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
A. J. Williams, R. Berti, J. R. Dave, P. J. Elliot, J. Adams, and F. C. Tortella
Delayed Treatment of Ischemia/Reperfusion Brain Injury: Extended Therapeutic Window with the Proteosome Inhibitor MLN519
Stroke, May 1, 2004; 35(5): 1186 - 1191.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
H. TERLAU and B. M. OLIVERA
Conus Venoms: A Rich Source of Novel Ion Channel-Targeted Peptides
Physiol Rev, January 1, 2004; 84(1): 41 - 68.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. J. Williams, X. M. Lu, B. Slusher, and F. C. Tortella
Electroencephalogram Analysis and Neuroprotective Profile of the N-Acetylated-alpha -Linked Acidic Dipeptidase Inhibitor, GPI5232, in Normal and Brain-Injured Rats
J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 48 - 57.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. C. Klein, M. Prorok, Z. Galdzicki, and F. J. Castellino
The Amino Acid Residue at Sequence Position 5 in the Conantokin Peptides Partially Governs Subunit-selective Antagonism of Recombinant N-Methyl-D-aspartate Receptors
J. Biol. Chem., July 13, 2001; 276(29): 26860 - 26867.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.