Stroke, Vol 24, 1063-1067, Copyright © 1993 by American Heart Association
MJ Leach, JH Swan, D Eisenthal, M Dopson and M Nobbs
BACKGROUND AND PURPOSE: The excitatory amino acid neurotransmitter
glutamate is involved in excitotoxic brain injury and neurodegeneration
after cerebral ischemia. Therefore, compounds that block the release of
glutamate may be useful as cerebroprotective agents. The purpose of this
study was to evaluate the cerebroprotective properties of a glutamate
release inhibitor, BW619C89. METHODS: In the studies reported here, the
effect of BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-
(2,3,5-trichlorophenyl)pyrimidine] on neurotransmitter release (endogenous
amino acids, gamma-aminobutyric acid, and acetylcholine) from slices of rat
brain cerebral cortex in vitro has been determined. The neuroprotective
efficacy of BW619C89 has been evaluated using the middle cerebral artery
occlusion model of focal cerebral ischemia in the Fischer 344 rat. RESULTS:
In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-)
evoked release of both endogenous glutamate and aspartate from rat cerebral
cortex slices with IC50 values of approximately 5 microM. BW619C89 was
approximately 10- fold less potent to inhibit veratrine-evoked
3H-gamma-aminobutyric acid release (IC50 = 51 microM), fourfold less potent
to inhibit 3H- acetylcholine release (IC50 = 21 microM), and at 10 microM
had only weak activity at excitatory amino acid (N-methyl-D-aspartate,
kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
binding sites. When administered intravenously to Fischer 344 rats 5
minutes after permanent middle cerebral artery occlusion, BW619C89 produced
marked reductions of both total (cortex and basal ganglia) and cortical
infarct volumes. Cortical infarct size was reduced by 20% at a dose of
BW619C89 of 5 mg/kg (n = 6, not significant); 43% at 10 mg/kg (n = 8, P
< .01); 59% at 20 mg/kg (n = 8, P < .001); 61% at 30 mg/kg (n = 8, P
< .001), and 53% at 40 mg/kg (n = 8, P < .001). BW619C89 at doses of
20 and 30 mg/kg also significantly reduced noncortical (basal ganglia)
infarct volumes, demonstrating that a proportion of this tissue also
appears to be salvageable. Behavioral effects observed were dose related,
generally minor, and at doses of 20 mg/kg IV and above consisted of body
tremor and mild ataxia lasting approximately 2 hours. CONCLUSIONS: These
results suggest that glutamate release inhibitors such as BW619C89 may
provide an alternative to excitatory amino acid receptor antagonists in the
treatment of focal cerebral ischemia and stroke.
ARTICLES
BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, England, UK.
This article has been cited by other articles:
 |
|
 |
|
  Y. Tanaka, Y. Tozuka, T. Takata, N. Shimazu, N. Matsumura, A. Ohta, and T. Hisatsune Excitatory GABAergic Activation of Cortical Dividing Glial Cells Cereb Cortex, September 1, 2009; 19(9): 2181 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 References PsychiatryOnline CME, May 1, 2007; 2007(1): 2 - 2. [Full Text]
|
|
|
|
 |
|
 Y. Chen, C. Ruetzler, S. Pandipati, M. Spatz, R. M. McCarron, K. Becker, and J. M. Hallenbeck Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury PNAS, December 9, 2003; 100(25): 15107 - 15112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Yarov-Yarovoy, J. C. McPhee, D. Idsvoog, C. Pate, T. Scheuer, and W. A. Catterall Role of Amino Acid Residues in Transmembrane Segments IS6 and IIS6 of the Na+ Channel alpha Subunit in Voltage-dependent Gating and Drug Block J. Biol. Chem., September 13, 2002; 277(38): 35393 - 35401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Shim, Adityanjee, J. W. Olney, J. W. Newcomer, and N. B. Farber Is NMDA Receptor Hypofunction in Schizophrenia Associated With a Primary Hyperglutamatergic State? Arch Gen Psychiatry, May 1, 2002; 59(5): 466 - 468. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Furuya, H. Takeda, S. Azhar, R. M. McCarron, Y. Chen, C. A. Ruetzler, K. M. Wolcott, T. J. DeGraba, R. Rothlein, T. E. Hugli, et al. Examination of Several Potential Mechanisms for the Negative Outcome in a Clinical Stroke Trial of Enlimomab, a Murine Anti-Human Intercellular Adhesion Molecule-1 Antibody: A Bedside-to-Bench Study Stroke, November 1, 2001; 32(11): 2665 - 2674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Anand, D. S. Charney, D. A. Oren, R. M. Berman, X. S. Hu, A. Cappiello, and J. H. Krystal Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine: Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists Arch Gen Psychiatry, March 1, 2000; 57(3): 270 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Melani, L. Pantoni, C. Corsi, L. Bianchi, A. Monopoli, R. Bertorelli, G. Pepeu, F. Pedata, and D. K. J. E. von Lubitz Striatal Outflow of Adenosine, Excitatory Amino Acids, {gamma}-Aminobutyric Acid, and Taurine in Awake Freely Moving Rats After Middle Cerebral Artery Occlusion : Correlations With Neurological Deficit and Histopathological Damage • Editorial Comment: Correlations With Neurological Deficit and Histopathological Damage Stroke, November 1, 1999; 30(11): 2448 - 2455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Davis and D. Barer Neuroprotection in acute ischaemic stroke. II: Clinical potential Vascular Medicine, August 1, 1999; 4(3): 149 - 163. [Abstract] [PDF]
|
|
|
|
|
|
R. C. Crumrine, K. Bergstrand, A. T. Cooper, W. L. Faison, and B. R. Cooper Lamotrigine Protects Hippocampal CA1 Neurons From Ischemic Damage After Cardiac Arrest Stroke, November 1, 1997; 28(11): 2230 - 2237. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. D. Teng and J. R. Wrathall Local Blockade of Sodium Channels by Tetrodotoxin Ameliorates Tissue Loss and Long-Term Functional Deficits Resulting from Experimental Spinal Cord Injury J. Neurosci., June 1, 1997; 17(11): 4359 - 4366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Ginsberg REVIEW {blacksquare} : Neuroprotection in Brain Ischemia: An Update (Part I Neuroscientist, March 1, 1995; 1(2): 95 - 103. [Abstract] [PDF]
|
|
|
|
|
|
K. W. Muir and K. R. Lees Clinical Experience With Excitatory Amino Acid Antagonist Drugs Stroke, March 1, 1995; 26(3): 503 - 513. [Abstract] [Full Text]
|
|
|
|
|
|
S. E. Smith and B. S. Meldrum Cerebroprotective Effect of Lamotrigine After Focal Ischemia in Rats Stroke, January 1, 1995; 26(1): 117 - 122. [Abstract] [Full Text]
|
|