[(S)-Alpha-Phenyl-2-Pyridine-Ethanamine Dihydrochloride], A Low Affinity Uncompetitive N-Methyl-d-Aspartic Acid Antagonist, Is Effective in Rodent Models of Global and Focal Ischemia1
- Edward F. Cregan1,
- James Peeling2,
- Dale Corbett3,
- Alastair M. Buchan5,
- John Saunders4,
- Roland N. Auer5,
- M. Gao5,
- Dennis J. Mccarthy1,
- Mark S. Eisman1,
- T. Mark Campbell2,
- Robert J. Murray1,
- Mary L. Stagnitto1 and
- Gene C. Palmer1
- 1Astra Arcus USA, Rochester, New York (E.F.C., D.J.M., M.S.E., R.J.M., M.L.S., G.C.P.); 2Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E OW3 Canada (J.P., T.M.C.); 3Basic Medical Sciences, Faculty of Medicine, Memorial University, St. John’s, Newfoundland A1B 3V6 Canada (D.C.); 4Institute for Biodiagnostics, National Research Council Canada, Winnipeg, Manitoba R3B 1Y6 (J.S.) and 5Clinical Neurosciences and Neuropathology, University of Calgary, Foothills Hospital, Calgary, Alberta T2N 4N1 Canada (A.M.B., R.N.A., M.G.)
Abstract
[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-d-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30–42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia
Footnotes
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Send reprint requests to: Dr. Gene C. Palmer, Astra Arcus USA, P.O. Box 20890, Rochester, NY 14602.
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↵1 This work was supported by the “Astra/Canada Neurodegenerative Network” collaborative research program, Astra Pharma Inc, Mississauga, Ontario, Canada.
- Abbreviations:
- ANOVA
- analysis of variance
- ARL 15896AR
- [(S)-alpha-phenyl-2-pyridine-ethanamine dihydrochloride]
- AUC
- area under the curve
- b.i.d.
- twice a day dosing
- CBF
- cerebral blood flow
- Cmax, maximal plasma concentration
- H & E, hematoxylin and eosin
- MCA
- middle cerebral artery
- MCAO
- middle cerebral artery occlusion
- MRI
- magnetic resonance imaging
- NMDA
- N-methyl-d-aspartic acid
- SHR
- spontaneously hypertensive rat
- t1/2, plasma half life
- Tmax, time to peak plasma concentration
- V/f
- volume of distribution/fraction absorbed
- 2-VO
- 2-vessel occlusion
- 4-VO
- 4-vessel occlusion
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- Received January 22, 1997.
- Accepted July 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
