(Stroke. 2000;31:766.)
© 2000 American Heart Association, Inc.
Original Contributions |
Is Pharmacological Neuroprotection Dependent on Reduced Glutamate Release?
From Clinica Neurologica (P.C., B.P., E.S., D.C., G.B.), Dipartimiento Neuroscienze, Università di Tor Vergata, Rome, Italy; I.R.C.C.S. Ospedale S. Lucia (D.C., G.B.), Rome, Italy; and the School of Pharmacy (A.H.H.), DeMontfort University, Leicester, UK.
Correspondence to Dr Paolo Calabresi, Clinica Neurologica, Dip. Neuroscienze, Universita’ di Tor Vergata, via di Tor Vergata, 00133 Rome, Italy. E-mail calabre{at}uniroma2.it
Background and Purpose—The aim of this study was to determinate the possible role of the ionotropic glutamate receptor in the expression of irreversible electrophysiological changes induced by in vitro ischemia and to test whether the neuroprotective action of various neurotransmitter agonists and drugs of clinical interest is related to a presynaptic inhibitory action at glutamatergic synapses.
Methods—Intracellular and extracellular recordings have been performed in a rat corticostriatal slice preparation. Different pharmacological compounds have been tested on corticostriatal glutamatergic transmission in control conditions and in an in vitro model of ischemia (oxygen and glucose deprivation).
Results—In vitro ischemia lasting 10 minutes produced an
irreversible loss of the field potential recorded from striatal
slices after cortical stimulation. Preincubation of the slices with
3 µmol/L 6-cyano-7-nitroquinoxaline-2,3-dione (an
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
[AMPA] receptor antagonist) allowed a significant
recovery of the field potential amplitude (P<0.05,
n=6), whereas incubation with 30 µmol/L aminophosphonovaleric
acid (an N-methyl-D-aspartate receptor
antagonist) did not produce a significant recovery after 10
minutes of ischemia (P>0.05, n=7). Bath
application of 3 mmol/L glutamate for 5 minutes produced a
complete but reversible inhibition of the field potential amplitude.
When a similar application was coupled with a brief period of
ischemia (5 minutes), which produced, per se, only a transient
inhibition of the field potential, it caused an irreversible loss of
this parameter. We also tested the possible neuroprotective
effect of neurotransmitter agonists reducing the release of glutamate
from corticostriatal terminals. Agonists acting on purinergic
(adenosine), muscarinic (oxotremorine), and metabotropic
glutamate receptors (L-serine o-phosphate
[L-SOP]) significantly (P<0.001, n=8 for each
agonist) reduced glutamatergic synaptic potentials, with each showing
different potencies. The EC50 was 26.4 µmol/L for
adenosine, 0.08 µmol/L for oxotremorine, and 0.89
µmol/L for L-SOP. Concentrations of these agonists producing the
maximal inhibition of the synaptic potential were tested on the
ischemia-induced irreversible loss of field potential.
Adenosine (P<0.05, n=9) and oxotremorine
(P<0.05, n=8) showed significant neuroprotective
action, whereas L-SOP was ineffective (P>0.05, n=10).
Similarly, putative neuroprotective drugs significantly
(P<0.001, n=10 for each drug) reduced the amplitude of
corticostriatal potential, with different EC50 values
(phenytoin, 33.5 µmol/L; gabapentin, 96.8 µmol/L;
lamotrigine, 26.7 µmol/L; riluzole, 6 µmol/L; and
sipatrigine, 2 µmol/L). Concentration of these drugs producing
maximal inhibition of the amplitude of corticostriatal potentials
showed a differential neuroprotective action on the ischemic
electrical damage. Phenytoin (P<0.05, n=10),
lamotrigine (P<0.05, n=10), riluzole
(P<0.05, n=9), and sipatrigine
(P<0.001, n=10) produced a significant neuroprotection,
whereas gabapentin (P>0.05, n=11) was ineffective. The
neuroprotective action of transmitter agonists and clinical drugs was
not related to their ability in decreasing glutamate release, as
detected by changes in the paired-pulse facilitation protocol.
Conclusions—Ionotropic glutamate receptors, and particularly AMPA-like receptors, play a role in the irreversible loss of field potential amplitude induced by ischemia in the striatum. Drugs acting by reducing glutamatergic corticostriatal transmission may show a neuroprotective effect. However, their efficacy does not seem to be directly related to their capability to decrease glutamate release from corticostriatal terminals. We suggest that additional modulatory actions on voltage-dependent conductances and on ischemia-induced ion distribution at the postsynaptic site may also exert a crucial role.
Editorial Comment
Cardiovascular Sciences, DuPont Pharmaceuticals Co, Wilmington, Delaware
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