Is pharmacological neuroprotection dependent on reduced glutamate release?

• Published in: Stroke (1970) 2000-03, Vol.31 (3), p.766-773
• Main Authors: Calabresi, P, Picconi, B, Saulle, E, Centonze, D, Hainsworth, A H, Bernardi, G
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Brain Ischemia - physiopathology; Cerebral Cortex - blood supply; Corpus Striatum - blood supply; Excitatory Postsynaptic Potentials - drug effects; Glutamic Acid - metabolism; In Vitro Techniques; L-Lactate Dehydrogenase - metabolism; Neuroprotective Agents - pharmacology; Rats; Rats, Wistar; Receptors, Glutamate - physiology; Receptors, Neurotransmitter - agonists
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.str.31.3.766

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. 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). 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 micromol/L 6-cyano-7-nitroquinoxaline-2,3-dione (an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] receptor antagonist) allowed a significant recovery of the field potential amplitude (P0.05, 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