title: Ionotropic glutamate receptors: still a target for neuroprotection in brain ischemia? Insights from in vitro studies.
abstract: Although experimental studies have widely shown that the pharmacological blockade of ionotropic glutamate receptors reduces ischemic damage, clinical trials with classical AMPA and NMDA glutamate receptor antagonists have provided negative results. To address the involvement of ionotropic glutamate receptors in ischemic damage, corticostriatal brain slices were prepared from adult rats. Extracellular recordings were performed in the striatum after stimulation of the glutamatergic corticostriatal fibres. In vitro ischemia was induced for a 10-min period by omitting oxygen and glucose from the external medium. Under control conditions, ischemia produced an irreversible loss of the corticostriatal field potential amplitude, AP5, a competitive NMDA receptor antagonist, induced a slight rescue of the potential, while ifenprodil, a positive modulator of the proton sensor of the NMDA receptors, allowed a complete recovery from the ischemic insult. Similar neuroprotection was achieved by utilizing either CNQX, a broad spectrum AMPA receptors antagonist, or Joro spider toxin, a selective blocker of calcium permeable AMPA receptors. Interestingly, while CNZX also fully suppressed physiological excitatory transmission, Joro spider toxin was ineffective on this parameter. Finally, lamotrigine and remacemide, two antiepileptic drugs that differentially affect excitatory transmission, exerted neuroprotective effects against ischemia. Noticeably, a combination of low concentrations of these two drugs exerted a stronger neuroprotection than a single drug given in isolation. Thus, it might be possible to reach a neuroprotective action by utilizing doses of these compounds low enough to avoid side effects. Our experimental data still support the idea that a negative modulation of excitatory transmission can be neuroprotective against ischemia. In addition, our findings support the concept that it is possible to produce a significant neuroprotective action in the absence of a relevant interference with normal synaptic transmission.
authors.affiliation: Dipartimento di Neuroscienze, Universitá di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. calabre@uniroma2.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Letizia M
authors.initials: LM
authors.lastname: Cupini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; C044936:JSTX spider toxin; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013111:Spider Venoms