Multiple mechanisms underlying the neuroprotective effects of antiepileptic drugs against in vitro ischemia.
OBJECTIVE
The possible neuroprotective effects of classic and new antiepileptic drugs on the electrophysiological changes induced by in vitro ischemia on striatal neurons were investigated. In particular, the aim of the study was to correlate the putative neuroprotective effects with the action of these drugs on fast sodium (Na+) and high-voltage-activated (HVA) calcium (Ca2+) currents.


METHODS
Extracellular field potentials were recorded from rat corticostriatal brain-slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose and oxygen were omitted. Na+ and HVA Ca2+ currents were analyzed by whole-cell patch-clamp recordings from acutely isolated rat striatal neurons. Excitatory postsynaptic potential was measured following synaptic stimulation in corticostriatal slices by sharp intracellular microelectrodes.


RESULTS
Neuroprotection against in vitro ischemia was observed in slices treated with carbamazepine (CBZ), valproic acid (VPA), and topiramate (TPM), whereas it was not achieved by using levetiracetam (LEV). Fast Na+ conductances were inhibited by CBZ and TPM, whereas VPA and LEV showed no effect. HVA Ca2+ conductances were reduced by CBZ, TPM, and LEV. VPA had no effect on this current. All antiepileptic drugs induced a small reduction of excitatory postsynaptic potential amplitude at concentrations higher than 100 microm without changes of paired-pulse facilitation.


CONCLUSIONS
The concomitant inhibition of fast Na+ and HVA Ca2+ conductances is critically important for the neuroprotection, whereas the presynaptic inhibition on glutamate transmission does not seem to play a major role.
Clinica Neurologica, Università di Perugia, Ospedale Silvestrini, S. Andrea delle Fratte, Perugia, Italy.
Cinzia
C
Costa
Giuseppina
G
Martella
Barbara
B
Picconi
Chiara
C
Prosperetti
Antonio
A
Pisani
Massimiliano
M
Di Filippo
Francesco
F
Pisani
Giorgio
G
Bernardi
Paolo
P
Calabresi
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D051381:Rats; D000077236:Topiramate; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid; D011188:Potassium