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(Stroke. 2006;37:1319.)
© 2006 American Heart Association, Inc.

Original Contributions

Multiple Mechanisms Underlying the Neuroprotective Effects of Antiepileptic Drugs Against In Vitro Ischemia

Cinzia Costa, MD; Giuseppina Martella, PhD; Barbara Picconi, PhD; Chiara Prosperetti, MD; Antonio Pisani, MD; Massimiliano Di Filippo, MD; Francesco Pisani, MD; Giorgio Bernardi, MD Paolo Calabresi, MD

From the Clinica Neurologica, Università di Perugia, Ospedale Silvestrini, S. Andrea delle Fratte, Perugia, Italy and Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy (P.C., C.C., M.d.F.); Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma, Tor Vergata; IRCCS Fondazione Santa Lucia, Rome, Italy (G.B., G.M., B.P., A.P., C.P.); and the Dipartimento di Neuroscienze, Psichiatria e Anestesiologia Università di Messina (F.P.), Messina, Italy.

Correspondence to Dr Paolo Calabresi, Clinica Neurologica, Università di Perugia, Ospedale Silvestrini, S. Andrea delle Fratte, 06156, Perugia, Italy. E-mail calabre{at}unipg.it

Background and Purpose— 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 µm 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.

Key Words: antiepileptic drugs • Ca²⁺ • electrophysiology • ischemia • Na²⁺

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