title: Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction.
abstract: Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC(50) value of 16.38 microM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC(50) value of 32.5 microM. Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 microM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity. Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.
authors.affiliation: Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Elisa
authors.initials: E
authors.lastname: Luchetti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Siliquini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Belcastro
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ientile
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000494:pharmacology; D000078305:Zonisamide
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D007555:Isoxazoles; D009574:Nitro Compounds; D011422:Propionates; D014475:Uncoupling Agents; D012402:Rotenone; D018698:Glutamic Acid; D000078305:Zonisamide; D005947:Glucose; C015392:3-nitropropionic acid; D001640:Bicuculline