Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction.
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.
Costa
Cinzia
C
Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
Tozzi
Alessandro
A
Luchetti
Elisa
E
Siliquini
Sabrina
S
Belcastro
Vincenzo
V
Tantucci
Michela
M
Picconi
Barbara
B
Ientile
Riccardo
R
Calabresi
Paolo
P
Pisani
Francesco
F
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
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