Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction

Cinzia Costa, Alessandro Tozzi, Elisa Luchetti, Sabrina Siliquini, Vincenzo Belcastro, Michela Tantucci, Barbara Picconi, Riccardo Ientile, Paolo Calabresi, Francesco Pisani

Research output: Contribution to journalArticle

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 μM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC 50 value of 32.5 μM. 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 μM) 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.

Original languageEnglish
Pages (from-to)217-224
Number of pages8
JournalExperimental Neurology
Volume221
Issue number1
DOIs
Publication statusPublished - Jan 2010

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Keywords

  • Electrophysiology
  • GABA
  • Neuroprotection
  • Parkinson's disease
  • Rotenone
  • Striatum
  • Zonisamide

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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