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.