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 language | English |
|---|---|
| Pages (from-to) | 217-224 |
| Number of pages | 8 |
| Journal | Experimental Neurology |
| Volume | 221 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2010 |
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Keywords
- Electrophysiology
- GABA
- Neuroprotection
- Parkinson's disease
- Rotenone
- Striatum
- Zonisamide
ASJC Scopus subject areas
- Neurology
- Developmental Neuroscience
Cite this
Electrophysiological actions of zonisamide on striatal neurons : Selective neuroprotection against complex I mitochondrial dysfunction. / Costa, Cinzia; Tozzi, Alessandro; Luchetti, Elisa; Siliquini, Sabrina; Belcastro, Vincenzo; Tantucci, Michela; Picconi, Barbara; Ientile, Riccardo; Calabresi, Paolo; Pisani, Francesco.
In: Experimental Neurology, Vol. 221, No. 1, 01.2010, p. 217-224.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Electrophysiological actions of zonisamide on striatal neurons
T2 - Selective neuroprotection against complex I mitochondrial dysfunction
AU - Costa, Cinzia
AU - Tozzi, Alessandro
AU - Luchetti, Elisa
AU - Siliquini, Sabrina
AU - Belcastro, Vincenzo
AU - Tantucci, Michela
AU - Picconi, Barbara
AU - Ientile, Riccardo
AU - Calabresi, Paolo
AU - Pisani, Francesco
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
KW - Electrophysiology
KW - GABA
KW - Neuroprotection
KW - Parkinson's disease
KW - Rotenone
KW - Striatum
KW - Zonisamide
UR - http://www.scopus.com/inward/record.url?scp=72749097853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=72749097853&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2009.11.002
DO - 10.1016/j.expneurol.2009.11.002
M3 - Article
C2 - 19913015
AN - SCOPUS:72749097853
VL - 221
SP - 217
EP - 224
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
IS - 1
ER -