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NEUROPHARMACOLOGY
Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, Laboratory of Experimental Neurology (M.G., M.L.C., E.G., G.B., N.B.M., N.B.) and Department of Neuroscience, University of Rome "Tor Vergata" (G.B., N.B.M.), Rome, Italy
Received March 5, 2007; accepted May 10, 2007.
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Abstract |
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; Ditzler, 1991; Sonkusare et al., 2005; Chen and Lipton, 2006; Volbracht et al., 2006). Its mechanism of action resides on the ability of memantine to bind N-methyl-D-aspartate (NMDA) receptors in a noncompetitive manner, acting as a low-affinity open-channel blocker (Lipton, 2004, 2006). Because of its peculiar pharmacological properties, memantine is proposed to be beneficial because it blocks excessive NMDA receptor activation without interfering with its physiological activity. In doing so, it is a well tolerated NMDA receptor antagonist able to reduce or prevent excitotoxic damage without producing undesired side effects, such as hallucination, agitation, catatonia, centrally mediated increase in blood pressure, and anesthesia, typical of other NMDA receptor antagonists.
Although NMDA receptors constitute the main target of memantine, other mechanisms of action have been reported, including reduced action potential firing in cultured neurons (Netzer and Bigalke, 1990) and block of 5-HT3 receptors (Reiser et al., 1988; Rammes et al., 2001) and nicotinic receptors (Maskell et al., 2003; Aracava et al., 2005). These results suggest the presence of additional mechanisms of action whose relative importance may be dependent on the brain area under investigation.
An antiparkinsonian activity has been described for memantine in animal models of Parkinson's disease and in parkinsonian patients (Danysz et al., 1997; Merello et al., 1999). In addition, memantine prevents cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Lange et al., 1997; Kucheryanu and Kryzhanovskii, 2000). Therefore, we focused our attention on the action of this drug on the dopamine neurons of the substantia nigra pars compacta (SNc), whose progressive degeneration is a hallmark of Parkinson's disease. Indeed, several lines of evidence indicate an overstimulation of glutamate receptors, especially of the NMDA subtype, as the main cause of the progressive loss of this neuronal population (Gardoni and Di Luca, 2006); thus, NMDA receptor antagonism by memantine in the SNc is expected to represent the main mechanism underlying its neuroprotective action. Accordingly, we now present evidence that memantine is effective in reducing NMDA-mediated currents of the dopamine neurons; however, we also show a novel mechanism of action of this drug, consisting of the ability to reduce ATP-sensitive potassium (KATP) conductances, opened in conditions of metabolic stress.
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Materials and Methods |
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Patch-Clamp Recordings. An individual slice was placed in a recording chamber on the stage of an upright microscope (Axioscope FS, Carl Zeiss Spa, Arese, Italy) and submerged in a continuously flowing (2.5 ml/min) solution at 33°C (±0.2°C). Neurons were visualized with infrared video microscopy (Hamamatsu Photonics Italia Srl, Milan, Italy). Borosilicate glass electrodes (3–4 M
) were filled with 135 mM potassium gluconate, 10 mM KCl, 2 mM MgCl2, 0.045 mM CaCl2, 0.1 mM EGTA, 10 mM HEPES, 2 mM ATP, and 0.3 mM GTP (pH 7.3, with KOH). In experiments with high calcium buffer, EGTA concentration was increased to 10 mM and CaCl2 was increased to 4 mM, whereas potassium gluconate was reduced to 115 mM. In experiments with high ATP, the filling solution was the same as the control solution but with 10 mM ATP. Whole-cell voltage-clamp (–60 mV holding potential) or current-clamp experiments were carried out with a MultiClamp 700A amplifier (Molecular Devices, Sunnyvale, CA), filtered at 1 kHz, and digitized at 10 kHz. Dopamine neurons were identified electrophysiologically based on a prominent Ih in response to hyperpolarizing voltage steps and a voltage sag when negative current steps were applied in currentclamp mode (Grillner and Mercuri, 2002). Data are expressed as mean ± S.E.M. and compared using the Student's t test, with p < 0.05 as minimal level for significance.
Pressure-applied NMDA (10 psi, 0.5–1.0 s) was used to obtain NMDA-mediated inward currents (INMDA) through a patch electrode filled with NMDA (100 µM) dissolved in ACSF and connected to a Pneumatic Pico-pump PV 800 (WPI, Berlin, Germany). The puff electrode was positioned above the slice in close proximity to the recorded neuron. Hypoxic insults were obtained by exposing the slices for 2 to 3 min to ACSF saturated with 95% N2/5% CO2.
Multielectrode Recordings. Individual slices were placed over an 8 x 8 array of planar microelectrodes, each 20 x 20 µm in size, with an interpolar distance of 100 µm (MED-P2105; Matsushita Electric Industrial Co., Ltd., Kadoma, Japan). Slices were submerged under a nylon mesh and positioned over the multielectrode array under visual control through an upright microscope (Leica DM-LFS; Leica Microsystems, Wetzlar, Germany) in such a way that the area close to the medial terminal nucleus of the accessory optic tract covered most of the electrodes (Geracitano et al., 2005). Extracellular signals were acquired using the Panasonic MED64 System (Alpha MED Sciences, Kadoma, Japan). Signals were low-cut filtered at 100 Hz and digitized at 20 kHz with a 6071E Data Acquisition Card (National Instruments, Austin, TX) using the MED64 Conductor Software (Alpha MED Sciences). The frequency of the fast transients corresponding to spontaneous action potentials was calculated off-line with Spike2 software (Cambridge Electronic Design Ltd, Cambridge, UK) using an amplitude threshold adjusted by visual inspection in each individual active channel. Spikes recorded by a single channel could differ in shape and amplitude, reflecting spontaneous action potentials arising from more than one neuron; therefore, spike-sorting discrimination of multiunit responses was achieved by generating spike templates with Spike2 (Cambridge Electronic Design Ltd) sorted with a normal mixtures algorithm on independent clusters obtained from principal component data.
On average, we detected spikes from 34.6 ± 1.5 active channels in each midbrain slice (n = 14); however, following the spike-sorting procedure, activity arising from 82.7 ± 3.6 cells/slice could be obtained. Because dopamine neurons of the SNc are selectively hyperpolarized by dopamine (Grillner and Mercuri, 2002), we used sensitivity to dopamine (30 µM) as a criterion to discriminate spikes originating from this neuronal population. Of the total number of cells, 43.4 ± 2.0 cells/slice met this pharmacological criterion and was considered for further analysis. Hypoglycemic conditions were obtained by perfusing the slices in ACSF containing 1 mM glucose for 25 to 30 min before challenge with memantine or tolbutamide (Figs. 6 and 7). This procedure caused an overall reduction of firing frequency in the dopamine cell population, and a complete loss of activity occurred in some of them. Only the dopamine cells whose firing could still be detected during the experimental session in hypoglycemia were considered to evaluate the effects of memantine or tolbutamide.
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Results |
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NMDA Receptor-Independent Increase of Dopamine Neuron Firing Rate by Memantine. We then investigated the effects of memantine on dopamine neuron firing properties. Neurons were recorded in current-clamp mode to detect their typical spontaneous tonic action potential discharge (Grillner and Mercuri, 2002). We found that memantine on its own was capable of increasing the basal firing frequency of the recorded neurons. At 30 µM, memantine reversibly increased the firing frequency from 1.1 ± 0.2 to 2.0 ± 0.3 Hz (p < 0.002 paired t test, n = 11) (Fig. 2A). At higher concentration (100 µM), memantine increased the firing rate from 1.4 ± 0.1 to 3.2 ± 0.3 Hz (p < 0.001 paired t test, n = 21) (Fig. 2, A and D), and in 12 cells it transformed their typical tonic firing into rhythmic bursts of action potentials (Fig. 2B).
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To examine whether this effect of memantine could be because of reduction of tonic NMDA receptor stimulation within the neuronal circuitry, we repeated the same experiments in the presence of 10 µM MK-801 or 50 µM AP5; however, both of these NMDA receptor antagonists did not mimic or prevent the effects of 100 µM memantine on dopamine neuron firing (Fig. 2, C and D).
Memantine has also been reported to act as an antagonist of 5-HT3 and 
7-containing nicotinic receptors (Reiser et al., 1988; Rammes et al., 2001; Maskell et al., 2003; Aracava et al., 2005); however, in the presence of the 5-HT3 receptor antagonist mirtazapine (100 µM) and the 7-containing nicotinic receptor antagonist methyllycaconitine (10 nM), memantine (100 µM) still produced a significant increase in dopamine neuron firing rate (Fig. 2D).
No Effect of Memantine in Multielectrode Recordings of Dopamine Neuron Firing Rate. We then tried to corroborate these results using a less invasive technique of spontaneous firing recording in the same midbrain slice preparation, consisting of single unit's detection from an 8 x 8 array of planar electrodes (Geracitano et al., 2005). Because dopamine neurons of the SNc are selectively hyperpolarized by dopamine (Grillner and Mercuri, 2002), spikes originating from dopamine neurons were identified based on their sensitivity to brief (30–60 s) exposure to 30 µM dopamine. Using this pharmacological criterion, we recorded the spontaneous firing arising from 302 presumed dopamine neurons from six midbrain slices. Their basal firing rate was 2.08 ± 0.10 Hz, and no significant alteration in spontaneous firing was observed following 100 µM memantine perfusion (2.05 ± 0.01 Hz in memantine, p > 0.27 paired t test) (Fig. 3).
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We first increased the calcium buffering properties of the patch-clamp electrode filling solution using high (10 mM) EGTA; however, 100 µM memantine still increased the neuronal firing (n = 3; data not shown). In contrast, when the dopamine neurons were recorded with high (10 mM) intracellular ATP, no significant change in their firing rate was observed in 100 µM memantine (from 1.6 ± 0.2 to 1.7 ± 0.2 Hz in memantine; n = 8, p > 0.2 paired t test) (Fig. 4, A and C).
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; Guatteo et al., 1998; Marinelli et al., 2000; Liss et al., 2005). Thus, we hypothesized that memantine depolarized the dopamine neurons by blocking KATP channels, partially opened in neurons recorded using a standard 2 mM ATP filling solution. In agreement with this hypothesis, we found that perfusion with the KATP channel antagonist tolbutamide (300 µM) did not change the firing rate of dopamine neurons recorded with 10 mM intracellular ATP (from 1.7 ± 0.1 to 1.6 ± 0.1 Hz in tolbutamide; n = 9, p > 0.3 paired t test), whereas it increased the firing rate of neurons recorded using 2 mM ATP (from 1.3 ± 0.2 to 2.5 ± 0.3 Hz in tolbutamide, p < 0.01 paired t test, n = 6) (Fig. 4C). Moreover, in the same neurons, no further increase in the frequency of action potential discharge was observed when 100 µM memantine was added in the continuous presence of tolbutamide (2.5 ± 0.3 Hz in tolbutamide and memantine; p > 0.54 paired t test, n = 6) (Fig. 4, B and C).
Memantine Reduces KATP-Mediated Outward Currents Induced by Hypoxia. The previous experiments strongly suggest that memantine reduces the opening of tolbutamide-sensitive KATP channels. To further confirm this hypothesis, we directly tested the involvement of KATP conductances by briefly exposing the slice (2–3 min) to a hypoxic medium. These experiments were performed in the continuous presence of 10 µM MK-801 to rule out indirect actions through NMDA receptors. As previously shown (Guatteo et al., 1998), this experimental protocol induces the development of a KATP-dependent outward current in dopamine neurons recorded in voltage-clamp mode. As shown in Fig. 5, bath perfusion of 30 µM memantine reversibly reduced hypoxia-induced outward current (IHYPO) to 73.6 ± 3.8% of control (n = 12). Increasing the memantine concentration to 100 µM produced further inhibition of IHYPO to 47.9 ± 3.6% of control (n = 11). Moreover, IHYPO was abolished by tolbutamide (300 µM, n = 4), thus confirming an effect of memantine on KATP conductances.
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Multielectrode Recordings of Firing Rate Increase in Hypoglycemic Conditions. Exposure of the dopamine neurons to a hypoglycemic medium inhibits SNc dopamine neurons through activation of KATP channels (Marinelli et al., 2000). Therefore, we tested whether the spontaneous firing rate of dopamine neurons recorded with the multielectrode system could be increased by memantine in hypoglycemic conditions. To avoid an excessive metabolic stress, we perfused the slices in 1 mM glucose, a threshold dose for dopamine neuron hyperpolarization (Marinelli et al., 2000). As shown in Fig. 6, when the recordings were obtained in ACSF containing 1 mM glucose, a low overall firing rate was detected (compare with Fig. 3). In these experimental conditions, 100 µM memantine reversibly increased the firing rate of presumed dopamine neurons. When glucose was increased to 2 mM in the same slice, the overall firing rate increased, and 100 µM memantine became ineffective, in accordance with what was previously observed in normoglycemic conditions (Fig. 3). Similar results were obtained from 47 presumed dopamine neurons from four midbrain slices perfused in 1 mM glucose. Their basal firing rate increased from 0.37 ± 0.09 to 1.51 ± 0.28 Hz (p < 0.0001 paired t test) in 100 µM memantine.
In accordance with the hypothesis of an involvement of KATP channels, we found that 300 µM tolbutamide increased the spontaneous firing rate in hypoglycemic conditions, and no further increase was induced by 100 µM memantine (Fig. 7). When glucose was increased to 10 mM in the same slice, the overall firing rate increased, and 300 µM tolbutamide became ineffective (Fig. 7). In 74 presumed dopamine neurons recorded from four midbrain slices perfused in 1 mM glucose, 300 µM tolbutamide increased their firing rate from 0.51 ± 0.05 to 1.72 ± 0.12 Hz (p < 0.0001 paired t test). Exposure to 100 µM memantine in hypoglycemia and tolbutamide did not produce a further increase in firing rate (1.56 ± 0.11 Hz).
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Discussion |
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Three lines of evidence point at this conclusion. First, we have shown that action potential discharge of the dopamine neurons increased in frequency on memantine perfusion in dopamine neurons recorded using the patch-clamp whole-cell technique. This effect was evident when the internal patch-clamp electrode solution contained 2 mM ATP, whereas under high (10 mM) internal ATP, memantine was ineffective. During whole-cell recordings, ATP internal concentration is largely imposed by the filling solution composition; thus, the concentration of ATP in the patch-clamp electrode greatly affects the degree of KATP channel opening in response to metabolic stress. For example, previous experiments from our laboratory have shown that dopamine neurons exposed to a hypoxic medium develop a KATP-dependent current only when they are recorded with 2 mM ATP in the patch-clamp electrode solution, whereas no KATP outward current is induced by hypoxia if internal ATP is set to 10 mM (Guatteo et al., 1998). On this basis, we hypothesized that memantine increased the firing rate of dopamine neurons recorded in whole-cell conditions by closing KATP channels partially open under 2 mM internal ATP. This hypothesis was confirmed by the observation that the KATP channel antagonist tolbutamide produced an analogous increase in the firing rate of dopamine neurons recorded with 2 mM internal ATP, whereas the same antagonist was ineffective when intracellular ATP was set to 10 mM. Moreover, the frequency increase induced by tolbutamide in 2 mM ATP occluded any additional increase by memantine.
The second point supporting our hypothesis derives from experiments conducted using the noninvasive, extracellular 8 x 8 planar multielectrode device. Presumed dopamine neurons, identified based on their sensitivity to exogenously applied dopamine, were insensitive to memantine in control experimental conditions. However, memantine markedly increased the dopamine neuron firing rate in slices perfused in 1 mM glucose ACSF instead of 10 mM. Previous experiments from our laboratory showed that 1 mM glucose is a threshold hypoglycemic condition for the development of a KATP-dependent hyperpolarization in dopamine neurons of the SNc (Marinelli et al., 2000). Conceivably, the reduced basal firing rate in 1 mM glucose, compared with controls, was caused by a more hyperpolarized state of the dopamine neuronal population because of the opening of KATP conductances in 1 mM glucose. Thus, memantine increased dopamine neuron firing rate by closing these constitutively open KATP channels. This hypothesis was confirmed by the observation that the KATP channel antagonist tolbutamide mimicked the effects of memantine and occluded additional increase in the firing rate by memantine in hypoglycemia. Both memantine and tolbutamide were ineffective under higher glucose concentration because no tonic KATP-dependent current was present in these conditions.
Indeed, these experiments also suggest that the tonic activation KATP conductance observed in our patch-clamp whole-cell recordings, using 2 mM internal ATP, is a nonphysiological phenomenon because no such tonic KATP current seems to be evident using the less invasive multielectrode extracellular technique.
Finally, the third, more direct, piece of evidence of memantine effects on KATP conductances derives from our experiments using brief exposures of the dopamine neurons to hypoxia. Dopamine neurons respond to oxygen deprivation with an early hyperpolarization, largely because of the opening of KATP channels (Mercuri et al., 1994; Guatteo et al., 1998; Geracitano et al., 2005). Memantine reversibly reduced this tolbutamide-sensitive outward current, even in the presence the open-channel NMDA receptor antagonist MK-801, thus ruling out any possible indirect effect through inhibition of NMDA receptors.
As shown in Fig. 2, memantine not only increased the firing rate of the dopamine neurons but also changed occasionally their firing mode from tonic to bursting behavior. This change in the firing pattern may have important functional implications because burst firing of the dopamine neurons has been associated with increased release of dopamine in the areas of nigral projection (Gonon and Buda, 1985; Suaud-Chagny et al., 1992; Floresco et al., 2003; Phillips et al., 2003). However, such a change was observed using high doses of memantine, and more importantly we never observed burst firing in neurons recorded using the extracellular multielectrode technique. Probably burst generation by memantine is linked to some unspecific effect, amplified by a more invasive technique like whole-cell patch-clamp recording. However, we cannot exclude the possibility that this burst-inducing effect of memantine emerges under more complex pathological alterations of the intracellular composition, somehow mimicked in our patch-clamp recording conditions.
Clinical Relevance. A question arising from our experimental observation is whether the above effects, obtained from dopamine neurons recorded in an in vitro slice preparation, also occur in patients under memantine treatment. According to in vivo measurements, treatment with a standard 20-mg daily dose of memantine should result in a steady-state brain level of this drug approaching the low micromolar range (Hesselink et al., 1999; Danysz et al., 2000); therefore, it is suggested that results obtained using higher concentrations may reflect unspecific and nonclinically relevant effects (Chen and Lipton, 2006). However, attention should be given to the limiting factor offered in a slice preparation by the need of the drug to diffuse within the brain tissue during a relatively short time of bath perfusion. Consequently, the effective concentration of the drug reaching the neuronal membranes is not the same as that of the extracellular medium. Indeed, an almost complete block of NMDA receptor-mediated responses can be achieved in isolated cell cultures at concentrations of memantine close to 10 µM (Chen et al., 1992), whereas in our brain slice preparation, inhibition of NMDA receptor-mediated responses hardly exceeded 50% at 30 µM memantine or 75% at a concentration of 100 µM (Fig. 1B). This difference supports the clinical relevance of our present results, as they should be compared with those obtained on isolated neurons using lower concentrations of memantine. In addition, we have also shown that the effects of 100 µM memantine were completely prevented in patch-clamp recordings obtained with a 10 mM ATP filling solution, and the same concentration of memantine did not modify the firing rate of the dopamine neurons using the multielectrode device in normoglycemic conditions. Both of these observations rule out unspecific effects simply caused by a high dose of memantine.
Memantine and Parkinson's Disease. According to our observations, memantine does not affect the basal firing activity of the dopamine neurons in physiological conditions, whereas in conditions of metabolic stress, a significant effect of memantine emerges, resulting in recovery of firing activity of previously silenced dopamine neurons. This property may be particularly relevant in terms of firing dependent dopamine release and in relation to prevention of neuronal loss in Parkinson's disease. The activity of complex I of the mitochondrial respiratory chain is reduced in dopamine neurons of parkinsonian patients (Schapira, 2001), and drugs acting as inhibitors of complex I, like rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induce dopamine neuron degeneration (Betarbet et al., 2000; Przedborski and Vila, 2003). Inhibition of mitochondrial complex I may lead to reduction of ATP and increased production of reactive oxygen species (Höglinger et al., 2003; Testa et al., 2005), causing the opening of KATP channels and dopamine neuron silencing (Avshalumov et al., 2005; Berretta et al., 2005; Geracitano et al., 2005). A recent report by Liss et al. (2005) proposed that the selective vulnerability of the SNc dopamine neurons in Parkinson's disease is casually correlated with the opening of KATP conductances in these neurons; thus, the presence of functional KATP channels promotes the selective loss of SNc dopamine neurons in both a genetic model of Parkinson's disease and in response to mitochondrial complex I inhibition. At present, the mechanism through which KATP channel opening contributes to dopamine neuron degeneration is still unclear. There is evidence that increasing neuronal excitability protects dopamine neurons from degeneration (Salthun-Lassalle et al., 2004); for this reason, Liss et al. (2005) proposed that drugs acting at KATP channels of SNc dopamine neurons should cause a recovery from their functional silencing, thus providing a clinical benefit in the treatment of Parkinson's disease. Indeed, memantine has been shown to prevent cell death associated with Parkinson's disease (Danysz et al., 1997; Lange et al., 1997; Merello et al., 1999; Kucheryanu and Kryzhanovskii, 2000), although prevention of excitotoxic neuronal damage through an uncompetitive inhibition of NMDA receptors has been proposed as its underlying mechanism of action. Our results show that memantine does inhibit NMDA responses in the SNc; however, memantine may also have beneficial results in Parkinson's disease patients because it reduces dopamine neuron silencing through closure of KATP conductances.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: memantine, 1-amino-3,5-dimethyl-adamantane; NMDA, N-methyl-D-aspartate; SNc, substantia nigra pars compacta; KATP, ATP-sensitive potassium; ACSF, artificial cerebrospinal fluid; dopamine, 3,4-dihydroxyphenethylamine; AP5, D-(–)-2-amino-5-phosphonoeptanoic acid; MK-801, (5S, 10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate; tolbutamide, 1-buthyl-3-(4-methylbenzenesulfonyl)urea; mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine; methyllycaconitine, [1,4(S),6
,14,16]-20-ethyl-1,6,14,16-tetramethohy-4-[[[2-(3-methyl-2,5-dioxo-1-pyrrolidinyl) benzoyl]oxy]methyl]aconitane-7,8-diol citrate; INMDA, NMDA-mediated inward current; IHYPO, hypoxia-induced outward current; 5-HT, serotonin.
Address correspondence to: Nicola Berretta, Fondazione Santa Lucia I.R.C.C.S., Via del Fosso di Fiorano, 64, 00143 Rome, Italy. E-mail: n.berretta{at}hsantalucia.it
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Aracava Y, Pereira EF, Maelicke A, and Albuquerque EX (2005) Memantine blocks 7 nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther 312: 1195–1205.
Avshalumov MV, Chen BT, Koos T, Tepper JM, and Rice ME (2005) Endogenous hydrogen peroxide regulates the excitability of midbrain dopamine neurons via ATP-sensitive potassium channels. J Neurosci 25: 4222–4231.
Berretta N, Freestone PS, Guatteo E, de Castro D, Geracitano R, Bernardi G, Mercuri NB, and Lipski J (2005) Acute effects of 6-hydroxydopamine on dopaminergic neurons of the rat substantia nigra pars compacta in vitro. Neurotoxicology 26: 869–881.[CrossRef][Medline]
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, and Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3: 1301–1306.[CrossRef][Medline]
Chen HS and Lipton SA (2006) The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97: 1611–1626.[CrossRef][Medline]
Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, and Lipton SA (1992) Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci 12: 4427–4436.[Abstract]
Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, and Quack G (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents—preclinical studies. Neurosci Biobehav Rev 21: 455–468.[CrossRef][Medline]
Danysz W, Parsons CG, and Quack G (2000) NMDA channel blockers: memantine and amino-aklylcyclohexanes–in vivo characterization. Amino Acids 19: 167–172.[CrossRef][Medline]
Ditzler K (1991) Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittelforschung 41: 773–780.[Medline]
Fleischhacker WW, Buchgeher A, and Schubert H (1986) Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 10: 87–93.[CrossRef][Medline]
Floresco SB, West AR, Ash B, Moore H, and Grace AA (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6: 968–973.[CrossRef][Medline]
Gardoni F and Di Luca M (2006) New targets for pharmacological intervention in the glutamatergic synapse. Eur J Pharmacol 545: 2–10.[CrossRef][Medline]
Geracitano R, Tozzi A, Berretta N, Florenzano F, Guatteo E, Viscomi MT, Chiolo B, Molinari M, Bernardi G, and Mercuri NB (2005) Protective role of hydrogen peroxide in oxygen-deprived dopaminergic neurones of the rat substantia nigra. J Physiol 568: 97–110.
Gonon FG and Buda MJ (1985) Regulation of dopamine release by impulse flow and by autoreceptors as studied by in vivo voltammetry in the rat striatum. Neuroscience 14: 765–774.[CrossRef][Medline]
Grillner P and Mercuri NB (2002) Intrinsic membrane properties and synaptic inputs regulating the firing activity of the dopamine neurons. Behav Brain Res 130: 149–169.[CrossRef][Medline]
Guatteo E, Mercuri NB, Bernardi G, and Knöpfel T (1998) Intracellular sodium and calcium homeostasis during hypoxia in dopamine neurons of rat substantia nigra pars compacta. J Neurophysiol 80: 2237–2243.
Hesselink MB, De Boer BG, Breimer DD, and Danysz W (1999) Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study. Pharm Res 16: 637–642.[CrossRef][Medline]
Höglinger GU, Carrard G, Michel PP, Medja F, Lombes A, Ruberg M, Friguet B, and Hirsch EC (2003) Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease. J Neurochem 86: 1297–1307.[Medline]
Kucheryanu VG and Kryzhanovskii GN (2000) Effect of glutamate and antagonists of N-methyl-D-aspartate receptors on experimental parkinsonian syndrome in rats. Bull Exp Biol Med 130: 629–632.[Medline]
Lange KW, Kornhuber J, and Riederer P (1997) Dopamine/glutamate interactions in Parkinson's disease. Neurosci Biobehav Rev 21: 393–400.[CrossRef][Medline]
Lipton SA (2004) Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx 1: 101–110.
Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 5: 160–170.[CrossRef][Medline]
Liss B, Haeckel O, Wildmann J, Miki T, Seino S, and Roeper J (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8: 1742–1751.[CrossRef][Medline]
Marinelli S, Bernardi G, Giacomini P, and Mercuri NB (2000) Pharmacological identification of the K+ currents mediating the hypoglycemic hyperpolarization of rat midbrain dopaminergic neurones. Neuropharmacology 39: 1021–1028.[CrossRef][Medline]
Maskell PD, Speder P, Newberry NR, and Bermudez I (2003) Inhibition of human 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors. Br J Pharmacol 140: 1313–1319.[CrossRef][Medline]
Mercuri NB, Bonci A, Johnson SW, Stratta F, Calabresi P, and Bernardi G (1994) Effects of anoxia on rat midbrain dopamine neurons. J Neurophysiol 71: 1165–1173.
Merello M, Nouzeilles MI, Cammarota A, and Leiguarda R (1999) Effect of memantine (NMDA antagonist) on Parkinson's disease: a double-blind crossover randomized study. Clin Neuropharmacol 22: 273–276.[Medline]
Netzer R and Bigalke H (1990) Memantine reduces repetitive action potential firing in spinal cord nerve cell cultures. Eur J Pharmacol 186: 149–155.[CrossRef][Medline]
Phillips PE, Stuber GD, Heien ML, Wightman RM, and Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422: 614–618.[CrossRef][Medline]
Przedborski S and Vila M (2003) The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. AnnNY Acad Sci 991: 189–198.[Medline]
Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, and Parsons CG (2001) The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT3 receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 306: 81–84.[CrossRef][Medline]
Reiser G, Binmoller FJ, and Koch R (1988) Memantine (L-amino-3, 5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. Brain Res 443: 338–344.[CrossRef][Medline]
Salthun-Lassalle B, Hirsch EC, Wolfart J, Ruberg M, and Michel PP (2004) Rescue of mesencephalic dopaminergic neurons in culture by low-level stimulation of voltage-gated sodium channels. J Neurosci 24: 5922–5930.
Schapira AH (2001) Causes of neuronal death in Parkinson's disease. Adv Neurol 86: 155–162.[Medline]
Sonkusare SK, Kaul CL, and Ramarao P (2005) Dementia of Alzheimer's disease and other neurodegenerative disorders—memantine, a new hope. Pharmacol Res 51: 1–17.[CrossRef][Medline]
Suaud-Chagny MF, Chergui K, Chouvet G, and Gonon F (1992) Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area. Neuroscience 49: 63–72.[CrossRef][Medline]
Testa CM, Sherer TB, and Greenamyre JT (2005) Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res 134: 109–118.[Medline]
Volbracht C, van Beek J, Zhu C, Blomgren K, and Leist M (2006) Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J Neurosci 23: 2611–2622.[CrossRef][Medline]
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