Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents — preclinical studies

Danysz, Wojciech; Parsons, Chris G.; Kornhuber, Johannes; Schmidt, Werner; Quack, G.

doi:10.1016/s0149-7634(96)00037-1

Cited by 302 publications

(159 citation statements)

References 118 publications

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“…This raises the possibility that the beneficial effects seen in AD patients may be attributable to the interaction of memantine with other transmitter systems. In fact, in their review of the preclinical studies for memantine as an anti-parkinsonian agent, Danysz et al (1997) provide extensive evidence for interactions of memantine with dopaminergic, serotonergic, and cholinergic transmitter systems. It has also been found recently that memantine may interact more potently with cholinergic receptors than NMDA receptors (Aracava et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…It was only necessary to test two doses because the first dose (20 mg/kg) provided significant neuroprotection and the next lower dose (10 mg/kg) did not. We chose 20 mg/kg as the initial dose because this is the dose that others have reported is effective in protecting the adult rat brain against excitotoxic neurodegeneration (Wenk et al, 1994;Misztal et al, 1996;Danysz et al, 1997;Chen et al, 1998). Control animals for these experiments consisted of rats treated with saline (n ϭ 3) or memantine at 10 (n ϭ 6) and 20 (n ϭ 6) mg/kg intraperitoneally.…”

Section: Methodsmentioning

confidence: 99%

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Low Doses of Memantine Disrupt Memory in Adult Rats

Creeley¹,

Wozniak²,

Labruyere³

et al. 2006

J. Neurosci.

121

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Memantine, a drug recently approved for treatment of Alzheimer's disease, has been characterized as a unique NMDA antagonist that confers protection against excitotoxic neurodegeneration without the serious side effects that other NMDA antagonists are known to cause. In the present study, we determined what dose of memantine is required to protect the adult rat brain against an NMDA receptormediated excitotoxic process and then tested that dose and a range of lower doses to determine whether the drug in this dose range is associated with significant side effects. Consistent with previous research, we found that memantine confers a neuroprotective effect beginning at an intraperitoneal dose of 20 mg/kg, a dose that we found, contrary to previous reports, produces locomotor disturbances severe enough to preclude testing for learning and memory effects. We then determined that, at intraperitoneal doses of 10 and 5 mg/kg, memantine disrupts both memory and locomotor behaviors. Rats treated with these doses performed at control-like levels in learning a hole-board task but were significantly impaired in demonstrating what they had learned when tested 24 h later. This impairment of memory retention was not state dependent in that it was demonstrable regardless of whether the rats were or were not exposed to memantine on the day of retention testing. We conclude that, in the adult rat, memantine behaves like other NMDA antagonists in that it is neuroprotective only at doses that produce intolerable side effects, including memory impairment.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Low Doses of Memantine Disrupt Memory in Adult Rats

Creeley¹,

Wozniak²,

Labruyere³

et al. 2006

J. Neurosci.

121

View full text Add to dashboard Cite

show abstract

“…At high doses, amantadine reduces NMDA receptor function by approximately 50%, an effect attributed to its instability within the NMDA receptor calcium channel. [51][52][53] This drug showed evidence of antidepressant activity in unipolar and bipolar depressed patients and in depressed patients with Parkinson disease (Table 1). [54][55][56][57] Amantadine was developed initially as an antiviral agent, in part due to its ability to reduce the entry of viruses into cells.…”

Section: Glutamatergic Abnormalities In Mood Disordersmentioning

confidence: 99%

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

et al. 2002

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Glutamate and ␥-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that unipolar, but not bipolar, depression is associated with reductions in cortical GABA levels. Antidepressant and mood-stabilizing treatments also appear to raise cortical GABA levels and to ameliorate GABA deficits in patients with mood disorders. The preponderance of available evidence suggests that glutamatergic and GABAergic modulation may be an important property of available antidepressant and mood-stabilizing agents. Future research will be needed to develop and evaluate new agents with specific glutamate and GABA receptor targets in the treatment of mood disorders. Molecular Psychiatry (2002) 7, S71-S80.

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“…Its antiviral action results from block of the M2 small viral membrane protein (Hay, 1992). Although the utility of amantadine in treating Parkinson's disease was initially assumed to result from effects on dopaminergic systems (Danysz et al, 1997), amantadine later was found to block the channel of NMDA receptors (Kornhuber et al, 1991;Lupp et al, 1992;Parsons et al, 1995;Blanpied et al, 1997). Increasing evidence suggests that the effectiveness of amantadine in treating nervous system disorders results predominantly from its inhibition of NMDA responses (Blanchet et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Blanpied¹,

Clarke²,

Johnson³

2005

J. Neurosci.

216

136

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The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.

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Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents — preclinical studies

Cited by 302 publications

References 118 publications

Low Doses of Memantine Disrupt Memory in Adult Rats

Low Doses of Memantine Disrupt Memory in Adult Rats

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

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