Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data

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Habituation, where a response is reduced when exposed to a continuous stimulus is one of the simplest forms of non-associative learning and has been shown in a number of organisms from sea slugs to rodents. However, very little has been reported in the zebrafish, a model that is gaining popularity for high-throughput compound screens. Furthermore, since most of the studies involving learning and memory in zebrafish have been conducted in adults, we sought to determine if zebrafish larvae could display non-associative learning and whether it could be modulated by compounds identified in previous rodent studies. We demonstrated that zebrafish larvae (7 days post fertilization) exhibit iterative reduction in a startle response to a series of acoustic stimuli. Furthermore, this reduction satisfied criteria for habituation: spontaneous recovery, more rapid reductions in startle to shorter intertrial intervals and dishabituation. We then investigated the pathways mediating this behavior using established compounds in learning and memory. Administration of rolipram (PDE4 inhibitor), donepezil (acetylcholinesterase inhibitor), and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) all increased the acoustic startle response and decreased habituation in the larvae, similar to previous rodent studies. Further studies demonstrated that NMDA blocked the memantine response and the effect of donepezil was blocked by mecamylamine but not atropine suggesting that the donepezil response was mediated by nicotinic rather than muscarinic receptors. Zebrafish larvae possess numerous advantages for medium to high-throughput screening; the model described herein therefore offers the potential to screen for additional compounds for further study on cognition function.

Section: Discussionmentioning

confidence: 99%

Non-Associative Learning in Larval Zebrafish

Best¹,

Berghmans²,

Hunt³

et al. 2007

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150

“…In the case of NMDA receptor affinity for memantine, there is relatively higher affinity in the cerebellum, the structure essential for eyeblink conditioning, than in forebrain regions (Bresink et al, 1995;Porter and Greenamyre, 1995). Memantine is a clinically welltolerated uncompetitive NMDA receptor antagonist with strong voltage dependency and rapid blocking/unblocking kinetics (Parsons et al, 1999). Mild glutamate toxicity to postsynaptic neurons is blocked by memantine at concentrations significantly lower than those concentrations that impair normal physiological function and synaptic plasticity.…”

Section: Nmda Receptor Antagonism and Eyeblink Classical Conditioningmentioning

confidence: 99%

“…Such kinetics may allow memantine to block ongoing pathologic processes that involve chronic NMDA activation, while simultaneously permitting normal neurophysiologic brain functions (Lipton and Chen, 2004). Memantine treatment has been directed primarily toward AD and other senile dementias (Jain, 2000;Tariot et al, 2004), although additional therapeutic applications have been suggested for this drug (Parsons et al, 1999).…”

Section: Nmda Receptor Antagonism and Eyeblink Classical Conditioningmentioning

confidence: 99%

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Woodruff-Pak

Tobia

Jiao³

et al. 2006

Combinations of drugs approved to treat Alzheimer's disease (AD) were tested in older rabbits with delay eyeblink classical conditioning, a form of associative learning severely impaired in AD. In Experiment 1 (n ¼ 49 rabbits), low doses (0.1, 0.5, 1.0, and 0.0 (vehicle) mg/kg) of memantine (Namendat) were tested. These three doses neither improved nor impaired acquisition at a statistically significant level. The 0.5 mg/kg dose had the greatest effect numerically and did not cause sensitization or habituation in explicitly unpaired controls. In Experiment 2 (n ¼ 56), doses of galantamine (Razadynet; 3.0 mg/kg) and donepezil (Ariceptt; 0.75 mg/kg) that had comparable magnitudes of cholinesterase inhibition were tested alone and in combination with 0.5 mg/kg memantine. Older rabbits treated with galantamine and with galantamine + memantine learned significantly better than vehicle-treated rabbits, but adding memantine did not improve learning over galantamine alone. Older rabbits treated with donepezil or a combination of memantine and donepezil did not learn significantly better than rabbits treated with vehicle. Galantamine has two mechanisms of action: mild cholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors (nAChRs). When equated for cholinesterase inhibition, galantamine had significant efficacy in the eyeblink conditioning model system, but donepezil did not, indicating that modulation of nAChRs may be the mechanism that significantly ameliorates learning deficits in this model. In the absence of AD neuropathology in older rabbits, memantine had no efficacy alone or in combination with the other drugs.

“…However, high affinity NMDA receptor channel blockers have been observed to elicit psychotomimetic properties in humans (Krystal et al, 1999), and thus have been useful only experimentally in vitro and in vivo. In contrast, memantine (1-amino-3,5-dimethyladamantane), an uncompetitive NMDA receptor antagonist of moderate affinity to the receptor-associated ion-channel, exhibits fast blocking and unblocking kinetics, high voltage dependency (Kornhuber et al, 1991;Parsons et al, 1993), and is well tolerated at clinical doses (Parsons et al, 1999). Memantine is suggested as a neuroprotective agent for the treatment of several dementias, particularly AD (Görtel-meyer and Erbler, 1992; Muller et al, 1995;Parsons et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

Marvanová

Lakso

Wong

2004

In this study, we monitored gene expression profiles using cDNA microarrays after an acute systemic administration of the high affinity N-methyl-D-aspartate (NMDA) uncompetitive antagonist MK-801 (1 mg/kg; 4 h), and the clinically used moderate affinity antagonist memantine (25 mg/kg; 4 h) in adult rat brains. From a microarray containing 1090 known genes, 13 genes were regulated by both treatments of which 12 were upregulated and one was downregulated. In addition, 28 and 34 genes were regulated (X1.5-or p0.67-fold change) by either memantine or MK-801, respectively. Genes commonly regulated by both treatments and not previously reported were confirmed by in situ hybridization (ISH) and include regenerating liver inhibitory factor-1 (RL/IF-1), GDP-dissociation inhibitor 1 (GDI-1), neural visinin Ca 2 þ -binding protein 2 (NVP-2), neuromedin B receptor, and Na þ /K þ transporting ATPase 2b. ISH with memantine (5-50 mg/kg) revealed regulation of these genes in other cortical and hippocampal regions. RL/IF-1 induction occurred at 1 h and returned to basal levels by 8 h, consistent with the profile of an immediate early gene. Western blot analysis showed increases (B30-65%) in GDI-1 protein present in both cytosolic and membrane fractions that were significant in the 84-kDa Rab bound form, suggesting that memantine influences Ras-like GTPase function. Genes regulated by a 5 mg/kg dose of memantine might be important in its therapeutic effects. These findings increase the number of known, differentially altered genes after treatment of uncompetitive NMDA receptor antagonists and suggest broader actions of these agents than previously realized.