Disease relevance of memantine

• Pharmacotoxic psychosis after memantine in Parkinson's disease [1].
• Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine [2].
• Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats [3].
• Polycyclic cage compounds have important pharmaceutical applications, ranging from the symptomatic and proposed curative treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease (e.g., amantadine and memantine), to use as anti-viral agents against influenza and the immunodeficiency virus (HIV) [4].
• Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia [5].
• We show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level [6].

Psychiatry related information on memantine

• In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia [7].
• Memantine and catatonic schizophrenia [8].
• OBJECTIVE: Our objective was to evaluate the pharmacokinetics of the Alzheimer's disease treatment memantine in subjects with normal and impaired renal function [9].
• Nitrous oxide, xenon, and memantine may be of therapeutic interest for treating drug dependence [10].
• Visual hallucinations from the addition of riluzole to memantine and bupropion [11].

High impact information on memantine

• Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists [12].
• Behavioral pain responses to noxious mechanical stimulation were inhibited in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor [13].
• A set of arginine-rich hexapeptides selectively blocked the NMDA receptor channel with IC50 approximately 100 nM, a potency similar to clinically tolerated blockers such as memantine, and only marginally blocked on non-NMDA glutamate receptors [14].
• In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases [7].
• This laboratory recently reported that memantine, an antiparkinsonian drug, is a potent N-methyl-D-aspartate antagonist capable of preventing the death of central neurons both in vitro and in vivo when given coincident to an EAA insult [15].

Chemical compound and disease context of memantine

• Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity [16].
• Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy [17].
• Other pharmacological treatment options are baclofen for periodic alternating nystagmus, gabapentin and memantine for acquired pendular nystagmus, and carbamazepine for superior oblique myokymia [18].
• OBJECTIVES: To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia [19].
• NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship [20].

Biological context of memantine

• We investigated the action of memantine on cholinergic synaptic transmission at cochlear outer hair cells (OHCs) [21].
• The measured gating process of channel activation and deactivation appeared at least 10-20-fold faster than the kinetics of memantine action [22].
• NMDA, and to a lesser extent memantine, induced apoptosis independently [23].
• CONCLUSIONS: Systemic treatment with memantine, a compound which does not lower intraocular pressure, was both safe and effective for reduction of functional loss associated with experimental glaucoma [24].
• Memantine treatment alone had no effect on ganglion cell survival [16].

Anatomical context of memantine

• Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model [25].
• In Xenopus laevis oocytes expressing hOCT2, electrogenic transport of norepinephrine, histamine, dopamine, serotonin, and the antiparkinsonian drugs memantine and amantadine was demonstrated by tracer influx, tracer efflux, electrical measurements, or a combination [26].
• Measurements of optic nerve head topography showed less IOP-induced change in memantine-treated animals [27].
• If this hypothesis is correct, and if it is correct that beta-amyloid deposits and neurofibrillary tangles arise long before the symptomatic onset of AD, then memantine, with its ability to alleviate glutamatergic receptor overstimulation, would be expected to provide therapeutic benefits beginning from the earliest stages of the disease [28].
• In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon [29].

Associations of memantine with other chemical compounds

• The release elicited by NMDA plus gp120 was prevented by the classical NMDA receptor antagonists dizocilpine or 7-chlorokynurenic acid, as well as by memantine [30].
• Thus, synaptic transmission in OHCs is inhibited by memantine block of Ca(2+) influx through nAChRs [21].
• The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF [31].
• Further interest is put on NMDA antagonists in preclinical and biological testing (memantine, dizocilpine, conantokins, Co101244/PD174494, ifenprodil, arcaine, L-701,324, eliprodil, CGP40116, LY235959, LY233053, MRZ2/576, LU73068, 4-Cl-KYN) [32].
• Ketamine increased serum prolactin and cortisol levels (p < 0.001), whereas memantine and placebo did not affect hormone levels [33].
• 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 [34].
• Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism [35].

Gene context of memantine

• The up-regulations observed after memantine (cortex, NR2B: 172+/-17%; hippocampus, NR1-1/1-2: 156+/-8%) or MK-801 (cortex, NR2B: 174+/-22%; hippocampus, NR1-1/1-2: 140+/-3%) were almost identical [36].
• 3. Memantine (0.3-30 microM) blocked L-glutamate (100 microM)-mediated currents in a concentration-dependent manner in NR1a/NR2A, NR1a/NR2B and NR1a/NR2D transfected cells with IC50 values (at -70 mV) of 0.93 +/- 0.15 microM, 0.82 +/- 0.12 microM and 0.47 +/- 0.06 microM (mean +/- s.c. mean), respectively [37].
• RESULTS: In HLM, memantine inhibited CYP2B6 and CYP2D6 activities, with KI (IC50) values of 76.7 (279.7) and 94.9 (368.7) microM, respectively [38].
• Treatment with memantine, an NMDA receptor antagonist, also increased the serine-phosphorylation of both GSK3 isoforms in mouse brain [39].
• Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits [40].

Analytical, diagnostic and therapeutic context of memantine

• We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization [41].
• In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer's disease for up to 52 weeks [42].
• Fifteen rats received 20 mg/kg x day memantine by a subcutaneous osmotic pump starting 2 days before ischemia, 13 rats received 10 mg/kg memantine intraperitoneally (ip) 0.5 and 4.5 hours after reperfusion, 13 rats received 10 mg/kg memantine ip 3.5 and 7.5 hours after reperfusion, and 15 rats received the vehicle alone [5].
• Control groups received vehicle injection with or without concurrent memantine therapy [16].
• The completion rate for the extension phase of the study was high (78%) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study [43].

References