Memantine NMDA antagonist

Merello M, NouzeUles Ml, Cammarota A, Leiguarda R (1999) Effect of memantine (NMDA antagonist) on Parkinson s disease a double-blind crossover randomized study. Clin Neuropharmacol 22 273-276... 

Even in Alzheimer s disease (AD), the possible involvement of a weak excitotoxic process cannot be ruled out. Indeed, mitochondrial abnormalities (such as cytochrome oxidase alterations) [36, 37] and increased levels of markers of oxidative stress [38] have been reported in AD. This has been the rationale for testing the NMDA antagonist memantine in Alzheimer s dementia [39]. 

NMDA antagonists The combined use of memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated. Approach such use with caution. 

Carlton SM, Hargett GL (1995) Treatment with the NMDA antagonist memantine attenuates nociceptive responses to mechanical stimulation in neuropathic rats. Netuosci Lett 198 115-118... 

Danysz W, Parsons CG, Mobius HJ, et al (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer s disease—an unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2 85-97 Davis SM, Lees KR, Albers GW, et al (2000) Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 31 347-354 DeKeyser J (1991) Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 14 562-565 Del Dotto P, Pavese N, Gambaccini G, et al (2001) Intravenous amantadine improves levodopa-induced dyskinesias an acute double-blind placebo-controlled study. Mov Disord 16 515-520... 

Bisaga, A., Comer, S. D., Ward, A. S., Popik, P., Kleber, H., Fischman, M. W. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology 2001, 157, 1-10. 

Fig. 10.3 Chemical structures of low affinity NMDA antagonists used for the treatment of AD, AD, AIDS dementia, and migrane. Memantine (a) Amantadine (b) (R,S)-N-2-(4-(3-thienyl)phenyl)-2-propanesulfonamide (LY392098) (c) and (R)-4 -[l-fluoro-l-methyl-2-(propane-2-sulphonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) (d)...

It seems that altered intracellular calcium homeostasis may be a crucial event in the initiation and progression of AD however the therapeutic value has thus far been mixed. For example, the use of calcium channel blockers, including dihydropy-ridines and non-dihydropyridines, has no effect on the risk of AD (Yasar et al., 2005), whereas the NMDA-antagonist memantine improves cognition in mild to moderate AD (Peskind et al., 2006). 

Of note, there have also been links between glutamate receptor stimulation and pathology. Excessive stimulation of glutamate receptors can cause seizure and it is hypothesized that NMDA overstimulation can cause neuronal cell death from an excessive influx of calcium. This has led to the development of NMDA antagonists like memantine to treat Alzheimer s Disease. 

The most important excitatory neurotransmitter in the central nervous system (CNS) is glutamate, reported to regulate Ca " accumulation through excessive activation of NMDA receptors. Memantine is an NMDA antagonist that has been used to treat neurological syndromes and cognitive dysfunction (Farlow et al., 2003). A small beneficial effect of memantine was observed at six months of treatment in moderate to severe AD (Areosa et al, 2005). 

Danysz, W., Gossel, M., Zajaczkowski, W., Dill, D., Quack, G. (1994). Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats Case of amantadine and memantine. J. Neurol. Transm. Park. Dis. Dement. Sect. 1 155-66. 

Recent studies have reported that galantamine also improves the cognitive performance of patients with autism (Nicolson et al., 2006) and, unlike other cholinesterase inhibitors, decreases the negative symptoms in patients with schizophrenia (Schubert et al., 2006). Eor more severe Alzheimer s disease, memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors, has also been approved. A number of newer drugs undergoing clinical trials for Alzheimer s disease work by a variety of other mechanisms, although a common theme appears to be neuroprotection (Robertson and Mucke, 2006). 

I Memantine. Memantine, an NMDA-antagonist, is a novel agent for treating AD. By blocking NMDA receptors, excitotoxic reactions, which ultimately lead to cell death, may be prevented. Memantine has been studied in patients with vascular dementia, and in patients with moderate and severe AD as monotherapy and in combination with donepezil with favorable results. It is currently indicated for use in AD patients with moderate to severe illness. 

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