NMDA antagonists Alzheimer disease

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]. 

Pharmacology Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer disease. Memantine is an NMDA receptor antagonist. 

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... 

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. 

Memantine is approved for treatment of moderate to severe Alzheimer s disease. It is an antagonist at glutamatergic NMDA-receptors. Memantine is well tolerated and has a small beneficial effect at six months in moderate to severe AD (McShane et al. 2006). For patients with dementia one has to be careful wit all kind of medications that may affect the central nervous system. Delirium and hallucinations are common adverse effects in patients with dementia. Agitation may be due to delirium and external causes should be ruled out before adding another psychoactive drug. Sleep disturbance is common in demented elderly patients. Sleep deprivation may in a patient with dementia induce delirium. Nonpharmacological treatment for delirium or hallucinations should be considered first. 

The key to successful brain protection for Alzheimer s disease is the newly introduced NMDA receptor antagonist, memantine. Family members should be advised that the protection provided by memantine will slow the progression of Alzheimer s disease, but it does not halt or reverse the course of the illness. Memantine is now commonly coadministered with a cholinesterase inhibitor. 

Memantine is the first in a novel class of Alzheimer s disease medications acting a.o. on the NMDA receptor of the glutamatergic system. It also acts as an uncompetitive antagonist at different neuronal nicotinic receptors at potencies possibly similar to the NMDA receptor. Memantine is approved for treatment of moderate to severe Alzheimer s disease and its use is associated with a moderate decrease in clinical deterioration of the disease. Common adverse drug reactions (>1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. 

Flupirtine is both a nonspecific antagonist NMDA and an agonist of opioid receptors. This analgesic is prescribed for migraine. Neuroprotector effects in neurodegenerative diseases (Alzheimer and prion diseases) are being investigatived. ... 

In this chapter, we use the term cognitive enhancers to refer to two classes of pharmacological agents used in the treatment of Alzheimer s disease the cholinesterase inhibitors and the A-methyl-D-aspartate (NMDA) receptor antagonists. 

A new class of medication, N-methyl-D-aspartate (NMDA)-receptor antagonist called memantine, was approved by the U.S. FDA and released in early 2004 under the brand name Namenda. It has been approved for the treatment of moderate to severe Alzheimer s disease and has been used in Germany for over 20 years. Clinical studies in the United States have shown modest effectiveness, with the main benefit being delayed deterioration of basic functions, such as the ability to go to the bathroom independently, feed oneself in a less messy fashion, be less easily distracted, and perhaps have less agitation. There is no evidence that it has any effect in the early stages of Alzheimer s disease or that it alters the ultimate course. Although these are modest benefits, they may allow a person to remain at home with family care and delay nursing-home placement for some period of time (Abramowicz, 2003). 

Among promising candidates as antidotes against CNS intoxication by OP nerve agents, memantine (MEM) has been shown to pose both anti-excitotoxic and anti-epileptic properties. Memantine is an uncompetitive NMDA receptor antagonist, clinically used for the treatment of Alzheimer s disease, Parkinson s disease and spasticity, in the absence of serious side effects (Ozsuer et al, 2005 Lipton, 2005). From a series of rat in vivo experiments, it is evident that pre-administration of memantine significantly protects... 

Trade names Akatinol Axura Ebixa Namenda (Forest) Indications Alzheimer s disease, Vascular dementia Category Adamantane NMDA receptor antagonist Half-life 60-80 hours... 

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). 

---