Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.
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PMID:Evaluation of memantine for neuroprotection in dementia. 1106 Jul 51

Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
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PMID:Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. 1551 30

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration. However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 +/- 5.5 to 129.7 +/- 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival.
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PMID:Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model. 1626 76

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
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PMID:NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. 1671 8

Most neuroprotective drugs have failed in clinical trials because of side-effects, causing normal brain function to become compromised. A case in point concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids, such as glutamate itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurological diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or co-agonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side-effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, even although effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block with the property of uncompetitive antagonism is the most appealing strategy for therapeutic intervention during excessive NMDAR activation as this action of blockade requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiological neurotransmission. Utilizing this molecular strategy of action, we review here the logical process that we applied over the past decade to help develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderate-to-severe Alzheimer's disease while being well tolerated. Memantine is also currently in trials for additional neurological disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. Additionally, taking advantage of memantine's preferential binding to open channels and the fact that excessive NMDAR activity can be down-regulated by S-nitrosylation, we have recently developed combinatorial drugs called NitroMemantines. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order to avoid systemic side-effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies appear to have even greater neuroprotective properties than memantine.
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PMID:The chemical biology of clinically tolerated NMDA receptor antagonists. 1680 72

Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.
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PMID:Inflammatory mediators leading to protein misfolding and uncompetitive/fast off-rate drug therapy for neurodegenerative disorders. 1767 53

Our objective is to describe the results of a phase II/III, 12-months, double-blinded, single-centre, randomized, parallel (1:1), clinical trial performed to evaluate the efficacy and safety of memantine in ALS. Patients with probable or definite ALS of less than 36 months disease duration and progression over a one-month lead-in period were randomly assigned to placebo or memantine at 20 mg/day. The primary endpoint was 12-months ALSFRS decline. Forced vital capacity, manual muscle testing, visual analogue scale, quality of life, motor unit number estimation and neurophysiological index were the secondary endpoints. The number of patients included was based on the assumption of a 50% change in the ALSFRS decline. Safety and adverse events were evaluated. Sixty-three patients were included in the trial. Memantine did not show more adverse events or laboratory changes than placebo. Primary and secondary outcomes were not different between groups by intention-to-treat and per-protocol analysis. The most sensitive measurements were neurophysiological, which declined linearly over time. In conclusion, the results of this study show that memantine is well tolerated and safe in ALS patients. We did not observe any evidence of efficacy for memantine but we cannot exclude a positive outcome on survival.
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PMID:A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. 2056 33