Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Memantine, an aminodamantane, has recently been approved to treat moderate-to-severe Alzheimer's disease in the US after over 20 years on the market in Europe for treatment of Parkinson's disease. The unique properties of Memantine allow for its selective inhibition of abnormally active NMDA receptor channels while preserving normal glutamate activity and healthy neuronal function. Recently, it has been shown that compounds such as nitroglycerin, used for years for ischemic coronary disease, can also regulate the NMDA receptor channel. Novel compounds have been synthesized in an attempt to combine these activities, in an attempt to synergistically improve upon the activities of both nitrates and aminoadamantanes. We have subjected these compounds to several laboratory tests to compare their ability to affect the function of the NMDA receptor and to dilate blood vessels. These tests provide an initial indication of which of the compounds may have enhanced activity relative to memantine. The results also provide guidance for the synthesis of additional compounds that are likely to have the properties that are being sought.
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PMID:The pharmacology of aminoadamantane nitrates. 1684 96

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

Memantine is reported to improve symptoms in moderate cases of Alzheimer's disease and Parkinson's disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affinity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/- 23 nM for rat striatal D2 receptors and 137 +/- 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H]MK 801 was 2200 +/- 400 nM. Memantine stimulated the incorporation of [(35)S]GTP-gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/- 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.
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PMID:Memantine agonist action at dopamine D2High receptors. 1800 Aug 14

Memantine (M) was used in the treatment of patients with Parkinson's disease (PD) with dementia. The drug was prescribed to 15 patients at first in a single dosage of 5 mg daily for one week, then the dosage was increased to 10 mg daily (one week), after to 15 mg daily (one week) and from the 4th week - to 20mg daily. Patients of the control group did not receive the drug. Efficacy and safety of M were assessed clinically and with a battery of widespread scales (UPDRS, MMSE, CGI etc), neuropsychological tests and the quality of life scale (PDQ-8). The study showed the ability of M to cause a stable improvement of mental state and its good tolerability. The efficacy of M in the cases studied was comparable with that in Alzheimer's disease.
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PMID:[Efficacy of memantine in Parkinson's disease with dementia]. 1915 21

The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22-week trial of 25 participants with a DSM-IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine-related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine-treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well-tolerated in PDD.
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PMID:Randomized controlled trial of memantine in dementia associated with Parkinson's disease. 1937 Jul 37

Memantine shows clinically relevant efficacy in patients with Alzheimer's disease and Parkinson's disease. Most in vivo and in vitro studies attribute the neuroprotective effects of memantine to the blockade of N-methyl-D-aspartate (NMDA) receptor on neurons. However, it cannot be excluded that mechanisms other than NMDA receptor blockade may contribute to the neuroprotective effects of this compound. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminergic (DA) neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on DA neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia dependent, as memantine failed to show any positive effect on DA neurons in neuron-enriched cultures. More specifically, it seems to be that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of glial cell line-derived neurotrophic factor (GDNF). Mechanistic studies showed that GDNF upregulation was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced DA neuronal damage through its inhibition of microglia activation showed by both OX-42 immunostaining and reduction of pro-inflammatory factor production, such as extracellular superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E(2), and tumor necrosis factor-alpha. These results suggest that the neuroprotective effects of memantine shown in our cell culture studies are mediated in part through alternative novel mechanisms by reducing microglia-associated inflammation and by stimulating neurotrophic factor release from astroglia.
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PMID:Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. 1953 10

Gait disorders form part of the axial symptoms observed in Parkinson's disease (PD) and also represent a major source of therapeutic failure in the later stages of PD, with the appearance of freezing of gait (FOG) and falls. Double-blind clinical trials and, above all, clinical experience have demonstrated that l-DOPA is effective in reducing FOG. Dopaminergic agonists appear to be less effective than l-DOPA and lack formal proof of their efficacy. The enzyme inhibitors provide modest benefits, which need to be confirmed. Hence, these symptoms appear to be partially doparesistant and justify investigation of other major neurotransmission systems. Of the various drugs with partial noradrenergic activity, methylphenidate may improve FOG and attention disorders. Memantine has shown some value in improving motor symptoms and gait in fluctuating parkinsonian patients - possibly by reducing the effect of glutamatergic hyperactivation of the subthalamic nucleus on the pedunculopontine nucleus (PPN). The PPN's dense cholinergic innervation also suggests that cholinesterase inhibitors may be of use, although any benefits must be set against a potential aggravation of rest tremor. The many interactions between the serotoninergic and dopaminergic systems require the implementation of clinical studies on the complex motor impact of serotoninergic treatments, which may aggravate the parkinsonian syndrome while improving gait (as is the case with paroxetine and ritanserin). This review seeks to develop the various pathophysiological hypotheses prompted by the results of fundamental studies and pilot clinical trials, with a view to justifying the implementation of confirmatory, double-blind, placebo-controlled therapeutic trials.
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PMID:[Pharmacological hypotheses and therapeutic strategies for gait disorders in Parkinson's disease]. 1981 97

There are currently no Food and Drug Administration-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition, and function. Forty-three individuals who met clinical criteria for FTLD [21 with frontotemporal dementia (FTD), 13 with semantic dementia (SD), and 9 with progressive nonfluent aphasia (PA)] received 26 weeks of open-label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the Mini Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), clinical dementia rating-sum of boxes, Neuropsychiatric Inventory (NPI), Frontal Behavior Inventory, Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale, and Unified Parkinson's Disease Rating Scale-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, Frontal Behavior Inventory, NPI, TFLS, and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and TFLS, but declined on the UPDRS. Memantine was well-tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.
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PMID:An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. 1981 61

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D(2) antagonist sulpiride (40 mg/kg) and 5-HT(2A/2C) antagonist ketanserin (2 and 4 mg/kg) but not with the selective D(1) antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D(2) or 5-HT(2A) receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.
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PMID:Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: involvement of dopamine D2 and 5-HT2A receptors. 2113 Aug 10


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