Evaluation of Cycloserine in the Treatment of Alzheimer's Disease

Td, Fakouhi; Ss, Jhee; Jj, Sramek; Benes, Charles O.; Schwartz, Pamela F.; Hantsburger, G; Herting, Robert L.; Ea, Swabb; Nr, Cutler

doi:10.1177/089198879500800405

Cited by 45 publications

(23 citation statements)

References 25 publications

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“…The most widely studied compound to date has been D-cycloserine. A large-scale double-blind, placebo controlled trial of 5, 15 and 50 mg/day D-cycloserine for treatment of AD failed to show overall significant benefit, 153 although some effect on implicit memory was observed. 154 Since then, conflicting results with higher doses have been reported, with one study failing to find efficacy in a dose-escalation study, 155 but another study finding efficacy of a fixed dose of 100 mg/day Dcycloserine on cognitive functioning.…”

Section: Alzheimer Diseasementioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Alzheimer Diseasementioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…We suggest alternative goals for therapy, but are aware that few of them are directly assessed by neuropsychological tests, although some are assessed by rating scales. [35][36][37] Level 1, Class C Lecithin 38,39 Level 1, Class C Arecholine 40 Level 1, Class C Nimodipine 41 Level 1, Class C Velnacrine 42 Level 1, Class D Physostigmine [43][44][45] Level 1, Class D Eptastigmine 46 Level 1, Class D Phosphatidylserine 47 Level 1, Class D Memantine 48 Level 1, Class D 4 Aminopyridine (4AP) 49 Level 1, Class D Naloxone 50 Level 1, Class D Linopirdine 51 Level 1, Class D Aniracetam 52 Level 1, Class D Milacemide 53 Level 1, Class D Nicergolin 54 Level 1, Class D Idebenone 55 Level 1, Class D Huperzine-A 56 Level 1, Class D 5'-methyltetrahydrofolic acid 57 Level 1, Class D Desferrioxamine 58 Level 1, Class D Xantinolnicotinate 59 Level 1, Class D Bespirdine 60 Level 1, Class D Cycloserine 61 Level 1, Class D Cyclandelate 62 Level 1, Class D Thyrotropin 63 Level 1, Class D…”

Section: Discussionmentioning

confidence: 99%

The Use of Medications for Cognitive Enhancement

Pryse-Phillips

Sternberg

Rochon

et al. 2001

Can. J. Neurol. Sci.

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Objective:To provide Canadian physicians and allied health care professionals with the evidence they need to help them make treatment decisions in the management of patients with Alzheimer’s disease or other dementias.Options:The full range and quality of diagnostic and therapeutic modalities available to Canadian physicians for the management of dementia.Outcomes:Improvement in the treatment of dementias, leading to reduced suffering, increased functional capacity and decreased economic burden.Evidence and values:The creation of these evidence-based consensus statements involved literature reviews of the subject by the authors; comparison of alternative clinical pathways and description of the methods whereby published data were analyzed; definition of the level of evidence for data in each case; evaluation and revision in a conference setting (involving primary care physicians, neurologists, psychiatrists, geriatricians, psychologists, consumers and other interested parties); insertion of tables showing key variables and data from various studies and tables of data with recommendations; and reassessment by all authors.Benefits, harms, and costs:A rational plan for the therapy of dementias is likely to lead to substantial benefits in both human and economic terms.Recommendations:Treatment decisions should be made taking into account the severity or stage of the disease, the availability of caregivers, the presence of disease affecting other bodily systems and the ability of the subject to pay the cost of the medications. Donepezil is considered to have positive effects upon certain tests of neuropsychological function and may produce some improvement in Alzheimer’s disease of mild to moderate severity as measured by rating scales. Its ability to improve quality of life remains uncertain. No other drug treatments* (apart from symptomatic therapies) are at present approved for the treatment of Alzheimer’s disease.Validation:These recommendations were created by a writing committee, evaluated and revised at a consensus conference and further reviewed and revised by the writing committee prior to publication.

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“…Supporting neurotrophic/cognitive effects, DCS can improve cognitive functions in animal studies [171,172] and is used clinically in conjunction with CBT interventions [127]. However, cognition-enhancing effects of DCS in AD have not been conclusively demonstrated [173][174][175].…”

Section: Cognitive Impairment and Dementiamentioning

confidence: 99%

D-Serine in Neuropsychiatric Disorders: New Advances

Durrant

Heresco-Levy

2014

Advances in Psychiatry

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D-Serine (DSR) is an endogenous amino acid involved in glia-synapse interactions that has unique neurotransmitter characteristics. DSR acts as obligatory coagonist at the glycine site associated with the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) and has a cardinal modulatory role in major NMDAR-dependent processes including NMDAR-mediated neurotransmission, neurotoxicity, synaptic plasticity, and cell migration. Since either over-or underfunction of NMDARs may be involved in the pathophysiology of neuropsychiatric disorders; the pharmacological manipulation of DSR signaling represents a major drug development target. A first generation of proof-of-concept animal and clinical studies suggest beneficial DSR effects in treatmentrefractory schizophrenia, movement, depression, and anxiety disorders and for the improvement of cognitive performance. A related developing pharmacological strategy is the indirect modification of DSR synaptic levels by use of compounds that alter the function of main enzymes responsible for DSR production and degradation. Accumulating data indicate that, during the next decade, we will witness important advances in the understanding of DSR role that will further contribute to elucidating the causes of neuropsychiatric disorders and will be instrumental in the development of innovative treatments.

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Evaluation of Cycloserine in the Treatment of Alzheimer's Disease

Cited by 45 publications

References 25 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

The Use of Medications for Cognitive Enhancement

D-Serine in Neuropsychiatric Disorders: New Advances

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