scholarly journals Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

2019 ◽  
Vol 7 (4) ◽  
pp. 190-199
Author(s):  
A. P. Pereverzev ◽  
O. D. Ostroumova ◽  
O. N. Tkacheva ◽  
Y. V. Kotovskaya
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Adverse Drug Reactions ◽  
Cholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Competitive Inhibitor ◽  
Nmda Receptor Antagonists ◽  
Drug Reactions ◽  
Receptor Antagonists ◽  
Increased Risk

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly. 

Activation of Peripheral NMDA Receptors Contributes to Human Pain and Rat Afferent Discharges Evoked by Injection of Glutamate into the Masseter Muscle

2003 ◽  
Vol 90 (4) ◽  
pp. 2098-2105 ◽  
Author(s):  
Brian E. Cairns ◽  
Peter Svensson ◽  
Kelun Wang ◽  
Steen Hupfeld ◽  
Thomas Graven-Nielsen ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hypertonic Saline ◽  
Muscle Pain ◽  
Masseter Muscle ◽  
Human Subjects ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Human Experiments ◽  
Masticatory Muscle Pain

Peripheral N-methyl-d-aspartate (NMDA) receptors are found in deep tissues and may play a role in deep tissue pain. Injection of the endogenous NMDA receptor agonist glutamate into the masseter muscle excites deep craniofacial afferent fibers in rats and evokes pain in human subjects. It is not clear whether peripheral NMDA receptors play a role in these effects of glutamate. Accordingly, the effect of NMDA on afferent activity as well as the effect of locally administered NMDA receptor antagonists on glutamate-evoked afferent discharges in acutely anesthetized rats and muscle pain in human subjects was examined. Injection of NMDA into the masseter muscle evoked afferent discharges in a concentration-related manner. It was found that the NMDA receptor antagonists 2-amino-5-phosphonvalerate (APV, 10 mM), ketamine (10 mM), and dextromethorphan (40 mM) significantly decreased glutamate-evoked afferent discharges. The effects of APV and ketamine, but not dextromethorphan, were selective for glutamate-evoked afferent discharges and did not affect hypertonic saline-evoked afferent discharges. In human experiments, it was found that 10 mM ketamine decreased glutamate-evoked muscle pain but had no effect on hypertonic saline-evoked muscle pain. These results indicate that injection of glutamate into the masseter muscle evokes afferent discharges in rats and muscle pain in humans in part through activation of peripheral NMDA receptors. It is conceivable that activation of peripheral NMDA receptors may contribute to masticatory muscle pain and that peripherally acting NMDA receptor antagonists could prove to be effective analgesics for this type of pain.

Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors

2016 ◽  
Vol 31 (5) ◽  
pp. 405-412 ◽  
Author(s):  
Xiaodong Shi ◽  
Xiaotian Lin ◽  
Rui Hu ◽  
Nan Sun ◽  
Jingru Hao ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Cholinesterase Inhibitors ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists

NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy

2019 ◽  
Vol 25 (33) ◽  
pp. 3506-3518 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Mohammad A. Sufian ◽  
Md. Sahab Uddin ◽  
Mst. Marium Begum ◽  
Shammi Akhter ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Symptomatic Relief ◽  
Critical Role ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Disease Condition ◽  
And Behavior ◽  
With Memory

: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.

Characterization of l-Homocysteate–Induced Currents in Purkinje Cells From Wild-Type and NMDA Receptor Knockout Mice

1999 ◽  
Vol 82 (5) ◽  
pp. 2820-2826 ◽  
Author(s):  
Michisuke Yuzaki ◽  
John A. Connor
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Purkinje Cells ◽  
Hippocampal Neurons ◽  
Hill Coefficient ◽  
Nmda Receptor Antagonists ◽  
Wild Type ◽  
Receptor Antagonists ◽  
Homocysteic Acid ◽  
In Cells

l-Homocysteic acid (HCA), an endogenous excitatory amino acid in the mammalian CNS, potently activates N-methyl-d-aspartate (NMDA) receptors in hippocampal neurons. However, the responses to HCA in Purkinje cells, which lack functional NMDA receptors, have been largely unexplored: HCA may activate conventional non-NMDA receptors by its mixed agonistic action on both NMDA and non-NMDA receptors, or it may activate a novel non-NMDA receptor that has high affinity for HCA. To test these possibilities, we compared the responses to HCA in cultured Purkinje cells with those in hippocampal neurons by using the whole cell patch-clamp technique. To clearly isolate HCA responses mediated by non-NMDA receptors, we complemented pharmacological methods by using neurons from mutant mice (NR−/−) that lack functional NMDA receptors. A moderate dose of HCA (100 μM) induced substantial responses in Purkinje cells. These responses were blocked by non-NMDA receptor antagonists but were insensitive to NMDA receptor antagonists. HCA also activated responses mediated by non-NMDA receptors in both wild-type and NR1−/− hippocampal neurons. HCA responses in Purkinje cells had a pharmacological profile (EC50 and Hill coefficient) very similar to that of non-NMDA receptor components of HCA responses in hippocampal neurons. Moreover, the amplitude of the non-NMDA receptor component of HCA responses was directly correlated with that of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)– and kainate-induced responses in both types of neurons. Finally, in both types of neurons, HCA currents mediated by non-NMDA receptors were potently blocked by the AMPA receptor antagonist GYKI52466. These findings indicate that HCA-activated AMPA receptors in Purkinje cells are similar to those in hippocampal neurons and that there is no distinct HCA-preferring receptor in Purkinje cells. We also found that in hippocampal neurons, the EC50s of HCA for non-NMDA receptors and for NMDA receptors were more similar than originally reported; this finding indicates that HCA is similar to other mixed agonists, such as glutamate. HCA responses may appear to be selective at NMDA receptors in cells that express these receptors, such as hippocampal neurons; in cells that express few functional NMDA receptors, such as Purkinje cells, HCA may appear to be selective at non-NMDA receptors.

scholarly journals Brain NMDA Receptors in Schizophrenia and Depression

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 947 ◽  
Author(s):  
Albert Adell
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Psychotic Symptoms ◽  
Positive Symptoms ◽  
Nmda Receptor Antagonists ◽  
Healthy Individuals ◽  
Treatment Resistant ◽  
Receptor Antagonists ◽  
Antidepressant Effects ◽  
Resistant Depression

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.

scholarly journals Dementia Management Act and Death Toll by Dementia Drug

2021 ◽  
Author(s):  
Jong-hoon Lee
Keyword(s):  
Nmda Receptor ◽  
South Korea ◽  
Acetylcholinesterase Inhibitors ◽  
Medical Data ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Death Toll ◽  
Dementia Patients ◽  
Psychotropic Medicines ◽  
All Cause Mortality

Abstract The Dementia Management Act (DMA) came into effect on August 4, 2011, in South Korea. Medical data on the correlation between Alzheimer's disease (AD) and anti-AD drug (AAD) groups were observed from 2010 to 2019. This study investigated the increase and decrease in deaths and AAD used to treat AD. It is known that psychotropic medicines should not be administered for dementia patients because they increase all-cause mortality. This study demonstrated that acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists increase the death toll when used to treat dementia.

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

2021 ◽  
pp. 019262332110077
Author(s):  
Catherine A. Picut ◽  
Odete R. Mendes ◽  
David S. Weil ◽  
Sarah Davis ◽  
Cynthia Swanson
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nmda Receptor Antagonists ◽  
Neonatal Rats ◽  
Receptor Antagonists ◽  
Fluoro Jade B ◽  
Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

Sign in / Sign up

Export Citation Format

Share Document