We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-d-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 µs of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the "clamshell" motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

• MeSH
• Rats MeSH
• Receptors, N-Methyl-D-Aspartate chemistry   metabolism   MeSH
• Molecular Dynamics Simulation * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Ifenprodil as a specific antagonist of NMDA receptors containing a dominant NR2B subunit exhibits age-dependent anticonvulsant action. Possible changes of this action due to status epilepticus (SE) elicited at early stage of development were studied using cortical epileptic afterdischarges (ADs) as a model. METHODS: Lithium-pilocarpine SE was induced at postnatal day 12 and effects of ifenprodil were studied 3, 6, 9, and 13 days after SE in rat pups with implanted epidural electrodes. Controls (LiPAR) received saline instead of pilocarpine. ADs were elicited by low frequency stimulation of sensorimotor cortex. Intensity of stimulation current increased in 18 steps from 0.2 to 15 mA. Ifenprodil (20 mg/kg) was administered intraperitoneally (ip) after the stimulation with 3.5-mA current. Threshold for four different phenomena as well as duration of ADs were evaluated. RESULTS: The threshold for the transition into the limbic type of ADs was higher in 15-day-old SE rats than in LiPAR controls. Opposite difference was found in 18-day-old animals, older rats did not exhibit any difference. Isolated significant changes in total duration of ADs were found after high stimulation intensities. These changes appeared in 18-day-old rats where ADs were shorter in SE than in control LiPAR rats. CONCLUSIONS: Changes in ifenprodil action were found only in the first week after SE but not in the second week. Interpretation of the results is complicated by failure of significant differences between SE and LiPAR rats probably due to a high dose of paraldehyde.

• MeSH
• Excitatory Amino Acid Antagonists pharmacology   MeSH
• Anticonvulsants pharmacology   MeSH
• Lithium Chloride MeSH
• Electric Stimulation MeSH
• Disease Models, Animal MeSH
• Cerebral Cortex drug effects   physiopathology   MeSH
• Brain Waves drug effects   MeSH
• Animals, Newborn MeSH
• Pilocarpine MeSH
• Piperidines pharmacology   MeSH
• Rats, Wistar MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   MeSH
• Status Epilepticus chemically induced   drug therapy   physiopathology   MeSH
• Age Factors MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.

• MeSH
• Acetylcholine metabolism   MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Biogenic Monoamines metabolism   MeSH
• Energy Metabolism drug effects   MeSH
• Central Nervous System Agents chemistry   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Synaptic Transmission drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• Cells * MeSH
• Molecular Biology MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• NML Fields
• molekulární biologie, molekulární medicína
• NML Publication type
• učebnice vysokých škol

Ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, was expected to exhibit anticonvulsant action in rat pups up to the third postnatal week because of predominance of NR2B subunit at early development. Cortical epileptic afterdischarges (ADs) were used to study possible effects on threshold current intensities and duration of ADs in 12-, 15-, 18-, and 25-day-old rats. A series of 18 stimulation series with stepwise increasing current intensities (from 0.2 to 15 mA) was applied with 10-min intervals. The first experiment studied rats pretreated with ifenprodil (20 or 40 mg/kg), the second experiment studied an effect of ifenprodil on already present ADs-the dose of 20 mg/kg was administered after stimulation with the 3.5-mA current intensity. Pretreatment with ifenprodil resulted in an anticonvulsant effect in 15-day-old rats only, on the contrary, proconvulsant action was found in 18- and 25-day-old animals (decrease of thresholds especially for transition into the second, limbic type of ADs and increase in duration of ADs). Anticonvulsant effect was found in 12-, 15-, and 18-day-old rats in the second experiment-ADs were shortened. In contrast, no effect was observed in 25-day-old animals. An anticonvulsant action of ifenprodil is not only age-dependent but also activation-dependent.

• MeSH
• Anticonvulsants therapeutic use   MeSH
• Electric Stimulation MeSH
• Animals, Newborn MeSH
• Pentylenetetrazole MeSH
• Piperidines therapeutic use   MeSH
• Rats, Wistar MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   MeSH
• Aging physiology   MeSH
• Seizures chemically induced   drug therapy   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

V diagnostice Alzheimerovy nemoci je zásadní včasné rozpoznání přítomnosti syndromu demence, následováno určením Alzheimerovy nemoci jako jeho nejpravděpodobnější příčiny. Přechodným stavem mezi normálním stárnutím a demencí je mírná kognitivní porucha. Pomocné vyšetřovací metody již neslouží pouze k vyloučení jiných příčin demence, ale mohou přímo podpořit diagnózu Alzheimerovy nemoci. Klinickými studiemi je prokázán efekt používaných léků na zpomalení průběhu nemoci. Pro léčbu lehké až středně těžké formy Alzheimerovy nemoci jsou k dispozici inhibitory acetylcholinesterázy, pro těžkou formu parciální antagonista NMDA receptorů – memantin.

Early recognition of the dementia syndrome is the most important part in the diagnostics of Alzheimer‘s disease. It is followed by determination of Alzheimer‘s disease as the most likely cause of it. A clinical transitional state between the normal ageing and dementia is referred to as mild cognitive impairment. The auxiliary diagnostic methods are not only used to rule out other causes of dementia, but they can directly support the diagnosis of Alzheimer‘s disease. The clinical trials have proved that current drugs slow the progression of the disease. We can use acetylcholinesterase inhibitors for treatment of mild to moderate Alzheimer‘s disease, whereas severe stages of the disease are treated by memantin – NMDA receptor partial antagonist.

• Keywords
• biomarkery,
• MeSH
• Alzheimer Disease diagnosis   therapy   MeSH
• Biomarkers MeSH
• Cholinesterase Inhibitors therapeutic use   MeSH
• Dementia diagnosis   MeSH
• Cognition Disorders diagnosis   drug therapy   MeSH
• Humans MeSH
• Memantine therapeutic use   MeSH
• Therapeutics MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

V diagnostice Alzheimerovy nemoci je zásadní včasné rozpoznání přítomnosti syndromu demence, následováno určením Alzheimerovy nemoci jako jeho nejpravděpodobnější příčiny. Přechodným stavem mezi normálním stárnutím a demencí je mírná kognitivní porucha. Pomocné vyšetřovací metody již neslouží pouze k vyloučení jiných příčin demence, ale mohou přímo podpořit diagnózu Alzheimerovy nemoci. Klinickými studiemi je prokázán efekt používaných léků na zpomalení průběhu nemoci. Pro léčbu lehké až středně těžké formy Alzheimerovy nemoci jsou k dispozici inhibitory acetylcholinesterázy, pro těžkou formu parciální antagonista NMDA receptorů – memantin.

Early recognition of the dementia syndrome is the most important part in the diagnostics of Alzheimer‘s disease. It is followed by determination of Alzheimer‘s disease as the most likely cause of it. A clinical transitional state between the normal ageing and dementia is referred to as mild cognitive impairment. The auxiliary diagnostic methods are not only used to rule out other causes of dementia, but they can directly support the diagnosis of Alzheimer‘s disease. The clinical trials have proved that current drugs slow the progression of the disease. We can use acetylcholinesterase inhibitors for treatment of mild to moderate Alzheimer‘s disease, whereas severe stages of the disease are treated by memantin – NMDA receptor partial antagonist.

• Keywords
• biomarkery,
• MeSH
• Alzheimer Disease diagnosis   drug therapy   MeSH
• Biomarkers MeSH
• Cholinesterase Inhibitors administration & dosage   adverse effects   therapeutic use   MeSH
• Dementia diagnosis   MeSH
• Financing, Organized MeSH
• Cognition Disorders diagnosis   drug therapy   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Memantine administration & dosage   adverse effects   therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Aging MeSH
• Therapeutics MeSH
• Check Tag
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Review MeSH