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Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of aged but not of young mice
Abstract
Chronic treatment (2 weeks) with piracetam (500 mg/kg, once daily PO) elevated m-cholinoceptor density in the frontal cortex of aged (18 months) female mice by about 30-40%, but had no effect on m-cholinoceptor density in the frontal cortex of young (4 weeks) mice. The effect of piracetam on m-cholinoceptor density as determined by the specific binding of tritiated QNB was not affected by concomitant daily treatment with either choline (200 mg/kg) or scopolamine (4 mg/kg). It is concluded that the effect of piracetam on m-cholinoceptor density could explain the positive effects which have been reported for combinations of cholinergic precursor treatment with piracetam on memory and other cognitive functions in aged experimental animals and patients and could also represent part of the possible mechanism of action of piracetam alone.
... Пирацетам оказывает важное воздействие на нейромедиацию, которое не ограничивается каким-то одним типом нейромедиатора. Препарат взаимодействует с системой нейротрансмиттеров, оказывая модулирующее действие на холинергическую [76,84,88,94], серотонинергическую [91], норадренергическую [81] и глютаматергическую [86,93] нейротрансмиссию, что особенно важно, поскольку нарушения синаптической передачи с участием ацетилхолина и глутамата обусловливают «возрастные» нарушения памяти и других когнитивных функций [34,86,89]. При исследовании влияния пирацетама на основные нейромедиаторные процессы выявлено, что, несмотря на то что по своей химической структуре пирацетам можно рассматривать как циклическое производное ГАМК, согласно данным фармакокинетического исследования препарата [63,77], циклическая часть его молекулы не подвергается размыканию с образованием ГАМК, которая могла бы оказывать прямой эффект. ...
... Сравнительное исследование [84] влияния пирацетама на уровень биогенных моноаминов в коре мозга, полосатом теле, гипоталамусе и стволе мозга показало, что препарат разнонаправленно влияет на основные нейромедиаторные системы в различных участках головного мозга. Так, пирацетам достоверно повышает содержание серотонина (5-НТ) во фронтальной коре мозга и уменьшает -в полосатом теле, гипоталамусе и стволе мозга [91]. ...
... Влияние пирацетама на холинергическую систему мозга проявляется в усилении синтеза и выброса ацетилхолина, обратного захвата холина в мозге, в повышении чувствительности и числа мускариновых рецепторов [64]. При исследовании скорости оборота моноаминов установлено, что пирацетам ускоряет оборот дофамина в коре мозга и гипоталамусе и замедляет его в полосатом теле, ускоряет оборот норадреналина в стволе мозга и замедляет его в полосатом теле и гипоталамусе, ускоряет оборот 5-НТ в коре мозга и замедляет его в полосатом теле, гипоталамусе и стволе [84]. ...
The review considers the stages of experimental and clinical study of piracetam in the framework of evidence-based medicine, its wide practical application in various fields of clinical medicine. The main attention pays to the mechanisms of action of the drug, its properties and physiological effects. The specific dose-dependent relation is revealed for the clinical effects of piracetam: the efficiency grows higher dependent on high doses and prolongation of courses.
... It is known that piracetam stabilizes the phospholipids in cell membranes [9] that, in turns, improve the recovering of receptors for glutamate [10] and acetylcholine [11]. This nootropic interacts with polar heads of phospholipids that were affected by oxidation, restoring the lipid organization and thus, the membrane fluidity [9]. ...
... S-P+ showed less proteins expression than all groups and a stress-like PCA. Previous studies showed that this drug seems to be implicated in the metabolism of specific proteins [10,11,48] or in total protein expression in liver and brain [49]. ...
Chronic psychological stress is an important public health issue which generates behavioral changes, anxiety, immunosuppression and oxidative damage. Piracetam is a cognitive enhancer, at cellular level it protects from oxidative stress. The aim of this study was to evaluate the effect of psychological stress and of piracetam on circulating mononuclear cells by analyzing the biochemical spectrome using Synchrotron Radiation Fourier Transform Infrared Microspectroscopy (SR-μFTIR). Rats were exposed for five days to a stressor (cat odor) under oral administration of piracetam (600 mg/kg). SR-μFTIR analysis showed a decrease in bands associated to the lipids region (2852 cm-1, 2923 cm-1 and 2962 cm-1) and an increase absorption of the amide I band (1654 cm-1) under stress conditions. The principal component analysis showed increase oxidation of lipids (decrease of 3010 cm-1, 2923 cm-1 and 2852 cm-1 bands) as well as proteins denaturation (increase of 1610 cm-1 and 1690 cm-1 bands) under stress. Piracetam provided protection to polyunsaturated lipids (p ≤ 0.001) and lipids/proteins ratio (p ≤ 0.001). Behaviorally, this drug diminished fear and anxiety in stressed animals by the plus maze test (p ≤ 0.002). However, this drug induced oxidative stress in mononuclear cells from unstressed animals and altered their behavior.
... Пирацетам оказывает влияние на несколько нейротрансмиттерных систем: холинергическую [5][6][7][8], серотонинергическую [9], норадренергическую [10] и глутаматергическую [11]. Модуляция этих биохимических систем связана с увеличением количества постсинаптических рецепторов и восстановлением функции этих рецепторов. ...
... Учитывая данные о влиянии дисфункции системы ацетилхолина и глутамата на когнитивное снижение, эффекты пирацетама на холинергическую и глутаматергическую нейротрансмиссию представляют наибольший интерес. На животных моделях пирацетам влияет на уровень ацетилхолина в гиппокампе [8] и увеличивает количество мускариновых холинергических рецепторов в лобной коре у пожилых крыс на 40% [6]. Под влиянием пирацетама нормализовался холинергический дефицит, связанный со старением [5,7]. ...
The article discusses the possibility of using the complex drug Phezam, containing 400 mg of Piracetam and 25 mg of Cinnarizine in neurological practice. The advantage of a combination of nootropic and vasoactive substances is due to a balanced and diversified influence on the different links of pathogenesis diseases. Piracetam targets the turnover of cell membranes, neurotransmission, has a neuroprotective effect, influences the neuroplasticity, the energy exchange in the cage and the vascular mechanisms (blood cells, cardiovascular wall and coagulation). The second component of the drug Cinnarizine has vasodilatating properties, suppresses the activity of the labyrinth and improves flow blood properties. When discussing the drug-induced parkinsonism, the opposite effects of the drug components on the dopaminergic system are described. The Phezam has shown its efficacy in the preventive treatment of migraines (reducing of frequency and intensity of seizures). In patients with chronic brain ischemia Phezam improved a neurological status, cognitive functions, blood flow indicators, and quality of life. The positive effects of Phezam during the recovery period of ischaemic stroke with speech and moderate cognitive disorders are reported. The characteristics of the metering regime are the possibility to use low-and high-dosage therapy. The drug showed good tolerability and economic advantages over the use of active substances separately.
... Как раз влияние пирацетама на работу холинергических и глутаматергических систем и приводит к улучшению когнитивных функций. В эксперименте показано, что пирацетам изменяет уровни ацетилхолина в нейронах гиппокампа и увеличивает количество м-холиноре цеп торов в лобной коре старых крыс на 40%, при этом у молодых животных такого влияния не выявлено [14]. Также экспериментальное лечение пирацетамом в течение 14 дней старых лабораторных животных приводило к увеличению количества NMDA-рецепторов на 20% [15]. ...
... Статистически значимых различий по выраженности когнитивных расстройств между мужчинами и женщинами не было: у мужчин средний балл составил 23,03 ± 1,52, у женщин -22,98 ± 1,76 (р = 0,71). Степень выраженности эмоциональных расстройств по ГШ на визите 1 составила 15,38 ± 5,06 балла (6-30 баллов), при этом средний балл по подшкале депрессии был 7,74 ± 2,65 балла (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), а по подшкале тревоги -7,74 ± 3,31 балла (2-16). Средний балл по модифицированной шкале астении был 75,64 ± 9,26 балла (48-95), что соответствовало выраженной астении. ...
The article considers the key issues of the clinical pattern, diagnosis and treatment of chronic cerebral ischemia. The results of the observation program "Thiocetam for focal neurological, mild cognitive, asthenic and emotional disorders accompanying chronic organic disease of the central nervous system - discirculatory encephalopathy." The article demonstrates that Thiocetam has a beneficial effect against mild cognitive impairment, asthenic disorders, light and moderate emotional disorders in the studied population.
... Piracetam increases high-affinity choline uptake and elevates the density of frontal cortex acetylcholine receptors. 26,27 It also has effects on glutamate neurotransmission at the micromolar level. 23,28 In addition, piracetam potentiates potassium-induced release of glutamate from hippocampal nerves. ...
... Since the loss of striatal cholinergic neurons may be a basis for the development of tardive dyskinesia, 4 one explanation relates to the ability of piracetam to elevate the density of acetylcholine receptors in the brain. 26,27 Another explanation is derived from the theory that free radicals are neurotoxic and that the antioxidant properties of piracetam 54 may neutralize this damaging effect. ...
... Károsodott sejteknél, jellemzően időskorban csökkent a membránfluiditás (1). In vivo patkány és egérkísérleteknél kimutatták azt is, hogy a piracetám hatással van a szerotonerg (2), noradrenerg (3), kolinerg (4,5) és glutamáterg (6) rendszerre egyaránt. A receptorokra ugyan nincs direkt hatással (K i >10 µM) (7), csupán a posztszinaptikus receptorok számát és a receptorok stabilitását befolyásolja (1,2,(5)(6)(7)(8)(9). Kognitív zavarban a kolinerg és glutamáterg rendszerek károsodtak; mivel a piracetám ezeket a rendszereket elméletben javítja, feltételezték hatásosságát ebben az indikációban (8,9). ...
Piracetámtartalmú gyógyszerek 1971 óta vannak forgalomban, ezek elsődleges indikációja az időskori memóriazavar. Jelen összefoglaló célja, hogy bemutassa a piracetám alkalmazásával kapcsolatos ellentmondásokat. A hatóanyag idegrendszeri és vaszkuláris hatásait az öregedéssel együtt jelentkező membránfluiditás-csökkenés befolyásával magyarázzák. A piracetám tudományos irodalma jelentős, ugyanakkor szisztematikus Cochrane-összefoglalók és -metaanalízisek is megkérdőjelezték hatásosságát demencia, kognitív zavar, akut stroke utáni afázia kezelése és vazookkluzív krízis profilaxisa esetében is. Ezzel szemben akut vertigo és kortikális mioklónus kezelésében a hatásossága megfelelően alátámasztottnak tűnik. A hazánkban elérhető piracetámtartalmú gyógyszerek indikációi nem identikusak, továbbá az alkalmazási előiratban szereplő memóriazavar nem egyezik a betegtájékoztatóban leírt, az agy egyes funkcióinak javítására (pl. tanulás) vonatkozó indikációval. Felhasználása Magyarországon a fenti ellentmondások ellenére is jelentős, 2022-ben megközelítőleg 10 000 lakos alkalmazott piracetámtartalmú gyógyszert napi szinten, a napi terápiás adagnak megfelelő, 2400 mg-os dózisban. Az európai gyógyszeradatbázisok alapján megállapítható, hogy az elérhetőség, az indikációs kör és a kognitív zavarban javasolt napi dózis is különbözik országonként. Az Egyesült Államokban piracetámtartalmú gyógyszert nem engedélyeztek, illetve étrend-kiegészítőként való alkalmazását sem támogatja az FDA. Időskorban a demencia, a kognitív zavar előfordulása gyakoribb, azonban a piracetám alkalmazását ilyen indikációban a nemzetközi és hazai irányelvek, illetve a megfelelő gyógyszerelést elősegítő eszközök (ún. PIM-listák) egyöntetűen nem javasolják. Összességében elmondható, hogy a hazánkban demencia és kognitív diszfunkció kapcsán igen széles körben alkalmazott piracetám hatásosságára vonatkozóan tényleges tudományos evidenciákkal nem rendelkezünk, ezekben az indikációkban alkalmazása megalapozatlan.
... Use of piracetam has been shown to lead to both increases in ACh synthesis and release and to increases in high-affi nity ACh reuptake in the brains of elderly animals, resulting in increases in ACh to the level typical of young animals [Pepeu and Spignoli, 1989]. Administration of piracetam produced a 30-40% increase in the density of muscarinic cholinoreceptors in the frontal cortex in elderly mice but had no such effect in young mice [Pilch and Müller, 1988]. At the same time, neither piracetam nor pramiracetam nor oxyracetam nor pyroglutamic acid showed any affi nity for muscarinic receptors (IC 50 > 10000 nM) [Pugsley et al., 1983]. ...
The nootropic agents noopept and piracetam alter the amplitudes of acetylcholine-induced influx currents (ACh currents) in command neurons in the common snail. Both compounds have cholinopositive activity. The dose curve of the actions of noopept is bell-shaped, while the piracetam dose-response curve in the range of physiological concentrations shows a monotonous rise. Noopept increases the ACh current at low concentrations (10–10–10–8 M), while piracetam acts at significantly higher concentrations (starting from 10–4 M). The magnitudes of the maximal cholinopositive effects of noopept and piracetam (in the range of physiological concentrations) were identical, while the concentrations of nootropic drugs at which they were reached differed by seven orders of magnitude. The half-maximal concentration (EC50) of noopept was 10–10 M and that of piracetam was 10–3 M. The mechanisms of the cholinopositive actions of these drugs are discussed.
... Как раз влияние пирацетама на работу холинергических и глутаматергических систем и приводит к улучшению когнитивных функций. В эксперименте показано, что пирацетам изменяет уровни ацетилхолина в нейронах гиппокампа и увеличивает количество М-холинорецепторов в лобной коре старых крыс на 40%, при этом у молодых животных такого влияния не выявлено [37]. Также экспериментальное лечение пирацетамом в течение 14 дней старых лабораторных животных приводило к увеличению количества NMDA-рецепторов на 20% [15]. ...
... Pramiracetam, un composto piracetam-correlato, aumenta l'attività del trasportatore sodio-dipendente per la colina, intermedio della sintesi dell'acetilcolina, in sinaptosomi di ippocampo di ratto, suggerendo che gli effetti clinicamente rilevanti del piracetam sulla funzione cognitiva in diversi contesti fisiopatologici potrebbero dipendere da un potenziamento della frequenza di scarica dei neuroni colinergici presenti nella regione settoippocampale (Pugsley T.A. et al., 1983). Il coinvolgimento del sistema colinergico è dimostrato anche dall'osservazione che il piracetam aumenta la densità recettoriale colinergica (Pilch H. et al., 1988) e che il fenilpiracetam presenta un'elevata affinità di legame per il recettore colinergico nicotinico (nAch), ma non per il recettore glutammatergico NMDA (Kovalev G.I. et al., 2007). Il levetiracetam, che, pur essendo un composto piracetam-correlato, presenta un profilo clinicofarmacologico specifico differente da quello del piracetam, si lega, con elevata affinità, alla proteina vescicolare sinaptica 2A (SV2A), che rivestirebbe un ruolo critico nei processi di esocitosi delle vescicole sinaptiche e di trasduzione del segnale elettrico-chimico a livello della sinapsi (Lynch B.A. et al., 2004). ...
... на. Например, в литературе приводятся данные о том, что пирацетам увеличивает плотность М-холинорецепторов во фронтальной коре пожилых крыс [241]. Пирацетам модулирует активность нейротрансмиттерных и пластических процессов мозга [235,242,243] ...
Монография посвящена анализу методов синтеза и биологической активности рацетамов - структурных аналогов ноотропного препарата пирацетама. В книге систематизированы литературные данные и результаты собственных исследований по методам синтеза и фармакологическим свойствам наиболее известных рацетамов, содержащих пирролидоновый цикл. В первой главе представлены сведения о способах получения рацетамов, применяемых в медицинской практике или находящихся на разных стадиях разработки, а также о свойствах и строении со-кристаллических форм рацетамов с различными органическими кислотами и неорганическими солями. Вторая глава содержит анализ фармакологических свойств рацетамов, используемых в медицине или изучаемых в качестве биологически активных субстанций.
Книга предназначена для преподавателей, научных сотрудников, аспирантов, студентов магистратуры и бакалавриата, работающих в области органической, медицинской химии и фармакологии.
... Piracetam elevates the frontal cortex density of acetylcholine receptors by 30-40%, and also restoring the levels to those of healthy young mice. 11 Piracetam also elevates NMDAR density in the hippocampus by 20% and normalizes the enhanced affinity of L-glutamate for the NMDAR and also attenuates excess neuronal firing by reducing high voltage-dependent calcium influx into neurons. It also increases cerebral blood flow, cerebral oxygen usage, metabolic rate and cerebral glucose metabolic rates in chronic impaired human brain function conditions like multiinfarct dementia (due to stroke), senile dementia (Alzheimer type and pseudo dementia) and ischaemic cerebral infarcts. ...
Background: Pioglitazone (PIO), a Peroxisome Proliferator Activated Receptor γ (PPAR-γ) agonist, is an oral anti-diabetic agent belonging to the group of thiazolidinediones-TZDs used for the treatment of diabetes mellitus type 2 in monotherapy and in combination with a sulfonylurea, metformin, or insulin.Methods: All animals were allowed to acclimatize with laboratory conditions at least two weeks before starting the experiment and they were maintained under the same condition throughout the experiment. They were given food and water ad libitum. The experiments were performed as per the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA) guidelines. The animals were subjected to experimentation between 0900-1600 hours in noise free atmosphere with ambient temperature 23-300ºC.Results: There was no significant reduction in the within group comparisons of the basal and final scores in locomotor activity.Conclusions: The standard and test groups failed to produce any significant reduction in locomotor activity in the intergroup comparison as well as compared to normal control.
... Administration of aniracetam or piracetam affects the muscarinic receptor binding in the different brain regions [76]. Study by Pilch and Müller [77] had established the upregulation of m-cholinoceptor in the brain responding to the aging brain. ...
... Administration of aniracetam or piracetam affects the muscarinic receptor binding in the different brain regions [76]. Study by Pilch and Müller [77] had established the upregulation of m-cholinoceptor in the brain responding to the aging brain. ...
Nootropics or smart drugs are well-known compounds or supplements that enhance the cognitive performance. They work by increasing the mental function such as memory, creativity, motivation, and attention. Recent researches were focused on establishing a new potential nootropic derived from synthetic and natural products. The influence of nootropic in the brain has been studied widely. The nootropic affects the brain performances through number of mechanisms or pathways, for example, dopaminergic pathway. Previous researches have reported the influence of nootropics on treating memory disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Those disorders are observed to impair the same pathways of the nootropics. Thus, recent established nootropics are designed sensitively and effectively towards the pathways. Natural nootropics such as Ginkgo biloba have been widely studied to support the beneficial effects of the compounds. Present review is concentrated on the main pathways, namely, dopaminergic and cholinergic system, and the involvement of amyloid precursor protein and secondary messenger in improving the cognitive performance.
... The mechanisms lying behind the actions of piracetam are not fully elucidated. It has been reported that piracetam can restore changes that occur in brain membrane fluidity during aging, and elevates both muscarinic cholinergic and NMDA receptor density in rodents (Cohen and Muller 1993;Pilch and Muller 1988). Moreover, mitochondrial protective properties have been also described for piracetam ). ...
The review provides information about the features of cognitive dysfunctions that occur in various diseases and conditions, and data on the history of the creation and characteristic features of nootropics. The review presents the mechanisms of action and the spectrum of pharmacological effects of nootropic drugs from various groups: drugs that affect brain metabolism, neurotransmitter systems (cholinergic, glutamatergic, gabaergic and others), cerebral vasodilators, neuropeptides and their analogues, antioxidants, membrane protectors and others. The free radical and mitochondrial concepts of aging and the possibility of using nootropics for the correction of cognitive impairments arising from aging, dementia and other neurodegenerative diseases are considered.
—This review provides information about the features of cognitive dysfunctions that occur in various diseases and conditions, and data on the history of the creation and characteristic features of nootropics. The review presents the mechanisms of action and the spectrum of pharmacological effects of nootropic drugs from various groups: drugs that affect brain metabolism, neurotransmitter systems (cholinergic, glutamatergic, GABAergic, and others), cerebral vasodilators, neuropeptides and their analogues, antioxidants, membrane protectors, and others. The free radical and mitochondrial concepts of aging and the possibility of using nootropics for the correction of cognitive impairments arising from aging, dementia, and other neurodegenerative diseases are considered.
Background:
Oxiracetam may have a modest effect on preventing cognitive decline. Exercise can also enhance cognitive function. This trial aims to investigate the effect of oxiracetam on post-stroke cognitive impairment and explore whether this effect is modified by exercise. Furthermore, the mechanisms that mediate this effect will be investigated through a neural network analysis.
Methods:
This is a multicenter, randomized, double-blind, placebo-controlled phase IV trial. Patients who complained of cognitive decline 3 months after stroke and had a high risk of cognitive decline were eligible. Patients were randomly assigned to receive either 800 mg of oxiracetam or placebo twice daily for 36 weeks. After randomization, a predetermined exercise protocol was provided to each participant, and the degree of physical activity was assessed using wrist actigraphy at 4, 12, 24, and 36 weeks. Resting-state functional MRI was obtained in baseline and 36-week follow-up. Co-primary endpoints are changes in the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Secondary endpoints include changes in the NINDS-CSN VCIHS-Neuropsychology Protocol, Euro QoL, patient's global assessment, and functional network connectivity. If there is a significant difference in physical activity between the two groups, the interaction effect between physical activity and the treatment group will be examined. A total of 500 patients were enrolled from February 2018, and the last patient's final follow-up was completed in September 2022.
Conclusion:
This trial is meaningful not only to prove the efficacy of oxiracetam, but also evaluate whether exercise can modify the effects of medication and how cognitive function can be restored. Trial registrationhttp://cris.nih.go.kr (KCT0005137).
The racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture (MP-101). In vitro, dimiracetam was more potent than its R- or S-enantiomers in reducing the NMDA-induced [3H]D-aspartate release in rat spinal cord synaptosomes. Similarly, acute oral administration of dimiracetam was more effective than a single enantiomer in the sodium monoiodoacetate (MIA) paradigm of painful osteoarthritis. Then, we compared the in vitro effects of a broad range of non-racemic enantiomeric mixtures on the NMDA-induced [3H]D-aspartate release. Dimiracetam was a more potent blocker than each isolated enantiomer but the R:S 3:1 non-racemic mixture (MP-101) was even more potent than dimiracetam, with an IC50 in the picomolar range. In the chronic oxaliplatin-induced neuropathic pain model, MP-101 showed a significantly improved anti-neuropathic profile, and its effect continued one week after treatment suspension. MP-101 also performed better than dimiracetam in animal models of cognition and depression. Based on the benign safety and tolerability profile previously observed with racemic dimiracetam, MP-101 appears to be a novel, promising clinical candidate for the prevention and treatment of several neuropathic and neurological disorders.
It is often implied that antipsychotic-induced extrapyramidal side-effects are irrelevant to modern psychiatric therapeutics, rendered historic by newer, better treatments. This myth arises from limited awareness of the depth and breadth of neurological disruption antipsychotics can mediate. This volume discusses the extensive clinical boundaries of acute dystonias, drug-induced parkinsonism, akathisia and tardive dyskinesia, providing demographic and epidemiological context while illustrating how prescribing choices impact powerfully on their development. This new edition has been thoroughly updated and rewritten to include recent data, expanded references and a new chapter on the concept of 'atypical' antipsychotics. Written in a light, engaging style, liberally illustrated with clinical examples, it also invites readers to consider ongoing controversies - subjective drug effects, the relationship between 'akathisia' and restless legs, the status of the concept of 'atypicality', and so on. Informative reading for trainees as well as established practitioners in the fields of psychiatry, neurology, primary care and geriatrics.
In this study, the effect of the nootropic drug piracetam on brain oxidative stress and histopathological changes in brain, liver and kidney following exposure to toluene in rats was examined. Piracetam (150 or 300 mg/kg, subcutaneously, daily) was given along with toluene (500 mg/kg, intraperitoneally, daily) for one week. The brain content of malondialdehyde (MDA), reduced glutathione (GSH) and the activity of paraoxonase-1 (PON-1), and butyrylcholinesterase (BChE) in brain homogenates were determined. Histopathology of the brain, liver and kidney and brain Bax immunohistochemistry were performed. Results showed that exposure to toluene resulted in increased brain lipid peroxidation (MDA) and NO along with decreased reduced glutathione. Toluene also inhibited PON-1, and BChE activities. The administration of piracetam had no significant effect on brain lipid peroxidation. The level of reduced glutathione was unchanged by piracetam but PON1 activity was increased by the lower dose of the drug. Piracetam showed no significant effect on BChE activity in toluene treated rats. Histopathological examination of the brain of toluene only treated rats showed degenerated neurons in cerebral cortex, marked neuronal vacuolation in hippocampus and focal hemorrhage. Bax 3 immunohistochemical staining showed cytoplasmic reactivity in degenerated neurons. Rats given piracetam showed decreased cortical cellularity, increased number of degenerated neurons and increased BAX staining. The higher dose of the drug caused sinusoidal hemorrhage and intertubular hemorrhage in kidney. Collectively, these results indicate that treatment with piracetam wan not able to decrease neuronal damage in rats exposed to toluene.
Chronic cerebral hypoperfusion (CCH) is the most common cause of cognitive impairment, which is commonly found in Alzheimer’s disease (AD) and vascular dementia (VaD). Recently, studies have demonstrated that melatonin is an effective treatment in various neurodegenerative diseases. In this study, we aimed to investigate the effects of melatonin on CCH-induced AD pathology, endoplasmic reticulum (ER) stress, and synaptic plasticity, all of which are correlated with the activation of oxidative stress, apoptosis, and cognitive impairment. CCH was induced in male Wistar rats by bilateral common carotid artery occlusion (2VO). After surgery, rats were treated with melatonin (10 mg/kg) or piracetam (600 mg/kg) by oral gavage once a day for 4 weeks. At the end of the experiment, all rats were assessed for memory impairment by using the Morris water maze test. Subsequently, rats were sacrificed, and brains were removed to determine the levels of beta-amyloid (Aβ), malondialdehyde (MDA); the acetylcholinesterase (AChE) activity; subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL); and subjected to western blotting of proteins related to memory, AD pathology, oxidative stress, ER stress, and apoptosis. Melatonin alleviated brain injury during 2VO induction, as revealed by decreased the expression of AD markers, attenuated oxidative stress, suppressed the expression of proteins related to ER stress, apoptosis, and stimulated the expression of the synaptic markers resulting in promoted cognitive function. Therefore, our data demonstrated that melatonin ameliorated cognitive impairment in the 2VO model, and these beneficial effects were associated with reduction in oxidative stress, ER stress, and apoptosis.
The actions of the nootropes noopept and piracetam on depression of the acetylcholine-induced current in a cellular analog of habituation were studied. Mathematical modeling of experimental curves and their analysis using previously obtained results on the effects of inhibitors of different protein kinases and protein phosphatases on acquisition of depression of the acetylcholine-induced current in a cellular analog of habituation clarified the intracellular processes and targets on which these agents act.
Neuropsychiatric symptoms (NPS) like psychosis, depression and aggression are considered the main characteristics of Alzheimer’s disease (AD). Piracetam is a derivative of the neurotransmitter gammaaminobutyric acid (GABA) which is mainly responsible for the restoration of cell membrane fluidity. Piracetam has antithrombotic, neuroprotective, rheological and anticonvulsant properties and also improves neuroplasticity. It has been reported that piracetam decreases erythrocyte adhesion to vascular endothelium, inhibit the vasospasm and stimulate microcirculation. It is useful in the treatment of vertigo, cognitive disorders, dementia, dyslexia and sickle cell anemia. It improves learning, memory, brain metabolism and capacity. Piracetam protects the cells against hypoxia. Nowadays, there is increased use of nootropic drugs for the treatment of CNS disorders.
Tardive syndromes (TDS) are a group of delayed-onset iatrogenic movement disorders that results from exposure to dopamine receptor-blocking agents (DRBAs). Tardive is derived from the French word tardif meaning ‘late’. Dyskinesia is from the Greek word kinein meaning ‘to move’, while the prefix ‘dys’ means ‘disturbed’.
The various types of TDS may be accompanied by sensory symptoms like pain, paresthesia and, a feeling of inner restlessness. Based on the criteria from Diagnostic and statistical Manual of Mental Disorder, 5th edition (DSM-5), TDS develops during exposure to DRBA for at least 3 months or within 4 weeks and 8 weeks of withdrawal of oral and depot medication respectively. Most symptoms of TDS appear after 1 to 2 years of exposure to DRBA and usually not before 3 months. Severity of TDS ranges from barely noticeable mild involuntary movement to disabling condition. Its onset is usually insidious, evolving to full symptoms over days and weeks, and then followed by period of stability of the symptoms, and chronic waxing and waning course. In terms of phenomenology, there are a number of distinct types of tardive syndromes which can manifest singly or in combination. These include tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tics, tardive myoclonus, tardive tremors, and withdrawal-emergent tardive. Others are tardive blepharospasm, tardive stereotypy, tardive gait, tardive tourettism, and tics.
In this chapter these subtypes are described in details.
Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum.
We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category.
The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term.
When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA.
The approvals of the first two medications, valbenazine and deutetrabenazine, to treat tardive dyskinesia have ushered in a new era in neuropsychiatric care. Tardive syndromes are defined as delayed onset, persistent movement disorders or sensory phenomena that occur in association with exposure to dopamine receptor blocking agents (DRBAs). Their underlying pathophysiology remains to be fully elucidated, but clinicians can conceptualize tardive syndromes as persistent dopamine supersensitivity states. Tardive syndromes can potentially cause distress, disfigurement, embarrassment, and dysfunction, and are often permanent. Therefore, practitioners who prescribe DRBAs should be aware of this potential, carefully assess the risk/benefit ratio when considering the use of these medications, and be sure that patients are appropriately informed. Patients on DRBAs should be monitored for the development of tardive syndromes, including through the use of regularly scheduled Abnormal Involuntary Movement Scale (AIMS) (or similar) examinations. Clinicians prescribing DRBAs should be familiar with the diagnosis and management of tardive syndromes, and be able to institute treatment or refer patients when treatment is appropriate. Future research may focus on the potential benefit of earlier introduction of VMAT2 inhibitors to delay onset or progression of tardive syndromes. More effective treatments are still needed, as are effective, well-tolerated antipsychotics that do not cause tardive syndromes.
Although VMAT2-inhibitors are now established as first-line treatment for tardive dyskinesia, not all patients respond to, or tolerate them. Numerous other agents have been adopted to treat tardive dyskinesia, but with variable results and generally lower quality methodologic reports. Amantadine is the most promising but benzodiazepines, branched chain neutral amino acids, Vitamin B6, several nutraceuticals, and botulinum toxin injections might help some patients. In all cases, better placebo controlled trials are needed before definitive recommendations can be made.
Nootropika vom Typ Piracetam sollen eine stimulierende Wirkung auf die Lernfähigkeit und das Erinnerungsvermögen haben (siehe z. B. Mondadori et al. 1989), obwohl die meisten tierexperimentellen Hinweise dafür auf die Beobachtung einer Erleichterung der Aneignung und der Retention eines passiven Vermeidens basieren. Tatsächlich verfügt man über verhältnismäßig wenig Hinweise bezüglich einer Wirkung von nootropen Pharmaka auf andere Formen des Erlernens. Pramiracetam verbessert die Leistung in einem radialen Labyrinth (Murray und Fibiger 1986) und Piracetam scheint bei höherer Dosis (400 mg/kg i. p.) die Diskriminierung zwischen einem bereits explorierten und einem neuen Objekt zu erleichtern (Ennaceur und Delacour 1987, Ennaceur et al. 1989). Schlußendlich verbessert Aniracetam wie cholinerge Agonisten die Retention von olfactiven Informationen, was der Ratte den Ausdruck von sozialem Wiedererkennen erlaubt (Perio et al. 1989).
The so-called membrane hypothesis of aging assumes that several functional deficits of the aging brain can be explained on the basis of age-related changes of the composition of brain cell membranes leading to an increased cholesterol to phospholipid ratio, increased levels of saturated fatty acids, and a decreased membrane fluidity [3, 22]. Since the integrity of the neuronal membrane seems to be fundamental for most biochemical mechanisms involved in cell to cell communication like transmitter release, receptor activation, and signal transduction, many functional deficits of the aging brain can be easily explained by this hypothesis [3].
Background: Piracetam is a potent antioxidant, a cerebral neuroprotector, a neuronal metabolic enhancer, and a brain integrative agent. More than 20 years ago, an intravenous preparation of piracetam demonstrated an improvement in the symptoms of tardive dyskinesia. The aim of our study was to reexamine the efficacy of piracetam in the treatment of tardive dyskinesia using an oral preparation. Method: The study was conducted at the Be'er Sheva Mental Health Center from May 2003 to December 2004 and involved a 9-week, double-blind, crossover, placebo-controlled trial assessing 40 DSM-IV schizophrenic and schizo-affective patients with DSM-IV-TR tardive dyskinesia. All study subjects received their usual antipsychotic treatment. Initially, subjects were randomly assigned to receive 4 weeks of treatment with either piracetam (4800 mg/day) or placebo. Thereafter, following a washout period of I week, they entered the crossover phase of the study for a further 4 weeks. The change in score of the Extrapyramidal Symptom Rating Scale from baseline to the study endpoint was the primary outcome measure. Results: The mean decrease in score from baseline to endpoint in the clinical global impression subscale in patients treated with piracetam was 1.1 points compared to 0.1 points in the placebo group (p =.004). The mean decrease in the tardive parkinsonism subscale was 8.7 points in patients treated with piracetam and 0.6 points in those on placebo (p =.00 1). The mean decrease in the tardive dyskinesia subscale was 3.0 points in the piracetam group in contrast to deterioration of condition in the placebo group by -0.2 points (p =.003). Conclusion: Piracetam appears to be effective in reducing symptoms of tardive dyskinesia. The specific mechanism by which piracetam may attenuate symptoms of tardive dyskinesia needs to be further evaluated. Clinical Trials Registration: ClinicalTrials.gov identifier NCT00 190008.
Results of the dexamethasone suppression test (DST) in demented nondepressed patients have varied considerably, and there is evidence that these depend on the type of dementia, ie, Alzheimer's disease (AD) or multi-infarct dementia (MID). AD is characterized by decreased central acetylcholine (Ach) activity, while MID is thought to be vascular in etiology. Pirecetam normalizes cerebral blood flow, along with other positive hemorheological properties. It may also increase central Ach levels. We performed the DST twice, 1 week apart, on 96 stable, demented geriatric inpatients. In 33 (21 AD, 11 MID), piracetam was started at an oral dose of 4.8 g/d 4-6 months before the first DST. The remaining 64 (39 AD, 25 MID) were untreated. Among untreated patients, those with MID were less suppressible (P < 0.001 and P = 0.01) and had more week-to-week variability (P = 0.0006) in the DST than AD patients. This is consistent with our previous findings. However, treated patients showed no difference in either post-dexamethasone cortisol levels or reproducibility of DST results. We interpret these findings to mean that piracetam, by increasing central Ach, makes AD patients less suppressible on the DST, and by maintaining more constant limbic blood flow, makes MID patients more DST stable.
Eine der vielen Veränderungen, die in unserem zentralen Nervensystem im Verlaufe des normalen Alterns nachweisbar sind, ist eine Abnahme der Dichte verschiedener Neurotransmitterrezeptoren. Eine Zusammenfassung solcher altersbedingter Rezeptorabnahmen im Zentralnervensystem von Ratte und Maus ist in Tabelle 1 dargestellt. Die Frage, inwieweit sich diese Veränderungen der Neurotransmitterrezeptoren mit zunehmendem Alter auch in entsprechenden Veränderungen der Rezeptoreffektorsysteme niederschlagen, ist noch nicht für alle dieser Rezeptoren untersucht. Erste Evidenzen für eine Abnahme der rezeptorgekoppelten Aktivierung der Adenylatzyklase existieren in der Ratte für den Dopaminrezeptor, den Histaminrezeptor und den β-adrenergen Rezeptor (MAKMAN et al. 1979; PALM U. WIEMER 1982).
Piracetam, a pyrrolidone, is a nootropic agent. Developed in the 1960s, piracetam was the first drug to be labeled a nootropic, which is an agent that purportedly enhances memory and learning .....
Synopsis
Piracetam is a derivative of γ- aminobutyric acid (GABA) and was the first commercially available nootropic drug. Although widely evaluated in the treatment of senile cognitive disorders and dyslexia, it has also been assessed as a treatment for deficits associated with acute stroke.
Data from a subgroup of patients in the Piracetam in Acute Stroke Study (PASS) suggest that piracetam may provide a modest level of neurological and functional protection when administered within several hours of a moderate or severe stroke. However, findings from this study have yet to be confirmed. Data from a number of small, short term studies in patients treated within a few days of stroke suggest that piracetam is more effective than placebo for the treatment of functional deficits.
Piracetam has shown varying degrees of efficacy against poststroke aphasia in several placebo- controlled studies when administered within several hours, a few days or several weeks or more after stroke. Its most likely role is one of early treatment (within several hours or a few days of stroke) in combination with speech therapy.
Conclusions: On the basis of current information, it seems reasonable to conclude that piracetam may have potential in the treatment of general poststroke deficits, but that further data (including those from an ongoing phase III study) are needed before more definitive conclusions can be drawn. The available data need to be considered against the absence of established treatment options in this indication and the generally modest efficacy of other investigational agents. The benign tolerability profile of piracetam is also relevant in this respect. Piracetam may be a useful option in patients with poststroke aphasia, especially when started soon after stroke, particularly since there are no established pharmacological treatment options for this indication and speech therapy has only limited success.
Pharmacodynamic Properties
Piracetam is a cyclic derivative of γ-aminobutyric acid (GABA) which has neuronal, haemorrheological and antithrombotic effects. It enhances a variety of types of neurotransmission, primarily through postsynaptic modulation of receptor density and activity. Placebo-controlled studies have shown that piracetam protects against hypoxia-induced changes in brain function and performance in healthy volunteers and patients, as assessed by electroencephalogram and psychometric evaluations. The drug has beneficial effects on cerebral microcirculation and metabolism in patients with cerebral ischaemia, improving cerebral blood flow and oxygen metabolism in ischaemic areas while having no significant effects in areas with normal perfusion.
Pharmacokinetic Properties
Maximum plasma concentrations (Cmax) of piracetam are reached about 30 to 50 minutes after oral administration in healthy volunteers and the drug has complete oral bioavailability. Values for Cmax of 15 to 37 mg/L were reported after single-dose administration of piracetam 800mg in healthy volunteers. Piracetam crosses the blood-brain barrier and appears to be preferentially retained in brain tissue. Plasma elimination half-life ranged from 4.3 to 6.6 hours after single-dose oral or intravenous piracetam administration in healthy volunteers and no metabolites have been detected. Although piracetam clearance is closely correlated with renal function, total and renal clearance rates of 98.9 and 65.8 ml/min (5.9 and 3.9 L/h) after oral administration in 16 healthy volunteers suggest an additional, nonrenal route.
Clinical Potential
Neurological and functional capacity in patients receiving piracetam within 13 hours of stroke was not significantly different from that in placebo recipients in the Piracetam in Acute Stroke Study (PASS). However, piracetam was significantly more effective than placebo in the subgroup of 360 patients in PASS who were treated within 7 hours of a moderate or severe stroke. Orgogozo scores at 4 weeks (the primary end-point) were 54.9 ± 31.9 with piracetam and 47.6 ± 30.4 with placebo (≈80 and 60% improvement from baseline). Piracetam was also more effective than placebo in this subgroup when Barthel scores at 12 weeks were analysed. There were no significant differences in mortality between piracetam and placebo (total or subgroup analyses).
Piracetam was significantly more effective than placebo according to analysis of patient response rates or assessments of a number of specific clinical parameters in 3 smaller, short term studies (treatment started within a few days of stroke). 74 to 85% of piracetam recipients experienced improvements in arm or leg movements or aphasia, compared with 21 to 35% of placebo recipients, in one study (n = 56). The number of patients who showed improvement or had no functional deficit at the end of another study was 47 to 100% higher with piracetam than with placebo for parameters of motor function, sensory disturbances and aphasia (n = 40).
The incidence of aphasia remission (assessed using the Frenchay Aphasia Screening Test) was significantly higher in piracetam recipients than in placebo recipients during PASS (33 vs 23% for treatment within 13 hours, p = 0.04; 37 vs 21% for treatment within 7 hours, p = 0.02). Analysis of Aachen Aphasia Test subscores from piracetam recipients showed improvements of up to 91% compared with placebo in 2 studies in which treatment was started several weeks or more after stroke in patients undergoing speech therapy. The benefit of piracetam was statistically significant according to multivariate analysis in one study and according to univariate analysis of 2 subtests in the other study. Piracetam produced significantly higher patient response rates than placebo during treatment of aphasia in 2 small, short term studies in which treatment was started within a few days of stroke.
Tolerability
Piracetam produces a relatively low incidence of generally mild adverse events. In an analysis of 91 double-blind studies involving 5867 patients (multiple indications and dosages), hyperkinesia, weight increase, nervousness, somnolence, depression and asthenia were significantly more frequent with piracetam than with placebo, although the incidence of each event in piracetam recipients was less than 2%. Spontaneous reports of 268 adverse events in 157 patients treated with piracetam were received during 9 years of postmarketing surveillance; central and peripheral nervous system, psychiatric, gastrointestinal and skin/appendage events were the most common.
Piracetam and placebo recipients had similar numbers of adverse events in PASS; 10 and 6 patients, respectively, withdrew from the study because of adverse events. Symptomatic haemorrhagic transformation of the infarct occurred in ≈4% of patients in each group. Ten patients in another clinical trial received piracetam after haemorrhagic infarction, with no apparent severe or unusual adverse events.
Dosage and Administration
Patients with cerebrovascular ischaemia should initially receive a 12g bolus of piracetam as soon as possible after stroke followed by 12 g/day intravenously in 3 or 4 divided doses for 1 month. Oral piracetam 4.8 g/day is recommended for maintenance therapy. Piracetam dosage should be reduced to one-quarter or one-half of the usual dosage in patients with mild or moderate renal failure and the drug is contraindicated in those with severe renal impairment.
The behavioral effects of two nootropic drugs, piracetam and oxiracetam, were investigated on measures of anxiety in an elevated-x-maze test in mice. In this test, the acute effects of 250, 500, and 1,000 mg/kg intraperitoneal (IP) piracetam and 50, 100, and 200 mg/kg IP oxiracetam were compared with those of an established reference drug, lorazepam (0.025, 0.050, and 0.10 mg/kg IP). The putative anxiolytic effects of ± propranolol, a beta-blocker with 5HT1A and 5HT1B antagonistic properties, were also evaluated. Results showed that both piracetam and oxiracetam had no significant effect on the percentage of entries made onto the open arms or the percentage of time spent in the open arms or the total arm entries. A pronounced anxiolytic effect was evident after treatment with 0.050 and 0.10 mg/kg IP lorazepam or 5 and 10 mg/kg IP ± propranolol. In conclusion, our data show that two nootropic drugs, piracetam and oxiracetam, acutely administered in mice, are devoid of anxiolytic properties in the elevated-x-maze test of anxiety.
This paper reviews the development of the concept of nootropics--compounds whose activity appears to be specific to enhancement and protection of those functions of plasticity of the central nervous system that we now call cognition. The rest of the review focuses on clinical and preclinical results reported on 2-pyrrolidinone-containing noortropics since 1986. Although the clinical efficacy of these compounds remains to be proved definitively, there are some double-blind trials that demonstrate superiority against placebo. Preclinically, a wide variety of laboratories continue to demonstrate and expand protective effects of nootropics against various insults of the CNS.
The human aging process is extremely complex and appears to affect all bodily functions equally. The tremendous advances in molecular biology over the past decade have made it possible to begin to study the basic mechanisms of aging at the molecular level and relate those findings to specific age-related diseases at the cellular, tissue, and organ level. It is likely that these advances will demonstrate that there are multiple mechanisms underlying the aging process at all levels and that multiple interventions will therefore be necessary to arrest, slow, or reverse the aging process. Factors already known to be intimately involved in aging include environmental, dietary, and genetic influences; each appears to be involved. Consequently, no single agent is likely to be found that will arrest or reverse all aging processes. Current research efforts focus mostly on modulation of single aging processes and on one or two major organ systems of the body. It is essential to distinguish intrinsic aging from age-dependent abnormalities, eg, in the cumulative assault of sunlight on the skin. Sunscreens block the cutaneous absorption of ultraviolet (uv) light radiation (280–315 nm) and prevent sunburning, premature aging, and cancer of the skin. Photoaged skin, long believed to be irreversibly damaged, has now been shown to undergo significant repair when uv exposures are stopped. Aging is associated with progressive deterioration in CNS function. A number of factors besides genetic considerations contribute to those degenerative changes, including nutritional elements and environmental toxins. The blood brain barrier (BBB) is a major modulator of nutrient delivery to the CNS. Senescence is associated with significant changes in BBB function including a decrease in BBB choline transport and brain glucose influx. Studies have confirmed that enhancing the cholinergic system could lead to reversal of age-related memory loss. Evidence indicating an activation of cholinergic mechanisms exists for pyrrolidinone derivatives, including piracetam, oxiracetam, aniracetam, pyroglutamic acid, tenilsetam, and pramiracetam, and for vinpocetine, naloxone, ebiratide, and phosphatidylserine. All these drugs prevent disruptions of several learning and memory paradigms. Cardiovascular disease remains the most common age-related disease and is the most common cause of morbidity and mortality in old age. Risk factors more prevalent in the elderly than in the young adult, that initiate and aggravate cardiovascular disease include hypertension, personality traits, genetics, diet, smoking, obesity, and impaired glucose tolerance. Pharmacological agents such as lovastatin are used for the treatment of hypercholesterolemia, and antiatherosclerogenic diets low in saturated fat and cholesterol, rich in fiber, and with substitution of polyunsaturated fat and restricted calories tend to normalize serum lipids and to cause lesions to involute. One important feature of aging is the remodeling of the ventricle and blood vasculature. Various agents such as vasodilators, hydroalazine, and isosorbide dinitrate have been used. Other possibilities include α-blockers and calcium antagonists. Normal aging is associated with a gradual decline in the immune response. A number of approaches have been devised to prevent the loss of immune responsiveness or to restore it once it is declining or has been lost. Recovery of T-regulatory effects on B-cell differentiation has been reported in elderly patients treated with IL-1 or IL-2. Levamisole, C11H12N2S, and the sodium salt of diethyl dithiocarbamate (imuthiol) restore T-cell function. Hypoxanthine derivatives such as isoprinosine and NPT 15392 induce T-cell maturation directly and promote T-cell function. Melatonin, the pineal neurohormone N-acetyl-5-methoxytryptamine, has been shown to antagonize the immunosuppressive effects of anxiety stress in mice. The 8-substituted guanosines have been found to stimulate nonspecific, as well as some specific immune responses. The transmembrane signaling component of cellular activation has been an area of intense research interest. The interactions between nutrition and immunity have been the subject of much investigation. It is now recognized that even mild deficiencies involving protein–calorie malnutrition or single nutrients are associated with impaired immune responses. Large doses of “essential” nutrients (eg, zinc) may have a deleterious effect on the immune system. However, corrections of deficiencies of iron, zinc, and vitamins C, E, and B complex are associated with improved immune responses in the elderly.
The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001–1 mg kg−1 i.p. – 0.01–0.1 1 mg kg−1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg−1 i.p.), mecamylamine (20 mg kg−1 i.p.), baclofen (2 mg kg−1 i.p.), and clonidine (0.125 mg kg−1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well-known nootropic drugs such as piracetam (30–100 mg kg−1 i.p.), aniracetam (100 mg kg−1 p.o.), rolipram (30 mg kg−1 p.o.), and nicotine (5 mg kg−1 i.p). DM232 (0.1 mg kg−1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg−1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg−1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam-like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev. Res. 56:23–32, 2002. © 2002 Wiley-Liss, Inc.
Tardive dyskinesia (TD) is characterized by repetitive, involuntary, purposeless movements of the tongue, lips, face, trunk,
and extremities that occur in patients treated with long-term dopaminergic antagonists and following exposure to L-dopa, amphetamine,
metoclopramide, cinnarizine, flunarizine and other substances. The term tardive dyskinesia refers to: classical TD (bucco-lingual-masticatory
triad), tardive akathisia, tardive dystonia, tardive tremor and other tardive extrapyramidal subsyndromes. The mechanisms
of TD remain unclear, although pathophysiologic theories have proposed mechanisms such as dopamine receptor supersensitivity,
the degeneration of cholinergic striatal interneurons, γ-aminobutyric acid (GABA) depletion, and an excess of free radicals.
Though a wide range of medications for the treatment of TD has been studied, management of this distressful side effect remains
a significant problem for patients and a therapeutic conundrum for physicians. According to current concepts, antioxidants
such as vitamins and other antioxidative agents may be considered active components of putative therapies because antioxidants
inhibit free radical distractive activities. This chapter focuses on evidence from clinical and basic science studies that
support the role of antioxidants (vitamins B6 and E, omega-3, ginkgo biloba, piracetam) as potential neuroprotective compounds and effective medications for the prevention
and management of TD.
KeywordsNeuroprotection-Vitamin B6-Vitamin E-Omega-3-Piracetam-Ginkgo biloba-Schizophrenia-Tardive dyskinesia-Clinical trials
Schizophrenia is a chronic and disabling mental disorder characterized by positive, negative and mood symptoms, disturbed
coping abilities with elevated distress and a significant decline in cognition, quality of life and psychosocial functioning.
About one-third of all patients with schizophrenia do not respond adequately to drug treatment. Today neuroscience and clinical
research have sufficiently advanced to introduce a novel generation of compounds with neuroprotective properties. The use
of neuroprotective agents in schizophrenia is not yet significantly established. An in-depth review of new compounds such
as neurosteroids, estrogen, omega-3 fatty acids, S-adenosylmethionine, cannabinoids, piracetam, modafinil, L-theanine, bexarotene
with neuroprotective properties is discussed. The mechanisms underlying the neuroprotective effects of these compounds vary
and differ from classically defined dopamine and serotonin receptors. This review highlights selective evidence supporting
a neuroprotective approach in the search for novel compounds, and suggests future directions for this exciting area. Neuroprotection
strategy may be a useful paradigm for treatment of prodromal and first-episode schizophrenia patients and might have a significant
impact on the subsequent course and outcome of the illness. The clinical effects of neuroprotective agents clearly merit further
investigation in schizophrenia spectrum disorders.
KeywordsSchizophrenia-Neurodevelopmental model-Neurodegenerative model-Apoptosis-Oxidative stress-Excitotoxicity-Stress sensitization-Neurotrophic factor expression-Alteration of neurosteroids-Vulnerability model-Neurocognitive domains-Quality of life deficit-Neuroprotective agents-Neurosteroids-Pregnenolone-Dehydroepiandrosterone-Bexarotene-Theanine
We studied the effects of administration of the new nootropic drug phenotropil (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) at a dose of 100 mg/kg on the quantitative characteristics of dopamine (DA), serotonin (5-HT), glutamate (NMDA), GABA-A (BDZ), and acetylcholine (nACh) receptors in rats using the conditioned passive avoidance task (PAT) under normal conditions and during scopolamine-induced amnesia ex vivo. We found that the cholinolytic drug scopolamine induced a substantial increase in the density (B
max) of n-choline receptors in the cortex (by 99% as compared to the control) and NMDA receptors in the hippocampus (by 93%). A single administration of phenotropil (100mg/kg, intraperitoneally) abolished the effect of scopolamine and decreased the number of nACh and NMDA receptors by 46% and 14%, respectively. Phenotropil also abolished the effect of scopolamine on the benzodiazepine receptors and dopamine D1 receptors. Scopolamine decreased the density of D1 receptors by 20% and BDZ receptors by 17%, whereas phenotropil increased the density of receptors by 16% and 25%, respectively. Phenotropil considerably increased the density of dopamine D2 and D3 receptors by 29% and 62%, respectively. Scopolamine also increased the density of D3 receptors by 44% as compared to the control. We did not find any changes in the binding characteristics of 5-HT2 receptors during scopolamine-induced amnesia or during phenotropil treatment. These results demonstrate the role of these receptors in the development of scopolamine-induced amnesia and in neurochemical mechanisms of the anti-amnestic effects of phenotropil.
Multiple neurotransmitter systems are affected in senile dementia of the Alzheimer's type (SDAT). Among them, acetylcholine has been most studied. It is now well accepted that the activity of the enzyme, choline acetyltransferase (ChAT) is much decreased in various brain regions including the frontal and temporal cortices, hippocampus and nucleus basalis of Meynert (nbm) in SDAT. Cortical M2-muscarinic and nicotinic cholinergic receptors are also decreased but only in a certain proportion (30-40%) of SDAT patients. For other systems, it appears that cortical serotonin (5-HT)-type 2 receptor binding sites are decreased in SDAT. This diminution in 5-HT2 receptors correlates well with the decreased levels of somatostatin-like immunoreactive materials found in the cortex of SDAT patients. Cortical somatostatin receptor binding sites are decreased in about one third of SDAT patients. Finally, neuropeptide Y and neuropeptide Y receptor binding sites are distributed in areas enriched in cholinergic cell bodies and nerve fiber terminals and it would be of interest to determine possible involvement of this peptide in SDAT. Thus, it appears that multi-drug clinical trials should be considered for the treatment of SDAT.
Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related
memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies,
and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and
demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can
be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions
reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce
memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments
are given and directions for future laboratory and clinical studies are suggested.
In an attempt to gain some insight into possible approaches to reducing age-related memory disturbances, aged Fischer 344 rats were administered either vehicle, choline, piracetam or a combination of choline or piracetam. Animals in each group were tested behaviorally for retention of a one trial passive avoidance task, and biochemically to determine changes in choline and acetylcholine levels in hippocampus, cortex and striatum. Previous research has shown that rats of this strain suffer severe age-related deficits on this passive avoidance task and that memory disturbances are at least partially responsible. Those subjects given only choline (100 mg/kg) did not differ on the behavioral task from control animals administered vehicle. Rats given piracetam (100 mg/kg) performed slightly better than control rats (p less than 0.05), but rats given the piracetam/choline combination (100 mg/kg of each) exhibited retention scores several times better than those given piracetam alone. In a second study, it was shown that twice the dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not enhance retention nearly as well as when piracetam and choline (100 mg/kg of each) were administered together. Further, repeated administration (1 week) of the piracetam/choline combination was superior to acute injections. Regional determinations of choline and acetylcholine revealed interesting differences between treatments and brain area. Although choline administration raised choline content about 50% in striatum and cortex, changes in acetylcholine levels were much more subtle (only 6-10%). No significant changes following choline administration were observed in the hippocampus. However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%). No measurable changes in striatum or cortex were observed following piracetam administration. The combination of choline and piracetam did not potentiate the effects seen with either drug alone, and in certain cases the effects were much less pronounced under the drug combination. These data are discussed as they relate to possible effects of choline and piracetam on cholinergic transmission and other neuronal function, and how these effects may reduce specific memory disturbances in aged subjects. The results of these studies demonstrate that the effects of combining choline and piracetam are quite different than those obtained with either drug alone and support the notion that in order to achieve substantial efficacy in aged subjects it may be necessary to reduce multiple, interactive neurochemical dysfunctions in the brain, or affect activity in more than one parameter of a deficient metabolic pathway.
The present study was initiated to examine the effect of pramiracetam sulfate [N-[2-[bis(1-methylethyl)amino]ethyl]-2 oxo-1-pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition-activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5-HT), 5-hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d-methamphetamine-induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC50 > 10 μM), and benzodiazepine receptors (IC50 > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5-HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium-dependent high-affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal-hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.
Alzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long-term habituation of locomotor activity and retention of a one-trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long-term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.
The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and palecortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
Auf der Suche nach biochemischen Angriffspunkten der Piracetamwirkung wurde der Einfluß der enzephalotropen Substanz auf den neuronalen und glialen Phospholipidstoffwechsel untersucht. Piracetam steigerte den Einbau von ³²P in Phosphatidylinositol und Phosphatidylcholin der Gliazellen und Neurone (Abb. 1 u. 2). Unter Berücksichtigung der wichtigen Rolle, welche Phosphatidylinositol bei den Vorgängen der synaptischen Erregungsübertragung und axonalen Erregungsfortleitung spielt, sprechen die Ergebnisse der vorliegenden Arbeit dafür, daß Piracetam exzitatorische Neurone stimuliert und in den Vorgang der synaptischen Erregungsübertragung eingreift. Der stimulatorische Effekt von Piracetam auf den Einbau von ³²P in Phosphatidylinositol und Phosphatidylcholin scheint durch Noradrenalin oder einen anderen Neurotransmitter vermittelt zu werden.
Gliazellen des Kaninchenkortex enthalten pro Einheit Protein etwa ein Drittel mehr Phosphatide als Neurone. Die Verteilung und das Muster der Phospholipide war in beiden Zellarten sehr ähnlich. Der Einbau von ³²P in Phosphatidylinositol und Phosphatidylcholin war etwas höher in den Neuronen als in den Gliazellen. Neurone zeigen im Vergleich zu Gliazellen einen höheren Phospholipid-Umsatz.
The purpose of the present study was to compare the effect of seven drugs, that have been reported to enhance cognitive functions, on rat hippocampal cholinergic neuronal activity. The latter was assessed by measuring the effects of the drugs on in vitro sodium-dependent high affinity choline uptake (HACU) into rat hippocampal synaptosomes 30 minutes after their in vivo administration. 3,4-Diaminopyridine (0.1 mg/kg IP), like pramiracetam (44 and 88 mg/kg IP), increased HACU with higher or lower doses being ineffective. Centrophenoxine (100 mg/kg IP) decreased HACU. Piracetam (100 and 500 mg/kg IP), aniracetam (10-200 mg/kg PO), lysine vasopressin (0.005-0.05 mg/kg IM) and 4-aminopyridine (0.01-3.0 mg/kg IP) were ineffective. The results indicate that 3,4-diaminopyridine and centrophenoxine, like pramiracetam may be increasing cognitive function in part by affecting hippocampal cholinergic neuronal activity. In addition, the findings indicate the usefulness of using in vitro HACU as a biochemical measurement to assess the potential effect of cognitive-enhancing drugs on cholinergic neuronal activity in vivo.
The influence of the nootropic drug piracetam (Normabrain) on specific ligand binding to several neurotransmitter and drug receptors was investigated using established receptor binding procedures. Even at concentrations of 20 mmol/l of piracetam no or only marginal inhibition was observed for the dopamine- and muscarinic cholinergic receptors and for the peripheral benzodiazepine binding site, while for the benzodiazepine receptor, the GABA receptor, the opiate receptor, and the serotonin receptor half-maximal inhibitory concentrations between 20 and 50 mmol/l could be determined. In contrast to these effects seen only at relatively high piracetam concentrations, piracetam is considerably more active at the L-glutamate receptor with a half-maximal inhibitory concentration of about 1 mmol/l. This relatively specific effect of piracetam at the L-glutamate receptor could also take place under therapeutic conditions in vivo, since brain levels of piracetam in man may range between 0.1 and 1 mmol/l. It is concluded that effects within the glutaminergic system of the brain could contribute to the therapeutical effects of piracetam in man.
This study examined the effects of different concentrations of centrophenoxine on physical properties of synaptic plasma membranes and liver microsomes using electron spin resonance procedures. Membranes of different age groups of mice were labeled with the 5-doxyl stearic acid spin-label and membrane fluidity determined in the presence and absence of different concentrations of centrophenoxine. Centrophenoxine had a direct effect on membranes as shown by a significant increase in membrane fluidity. This effect was greatest in liver microsomes as compared to synaptic plasma membranes. Age differences were not observed in centrophenoxine-induced fluidization. Effects of centrophenoxine in vivo may be due in part to the drug acting directly on the physical properties of the membrane lipid environment.
Chronic treatment (2 weeks) with either scopolamine (4 mg/kg, once daily p.o.) or choline (200 mg/kg, once daily p.o.) resulted in a pronounced muscarinic cholinergic receptor up- or down-regulation in the frontal cortex of young (4 weeks) but not of aged (18 months) female mice. It is speculated that a similar age-related decline of muscarinic receptor plasticity might contribute to the profound dysfunction of cholinergic neurotransmission in Alzheimer's disease.
Nootropics, a new class of drugs believed to activate mental functions, have been proposed as a treatment for clinical disorders in which cognition is impaired. We therefore administered the nootropic drug piracetam, alone and in combination with phosphatidylcholine (PC), to 18 patients with Alzheimer's disease (AD), and measured the effects of treatment on a broad range of cognitive functions. Piracetam was administered according to three double-blind crossover protocols and a replication study that differed in piracetam dose (2.4 to 9.9 g/day) and whether PC (18 g/day) was administered concurrently. The drug was well tolerated, and there were not toxic side effects. Plasma choline levels rose significantly during piracetam and PC administration; monoamine metabolites in cerebrospinal fluid were unaffected by treatment. Piracetam, either alone or in combination with PC, did not significantly affect cognition in the AD group as a whole, nor did it improve test performance in any single patient.
The aim of this work was to study the effects of the nootropic drug oxiracetam, on lipid metabolism in rat brain. Twenty-month-old rats and spontaneous hypertensive (SHR) rats with cerebrovascular lesions were used, which showed an impaired learning and memory rate if challenged with behavioral tests. Oxiracetam improves the in vitro and in vivo synthesis of phosphatidylcholine (PhC) and phosphatidylethanolamine (PhE) impaired by aging, when respectively added to the incubation medium or administered subacutely to animals. SHR rats drinking saline, and with cerebrovascular lesions, have a reduced choline incorporation into cerebral phospholipids and an increase of arachidonic acid release from the same lipids if compared to SHR rats (without cerebrovascular lesions) drinking water. They also show a decreased incorporation rate of arachidonic acid into PhC, PhE, and PhC plasmalogen and PhE plasmalogen. If oxiracetam is chronically administered (200 mg/kg/day for 14 weeks) a significant variation in the incorporation of both precursors takes place. In the first 2 h after the intracerebroventricular (i.c.v.) injection of choline and arachidonic acid the values are comparable to those observed in SHR rats with lesions; at longer time intervals, however, the rates of incorporation are similar and even better than those of SHR rats without lesions. Since the drug does not seem to influence the incorporation of the precursors in the first 2 h after their administration, we may assume that oxiracetam acts on the turnover of the phospholipids more than on their rate of synthesis from injected precursors.
Specific cholinergic muscarinic receptor binding was determined with L-[3H]quinuclidinyl benzilate ([3H]QNB) in homogenates from crude synaptosomal pellets prepared from mouse whole-brain homogenates. Specific total (high- and low-affinity) binding was determined in the absence of the agonist carbachol and low-affinity binding in its presence. These membrane preparations were fluidized by adding in vitro aliphatic alcohols ranging from ethanol to hexanol and by increasing the incubation temperatures. At 23 degrees C hexanol (14.7 mM) nearly doubled the low-affinity binding in the presence of carbachol (0.32 mM) and decreased high-affinity binding by the same amount. This suggested a change of muscarinic receptors from high- to low-affinity conformation. Increase of incubation temperature from 24 degrees C to 37 degrees C nearly tripled low-affinity binding. Brain homogenates from female C57BL/6J mice, ages 6, 12, 18, and 30 months, showed a progressively lower stimulation by hexanol of low-affinity [3H]QNB binding in the presence of carbachol. We postulate that this diminished change with age of [3H]QNB-receptor binding in response to alcohols may be a result of increasing membrane rigidity with advancing age. Rigidity of membranes may link aging at the membrane level, synaptic receptors, and impaired learning behavior.
Intracerebroventricular (ICV) injections of hemicholinium-3 (HC-3) to mice before the training trial in a passive avoidance task produced an amnesic effect at the 24-hour retention test. Pretreatment by IP injection of piracetam, etiracetam, or pramiracetam, 30 minutes before HC-3 injections antagonized the amnesic effects of HC-3. Pretreatment with choline was not effective. The depletion of cerebral acetylcholine by the HC-3 injection was not prevented by piracetam or etiracetam.
Age-related differences in muscarinic receptor plasticity were observed in young, adult and senescent Fischer 344 rats (3, 9 and 27 months old, respectively) following the chronic, intracerebroventricular (ivt) administration of a cholinergic agonist, oxotremorine, or antagonist, methylatropine. After three weeks treatment of young rats with ivt oxotremorine, the maximum number (Bmax) of 3H-QNB binding sites in frontal cortex, determined by saturation experiments, was reduced by 27%, with no apparent change in the affinity (Kd) of 3H-QNB for the muscarinic receptor. Conversely, chronic ivt methylatropine administered to 3 month old animals caused a 29% increase in Bmax with no significant change in Kd. Adult animals showed a somewhat lesser degree of muscarinic receptor plasticity (16% down-regulation after oxotremorine, 22% up-regulation after methylatropine). However, 3H-QNB binding parameters in frontal cortex from senescent rats were not significantly altered following identical treatments with oxotremorine or methylatropine. Thus, muscarinic receptor adaptation to chronic, cholinergic drug administration was impaired in aged animals. This reduced receptor plasticity with aging could have important implications for the long-term drug treatment of elderly patients and for the therapeutic efficacy of cholinergic drugs in age-related neurological disorders, such as Alzheimer's disease.
The difficulties involved in understanding the complex phenomena of geriatric cognitive dysfunction clearly call for an interdisciplinary approach. We have initiated multi-laboratory studies in order to assess the utility of the aged Fisher 344 rat as a potential animal model. Prior behavioral experiments have demonstrated that these aged animals suffer from age-related memory impairments conceptually similar to those which occur in humans. Neurophysiological and biochemical studies have focused on the task of assessing hippocampal functioning in this potential animal model. The hippocampus was chosen for these studies because changes in hippocampal function may contribute to the memory impairments associated with old age. The overall firing rate of single hippocampal pyramidal cells was reduced in OLD (26-28 months) rats when compared to YOUNG rats (6-8 months). This effect was due to a selective decrease in the simple spike firing rate. Since burst firing was relatively intact, these results argue against a generalized non-specific decrease in neuronal activity. This interpretation is supported by the observation that microiontophoretic application of glutamate stimulated the firing of hippocampal pyramidal cells to the same extent in both young and old animals. However, microiontophoretic application of GABA inhibited hippocampal pyramidal cell firing to a greater extent in old rats. This effect was not accompanied by any age-related alterations in 3H-muscimol binding in the dorsal hippocampi obtained from these same animals. The pyramidal cell stimulation produced by microiontophoretic application of acetylcholine was reduced in OLD rats. The number of muscarinic receptors (as measured by the binding of 3H-agonists and antagonists) in the dorsal hippocampi was reduced approximately 20% in the aged rats. All of these results have generated the following conclusions: (1) The neuronal activity of hippocampal pyramidal cells is reduced in aged rats, an effect which might contribute to the mnemonic disturbances observed in these animals. (2) Age-related alterations in the functional consequences of GABA receptor activation occurred independent of any change in the binding parameters of 3-muscimol. (3) The decrease in muscarinic binding sites is reminiscent of the decreases observed in aged human brain. Together with the decreased functional response to acetylcholine, these results provide strong evidence for a cholinergic hypothesis of geriatric cognitive dysfunction.
Piracetam has bee administered to young and old mice to investigate whether the age may differently modulate the activity of this centrally acting drug. After piracetam administration, old mice showed a notably greater increase of their brain tryptophan than young animals. Furthermore, piracetam significantly improves the learning capacity of young mice, but the drug is remarkably more active in improving the performance by old mice. These facts may then suggest that this compound is especially effective in restoring the neurobiological setting of the aging brain.
The influence of centrophenoxine treatment on beta-adrenoceptor density has been studied in the brain cortex of old mice. One group of 21-mth-old mice was injected intraperitoneally with 3.8 mg/day centrophenoxine daily for 5 days. A second group received the same daily treatment for 40 days. Two other groups of untreated mice of the same age served as controls. Receptor affinity showed no statistically significant changes in the four different groups investigated. As regards the receptor density, an increasing trend has been elicited between the 5-day treated mice and their controls; however, the increase was not statistically significant. The second group of old mice treated with centrophenoxine for 40 days exhibited a statistically significant increase in receptor density when compared with untreated animals. The modulation of beta-adrenoceptor density may be explained as the result of either a direct action on synaptic structure or an indirect effect mediated by thyroid hormones.
The effects of chronic treatment with piracetam (100 mg/Kg) plus choline (100 mg/Kg) on rabbits' hippocampal electrical activity and behavior have been studied. Animals were exposed to a neutral environment, in the absence of any external stimulus, and then to an object and a stuffed sparrow-hawk. Results show a drug related reduction in the amount of the hippocampal rhythmic slow activity (RSA) and an increase in RSA high frequency values in the presence of the object and of the stuffed animal, but not in the neutral environment. This would suggest that piracetam plus choline treatment has an effect on RSA in situations in which selective attention is required.
The effects of various piracetam + choline combinations on an experimental model of memory were investigated. Mice were given two sessions in a simple photo-cell activity cage and the decrease in activity at the second session (habituation) served as an index of retention. Retention was facilitated by post-session administration of 2000 mg/kg piracetam IP and 50 mg/kg piracetam + 50 mg/kg choline IP. Similar injections of choline alone (10 to 200 mg/kg IP), piracetam alone (10 to 1000 mg/kg IP) or other combinations of piracetam and choline were without effect. These results, consistent with those reported elsewhere, suggest that piracetam can interact with choline to facilitate memory processes in mice.
Muscarinic systems are significantly altered in the brains of laboratory animals and man as a result of normal aging. Cholinergic neurotransmission in cerebral cortex and hippocampus is also severely impaired in a major age-related neurological disorder, Alzheimer's disease. The objective of these studies was to assess specific 3H-quinuclidinyl benzilate (3H-QNB) binding to brain muscarinic receptors in young, adult and senescent Fischer 344 rats, and to relate receptor changes to differences in the pharmacologic actions of cholinergic drugs. Muscarinic receptor density declined with advanced age in the frontal cortex, corpus striatum and hypothalamus, but no age-related changes in receptor affinity were observed. Specific binding of 3H-QNB in hippocampus was not significantly altered. In contrast, the in vivo effects of oxotremorine (hypothermia and antinociception) were markedly enhanced in aged rats, whereas scopolamine-induced locomotor activity was reduced. Hence, senescent rats were more sensitive to the pharmacologic actions of a cholinergic agonist, but less responsive than young rats to a muscarinic antagonist. These seemingly contradictory results of binding experiments and pharmacological studies could be due, in part, to changes in subtypes of brain muscarinic receptors with advanced age. Alternatively, the age-related differences in cholinergic drug effects may reflect a decreased ability of the senescent animal to adapt to changes in its environment.
Nootropics are drugs which ameliorate the functional "plasticity" of the central nervous system. The nootropic drug acts at the telencephalic level through a series of bioenergetic, hemorheological, microcirculatory and neurochemical mechanisms. As to this, recent data show a facilitation by piracetam, of the efficiency of the central cholinergic system.
Muscarinic receptor binding and choline acetyltransferase, (ChAT, EC.2.3.1.6.) activity were assayed in four brain regions of C57BL/6J mice of four ages (4, 12, 18, and 24 months). In the cerebellum, there were no age differences in either of the cholinergic markers. However, significant age differences were noted in the Vmax for ChAT and in the Bmax for [3H]quinuclidinyl benzilate ( [3H]QNB) in the cortex, striatum and hippocampus. Increases were noted in Vmax of the synthetic enzyme in all three regions and for Bmax in the hippocampus. Bmax for [3H]QNB decreased in the cortex and striatum. The high- and lower-affinity muscarinic binding constants, the percentage of muscarinic binding to high affinity sites determined by carbamylcholine displacement of [3H]QNB, as well as the affinities of ChAT for acetyl coenzyme A and choline chloride showed no age differences in any brain region.
Hippocampal acetylcholine levels were significantly depressed 30 min after rats received Piracetam (30–300 mg/kg, intraperitoneally).
The number of synaptic cholinergic receptors in brains of mice decreases with aging after 18 months. Alterations in body weight, starvation, and circadian variations could not account for these changes. The decrease in receptors was not associated with significant changes in receptor affinity and brain protein and DNA and RNA content. The determination of postsynaptic cholinergic receptor density is a quantitative chemical correlate of aging of the rodent brain. Whether or not the declining receptor density is a cause of the age-related decline of learning behavior can be resolved by observing the effects of manipulations of receptor density on learning in animals.
Since 1922 when Wu proposed the use of the Folin phenol reagent for
the measurement of proteins (l), a number of modified analytical pro-
cedures ut.ilizing this reagent have been reported for the determination
of proteins in serum (2-G), in antigen-antibody precipitates (7-9), and
in insulin (10).
Although the reagent would seem to be recommended by its great sen-
sitivity and the simplicity of procedure possible with its use, it has not
found great favor for general biochemical purposes.
In the belief that this reagent, nevertheless, has considerable merit for
certain application, but that its peculiarities and limitations need to be
understood for its fullest exploitation, it has been studied with regard t.o
effects of variations in pH, time of reaction, and concentration of react-
ants, permissible levels of reagents commonly used in handling proteins,
and interfering subst.ances. Procedures are described for measuring pro-
tein in solution or after precipitation wit,h acids or other agents, and for
the determination of as little as 0.2 y of protein.
Combined piracetam and cholinergic pre-cursor treatment for primary degenerative dementia
- N Pomara
- Moore R N Block
- Hb
- R Berchou
- N Stanley
- Gershon
Pomara N, Block R, Moore N, Rhiew HB, Berchou R, Stanley N, Gershon S (1984) Combined piracetam and cholinergic pre-cursor treatment for primary degenerative dementia. IRCS Med Sci 12:388 389
Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice Habitua-tion of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes
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Pilch H, Mfiller WE (1987) Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice. J Neural Transm (in press) Platel A, Jalfre M, Pawelec C, Roux S, Porsolt RD (1984) Habitua-tion of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Pharmacol Bio-chem Behav 21:209 212
Centrophenoxine-in-duced increase of beta-adrenoceptor density in brain cortex of old mice Age-differences in choline acetyl-transferase activities and muscarinic receptor binding in brain regions of C 57 BL/6J mice
- C Viticchi
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Viticchi C, Gentile S, Piantanelli L (1984) Centrophenoxine-in-duced increase of beta-adrenoceptor density in brain cortex of old mice. Arch Gerontol Geriatr 3 : 77~82 Wailer SB, London ED (1983) Age-differences in choline acetyl-transferase activities and muscarinic receptor binding in brain regions of C 57 BL/6J mice. Exp Gerontol 18:419-425
Neurotransmitter function in relation to aging and alcoholism Alcohol-ism in the Elderly
- Freund
Freund G (1984) Neurotransmitter function in relation to aging and alcoholism. In: Hartford JT, Samorajski T (eds) Alcohol-ism in the Elderly. Raven Press, New York, pp 65 83
Profound effect of combining choline and piracetam on memo-ry enhancement and cholinergic functions in aged rats The cholinergic hypothesis of geriatric memory dysfunction Interaction of piracetam with several neurotransmitter receptors in the central nervous system
- Bartus Rt Rl Dean
- Ka Sherman
- E Friedman
- Rt Beer
- Rl Dean
- B Beer
- Lippa
- As
Bartus RT, Dean RL, Sherman KA, Friedman E, Beer B (1981) Profound effect of combining choline and piracetam on memo-ry enhancement and cholinergic functions in aged rats. Neu-robiol Aging 2: 3 8 Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408-417 Bering B, Miiller WE (1985) Interaction of piracetam with several neurotransmitter receptors in the central nervous system. Arz-neimittelforschung 35:1350-1352
The cholinergic hypothesis of dementia TIPS suppl. (Subtypes of muscarinic receptors II) Development of choli-nergic drugs for the treatment of Alzheimer's disease
- Iversen Ll Johns Ca
- V Haroutunian
- Mohs Rc Greenwald Bs
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- Horvath
- Tb
- Davis
- Kl
Iversen LL (1986) The cholinergic hypothesis of dementia TIPS suppl. (Subtypes of muscarinic receptors II) Johns CA, Haroutunian V, Greenwald BS, Mohs RC, Davis BM, Kanof P, Horvath TB, Davis KL (1985) Development of choli-nergic drugs for the treatment of Alzheimer's disease. Drug Dev Res 5 : 77-96
Profound effect of combining choline and piracetam on memory enhancement and cholinergic functions in aged rats
- RT Bartus
Profound effect of combining choline and piracetam on memory enhancement and cholinergic functions in aged rats
- R T Bartus
- R L Dean
- K A Sherman
- E Friedman
- B Beer
- RT Bartus