Piracetam (Nootropil™) Abstracts
J Dev Neurosci 21 (3): 117-24 (2003 May)
GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons
Pelsman A, Hoyo-Vadillo C, Gudasheva TA, Seredenin SB, Ostrovskaya RU, Busciglio J
Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, CT 06030, USA
The neuroprotective activity of a novel N-acylprolyl-containing dipeptide analog of the nootropic 2-oxo-1-pyrrolidine acetamide (Piracetam) designated as GVS-111 (DVD-111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H2O2, and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H2O2 for 1h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS-111 significantly increased neuronal survival after H2O2-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21±0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H2O2 or FeSO4, suggesting an antioxidant mechanism of action. GVS-111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N-tert-butyl-2-sulpho-phenylnitrone (s-PBN). In DS cortical cultures, chronic treatment with GVS-111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS-111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders.
Physiol Behav 77 (2-3): 403-9 (2002 Nov)
The effects of piracetam on cognitive performance in a mouse model of Down's syndrome
Moran TH, Capone GT, Knipp S, Davisson MT, Reeves RH, Gearhart JD.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Ross 618, 720 Rutland Avenue, Baltimore, MD 21205-2196
Piracetam is a nootropic agent that has been shown to improve cognitive performance in a number of animal model systems. Piracetam is reported to be used widely as a means of improving cognitive function in children with Down's syndrome (DS). In order to provide a preclinical assessment of the potential efficacy of piracetam, we examined the effects of a dose range of piracetam in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for a region of mouse chromosome 16 with homology to human chromosome 21. Daily piracetam treatment at doses of 0, 75, 150, and 300 mg/kg ip was initiated in 6-week-old male Ts65Dn and euploid control mice. Following 4 weeks of treatment, mice were tested in the visible and hidden-platform components of the Morris water maze and were placed overnight in computerized activity chambers to assess effects on overall activity. Piracetam treatment was continued through the 4 weeks of testing. In control mice, 75 and 150 mg/kg/day piracetam improved performance in both the visible- and hidden-platform tasks. Although low doses of piracetam reduced search time in the visible-platform component in Ts65Dn mice, all piracetam doses prevented trial-related improvements in performance in Ts65Dn mice. The 300-mg/kg/day-piracetam dose was associated with a reversal of the nocturnal spontaneous hyperactivity in Ts65Dn. These data do not provide support for piracetam treatment for individuals with DS.
Arch Pediatr Adolesc Med 155 (10): 1176-8 (2001 Oct)
Jim Croom
Department of Poultry Science, North Carolina State University, Raleigh, NC 27695-7608
I am greatly concerned about how the data in this article were analyzed, interpreted, and discussed. First, from the most fundamental standpoint, the authors did not truly test the efficacy of piracetam as presented in anecdotal accounts and they did not test the drug against a background of vitamin, mineral, amino acid, and other metabolites similar to those given to the children in the aforementioned programs.
Arch Pediatr Adolesc Med 155 (10): 1176 (2001 Oct)
Stephen L. Black
Department of Psychology, Bishop's University, Lennoxville, Quebec, Canada J1M 1Z7
In summary, it is regrettable when parents are given false hope through unproven remedies, and rigorous studies such as this one are essential to counter such claims. However, we should not let our experience with worthless media-publicized claims inhibit us from identifying positive effects when they are present. A more justifiable conclusion would have been that while dramatic effects were not observed, and there were indications of adverse effects with certain children, small gains in cognition and behavior were also evident.
Arch Pediatr Adolesc Med 155 (4): 442-448 (2001 Apr)
Piracetam therapy does not enhance cognitive functioning in children with Down syndrome
Lobaugh Nancy J.; Vladimir Karaskov; Vicki Rombough; Joanne Rovet; Susan Bryson; Rachel Greenbaum; Robert H. Haslam; Gideon Koren
Research and Cognitive Neurology Unit, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Ave, Room S604, Toronto, Ontario, Canada M4N 3M5
Background. Piracetam is widely used as a purported means of improving cognitive function in children with Down syndrome. Its efficacy, however, has not been rigorously assessed.
Objective. To determine whether 4 months of piracetam therapy (80-100 mg/kg per day) enhances cognitive function in children with Down syndrome.
Design. A randomized, double-blind, placebo-controlled crossover study.
Participants and Methods. Twenty-five children with Down syndrome (aged 6.5-13 years) and their caregivers participated. After undergoing a baseline cognitive assessment, children were randomly assigned to 1 of 2 treatment groups: piracetam-placebo or placebo-piracetam.
Main Outcome Measure. The difference in performance while taking piracetam vs while taking placebo on tests assessing a wide range of cognitive functions, including attention, learning, and memory.
Results. Eighteen children completed the study, 4 withdrew, and 3 were excluded at baseline. Piracetam therapy did not significantly improve cognitive performance over placebo use but was associated with central nervous system stimulatory effects in 7 children: aggressiveness (n = 4), agitation or irritability (n = 2), sexual arousal (n = 2), poor sleep (n = 1), and decreased appetite (n = 1).
Conclusion. Piracetam therapy did not enhance cognition or behavior but was associated with adverse effects.
Biochem Pharmacol 53 (2): 35-40 (1997 Jan 24)
Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain
Muller WE; Koch S; Scheuer K; Rostock A; Bartsch R
Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany
In vitro preincubation of brain membranes of aged mice with piracetam (0.1-1.0 mmol/L) enhanced membrane fluidity, as indicated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Piracetam had similar in vitro effects on brain membranes of aged rats and humans, but it did not alter brain membrane fluidity in young mice. Chronic treatment of young and aged rats with piracetam (300 mg/kg once daily) significantly increased membrane fluidity in some brain regions of the aged animals, but had no measurable effect on membrane fluidity in the young rats. The same treatment significantly improved active avoidance learning in the aged rats only. It is suggested that some of the pharmacological properties of piracetam can be explained by its effects on membrane fluidity.
Mov Disord 11 (6): 691-700 (1996)
Clinical trial of piracetam in patients with myoclonus: nationwide multiinstitution study in Japan. The Myoclonus/Piracetam Study Group
Ikeda A, Shibasaki H, Tashiro K, Mizuno Y, Kimura J
Department of Brain Pathophysiology, Kyoto University School of Medicine, Japan
Sixty patients with disabling myoclonus excluding mainly spinal myoclonus were treated by piracetam as an open-labeled study, and myoclonus score, neurological symptoms, functional disability, and intensity of myoclonus were scored before and after treatment, including a blinded video inspection. Electrophysiological correlation also was investigated before and after treatment. Piracetam was effective in myoclonus, especially that of cortical origin, in both monotherapy and polytherapy. Piracetam also had positive benefits on gait ataxia and convulsions but not on dysarthria, and feeding and hand writing improved much more significantly. Psychologically significant improvement was seen in decreased motivation, sleep disturbance, attention deficit, and depression, all of which might be possibly secondary benefits associated with improvement of myoclonus. There was no positive correlation between clinical and electrophysiological improvement. Tolerance was good, and side effects were transient. However, hemtological abnormalities observed in at least two patients in the present study should be kept in mind when relatively large doses of piracetam are administered, especially in combination with other antimyoclonic drugs.
Epilepsy Res 25 (3): 225-230 (1996)
Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam
Kasteleijn-Nolst Trenite DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J
Instituut voor Epilepsiebestrijding, Heemstede, The Netherlands
The experimental antiepileptic drug, levetiracetam (UCB L059), a piracetam analogue has been investigated in photosensitive patients in the "photosensitivity model", an early phase II study. A total of 12 patients (10 females, 2 males) with a mean age of 21.5 years (range 13-38) were investigated during a 3 day period in 3 centres (France, The Netherlands, Germany), using the same standardised method. The subjects were either treated with a single oral dose of 250 mg, 500 mg, 750 mg or 1000 mg. In addition, 4 patients took 250 mg b.i.d. for 3-5 days, after which they were re-examined. In 9 of 12 photosensitive patients (75%) a clear suppression (3 patients) or abolishment (6 patients) of IPS evoked photoparoxysmal EEG responses was found. This effect appeared to be dose-dependent, the higher the dose the greater the effect; complete abolishment was only seen at dosages of 750 mg and 1000 mg, occurring at peak plasma levels and lasting between 6 and 30 h. There was no indication of pharmacokinetic interaction with concomitant antiepileptic drugs such as valproic acid, ethosuximide or phenobarbitone. No serious side-effects were seen and some patients reported enhancement of their mood. Two patients with myoclonic jerks noticed a clear reduction of their myoclonus, although this was not one of the objectives of the study. In conclusion, levetiracetam showed a clear antiepileptic effect in the photosensitivity model.
Journal of Medicinal Chemistr 38 (1): 170-9 (1995 Jan 6)
X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore
Altomare C; Cellamare S; Carotti A; Casini G; Ferappi M; Gavuzzo E; Mazza F; Carrupt PT; Gaillard P; Testa B
Dipartimento Farmaco-Chimico, University of Bari, Italy
To detect possible molecular determinants of amnesia-reverting activity, the conformational properties of a number of rigid and flexible piracetam-type cognition enhancers have been assessed by X-ray diffraction, NMR spectroscopy, and ab initio and high-temperature-quenched molecular dynamics (QMD) calculations. The structures of the preferred conformers in solution derived from 1H-NMR spectral analysis were in good agreement with those found by QMD calculations. Interestingly, the calculation of the average molecular lipophilicity potential on the water-accessible surface of the selected conformers was helpful in interpreting the partitioning behavior observed by measuring octanol-water partition coefficients and capacity factors in reversed-phase high-performance liquid chromatography. While lipophilicity does not play a relevant role, the distance between polar groups, accounted for by the distance between carbonyl oxygens, emerges as a factor, among others, which should influence the amnesia-reversal activity of piracetam-type nootropics.
Pharmacology, Biochemistry & Behavior 49 (3): 683-8 (1994 Nov)
Effects of piracetam on indices of cognitive function in a delayed alternation task in young and aged rats
Roux S; Hubert I; Lenegre A; Milinkevitch D; Porsolt RD
I.T.E.M.-LABO, Le Kremlin-Bicetre, France
The effects of piracetam (64, 128, and 256 mg/kg PO) on the performance of a delayed alternation in a Skinner Box were investigated. Test sessions consisted of 36 trials during which animals were first presented with a single lever (left or right) followed 5, 10, or 20 s later by two levers. A press on the lever opposite to that presented previously (nonmatching to sample) was rewarded. The number of correct responses and the reaction times to the one- and two-lever presentations were recorded. All animals received all treatments in a balanced order. Aged animals showed clear deficits on all three parameters. Piracetam was without effect on the performance of young animals but dose-dependently decreased the choice reaction times (two levers) in aged animals without affecting the other two parameters. These results suggest that piracetam does not affect short-term memory but may facilitate choice behavior in aged animals.
Brain Res Rev 19 (2): 180-222 (1994 May)
Piracetam and other structurally related nootropics.
Gouliaev AH; Senning A
Department of Chemistry, Aarhus University, Denmark
Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.
Life Sciences 55 (25-26): 2057-66 (1994)
Interaction between psychological and pharmacological treatment in cognitive impairment
Deberdt W
UCB Pharma, Chemin du Foriest, Braine-l'Alleud, Belgium
In contrast to other kinds of psychotropic drugs, nootropics or cognition enhancing drugs may be indicated, not for the direct treatment of the pathology itself, but for improving or restoring the remaining brain functions. Brain functions are normally trained during various kinds of non-medical therapy, such as physiotherapy, speech therapy, occupational therapy, memory training etc. In research little attention has been paid to the combination of both kinds of therapeutic approaches, probably because of the important methodological difficulties. This combination however, offers various interesting perspectives: L. ISRAEL examined in two placebo-controlled studies the effects of either 160 mg/d of ginkgo biloba extractum (GBE) or piracetam 2.4 or 4.8 g/d, combined with a memory training program, in nondemented patients complaining of memory problems. The results of both studies suggest that nootropic drug treatment and memory training have each an effect on different cognitive functions and, hence, are complementary. Some functions, like attention/perception in the GBE study and learning in the piracetam study, seem to benefit from both treatments, suggesting a mutually potentiating effect of drug treatment and training. This potentiation is very clear in the treatment of dyslexic children: in a placebo-controlled study piracetam 3.3 g/d, in combination with normal school teaching and more specific logopedic therapy, allowed a normal progression during the full school year in reading accuracy and reading comprehension, while the placebo treated children getting a similar training progressed only with 50%. Recently promising results were obtained in the treatment of dysphasic patients with a combination of speech therapy and piracetam 4.8 g/d, especially when given during the first months after the stroke, or otherwise in combination with an intensive speech training. In both double-blind studies the piracetam treated group improved about 60% more than the group who only got speech therapy and placebo. All these data may be explained by the restorative or enhancing influence of nootropic drugs on neurotransmitter systems closely related to learning and memory functions. E.g. piracetam restores the availability and function of muscarinic and NMDA receptors in aging animals, most probably through a modulation of the psychico-chemical properties of the neuronal membrane such as the membrane fluidity.
Neurobiol Aging 2 (2): 105-11 (1981 Summer)
Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats
Bartus RT; Dean RL 3d; Sherman KA; Friedman E; Beer B
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.