Anticancer Effects of Curcumin 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 Neurobiol Aging (UNITED STATES) Summer 1981, 2 (2) p105-11,
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 GABAergic system of the dentate gyrus after withdrawal from chronic alcohol consumption: Effects of intracerebral grafting and putative neuroprotective agents
Alcohol and Alcoholism (United Kingdom), 1997, 32/4 (471-484)
We have demonstrated that, in the rat hippocampal formation, withdrawal from chronic alcohol consumption aggravates the ethanol-induced loss of pyramidal neurons and dentate granule cells. We have also shown that intracerebral grafting and piracetam could have a protective effect in these conditions. In this study we utilized immunocytochemical methods to investigate whether gamma-aminobutyric acid (GABA)ergic dentate gyrus cells, which are known to be inhibitory, were also affected by withdrawal from alcohol and, if so, whether putative neuroprotective agents could ameliorate the alterations found. Rats were alcohol-fed for 6 months and further divided into several groups: (1) alcohol-fed for an extra 6 months; (2) withdrawn from alcohol for 6 months; (3) withdrawn and grafted with newborn rat hippocampal tissue; (4) withdrawn and orally treated with piracetam for 6 months; (5) withdrawn and treated systemically with monosialoganglioside GM1 for 6 months; (6) withdrawn and treated with the vehicle used to dissolve the GM1. Control animals were pair-fed. All animals were killed 12 months after the beginning of the experiment and processed for GABA immunocytochemistry. GABA-immunoreactive (IR) neurons in the dentate gyrus were quantified and we found that alcohol-fed animals had a significant reduction in the numerical profile density of GABA-IR neurons in the dentate gyrus as a whole and in the hilus and in the granular layer of the suprapyramidal limb. Withdrawal from alcohol aggravated the GABAergic neuronal loss. Of the treatments used, only piracetam had a striking beneficial effect. Data gathered from the present work and from our previous studies indicate that the neuronal loss following chronic alcohol consumption and withdrawal affects both excitatory and inhibitory neurons in the dentate gyrus and that piracetam may have a useful protective role in this condition.
Piracetam as an adjuvant to language therapy for aphasia: A randomized double-blind placebo-controlled pilot study
Archives of Physical Medicine and Rehabilitation (USA), 1997, 78/3 (245-250)
Objective: To determine whether piracetam 4.8g/day together with intensive language therapy improved language function more than language therapy alone. Design: Double-blind, placebo-controlled parallel group study. Setting: Referral speech and language clinic of a university department of neurology. Patients: Sixty-six inpatients with aphasia present between 4 weeks and 36 months. Interventions: Intensive language therapy for 6 weeks in all patients. Thirty-two patients received piracetam 4.8g daily and 34 patients received placebo. Main Outcome Measure: The Aachen Aphasia Test (AAT), a standardized procedure for evaluating the severity of aphasia, was performed at baseline and after 6 weeks' treatment. Results: In 50 patients evaluated for efficacy, a trend toward improvement in the active group was observed in all subtests of the AAT. This trend was statistically significant for absolute differences in recovery of 'written language' and 'profile level.' Conclusion: Piracetam appears to have a positive adjuvant effect on the recovery of aphasia in patients receiving intensive language therapy.
Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain
Biochemical Pharmacology (USA), 1997, 53/2 (135-140)
In vitro preincubation of brain membranes of aged mice with piracetam (0.1-1.0 mmol/E) 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.
Piracetam in the treatment of myoclonus: An overview
Acta Neurologica Belgica (Belgium), 1996, 96/4 (270-280)
Myoclonus is a rare, but disabling symptom, occurring in a number of diseases of different origin. Aetiological and neurophysiological classifications, as well as the current treatment in myoclonus are discussed. An overview of the treatment of myoclonus with piracetam in 62 case reports, 3 open trials and 2 double-blind trials, covering 171 patients is reported.
Therapy of dementia - Neurologic and psychiatric aspects
Wiener Medizinische Wochenschrift (Austria), 1996, 146/21-22 (546-548)
According to the latest research the therapy of dementia includes following strategies: Above all there is a neccessity for thoroughly diagnostic tests to exclude diseases which secondarily induce reduced brain function. The early onset of non pharmacological treatments e.g. 'brain-jogging' is essential. Pharmacological therapy with nootropics (e.g. Codergocrin, Nicergolin, Ginkgo biloba, Piracetam, Pyritinol, Naftidrofuryl) is recommended as early as possible, because they have no relevant side effects. Calcium antagonists may also be administered because of their neuroprotective properties. One pharmacological approach to enhance cholinergic functions involves inhibiting ACH-degradation by inhibiting acetylcholinesterase. Although this relatively new therapy has benefits, in some patients it has not been effective and has a potential to cause serious adverse (hepatic) events; only mild to medium severe dementias of Alzheimer's disease should be treated with this therapeutic principle. In the case of personality disorders there are psychotherapy and the administration of psychoactive drugs necessary.
Piracetam and fipexide prevent PTZ-kindling-provoked amnesia in rats
European Neuropsychopharmacology (Netherlands), 1996, 6/4 (285-290)
Deficit in active and inhibitory avoidance behaviour has been found in pentylenetetrazole (PTZ)-kindled rats. This supports the view that memory deficit is an integral part of epilepsy. In the present study we examined the effect of the nootropic drugs piracetam and fipexide on memory deficit induced by PTZ-kindling in shuttle-box- and step-down-trained rats. The retention in piracetam- and fipexide-treated animals was significantly improved compared to the kindled controls. The mechanisms of action of the two drugs are considered. The favourable effects of nootropic drugs in cases of amnesia provoked by PTZ-kindling might be of interest in clinical practice.
p-Hydroxybenzyl alcohol attenuates learning deficits in the inhibitory avoidance task: Involvement of serotonergic and dopaminergic systems
Chinese Journal of Physiology (Taiwan), 1996, 39/4 (265-273)
p-Hydroxybenzyl alcohol (HBA), an aglycone of gastrodin, is an active ingredient of Gastrodia elata B(LUME). In this study, we investigated the action of HBA on acquisition of an inhibitory avoidance response in rats and used piracetam as a positive control. The results indicated that scopolamine, a cholinergic receptor antagonist, injected before training impaired retention. HBA did not attenuate the scopolamine-induced impairment, but piracetam did. p-Chloroamphetamine, a serotonin releaser, injected before training impaired retention. HBA at 5 mg/kg and piracetam at 100 mg/kg could counteract the p-chloroamphetamine-induced deficit. Apomorphine, a dopaminergic receptor agonist, also impaired retention. HBA at 5 mg/kg and piracetam at 300 mg/kg could ameliorate the apomorphine-induced amnesia. The above results indicated that HBA, different from piracetam, can attenuate impairments induced by p-chloroamphetamine and apomorphine, but had no effect on impairment induced by scopolamine in an inhibitory avoidance task in rats. Such findings suggest that HBA may act through suppressing dopaminergic and serotonergic activities and thus improves learning.
Photosensitive epilepsy: A model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam
Epilepsy Research (Netherlands), 1996, 25/3 (225-230)
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.
The morpho-functional state of the brain under conditions of hypokinesia and its possible pharmacological correction by GABA-ergic substances
Medical Journal of the Islamic Republic of Iran (Iran), 1996, 10/2 (153-158)
In this paper it has been shown that deterioration of the brain cortex capillary system and negative dynamics of cerebral tissue morphology occur under conditions of hypokinesia. Simultaneously, gamma-aminobutyric acid (GABA) and piracetam have been shown to favor the development of vasodilation and prevent further worsening of the cerebral blood supply. During the experiment, it was also established that among the substances investigated, the specific antagonist of GABA-receptors-bicuculline-displays the strongest cerebroprotective effect in early hypokinesia.
Clinical trial of piracetam in patients with myoclonus: Nationwide multiinstitution study in Japan
Movement Disorders (USA), 1996, 11/6 (691-700)
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, hematological 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.
Piracetam is useful in the treatment of children with sickle cell disease
Acta Haematologica (Switzerland), 1996, 96/4 (221-226)
The management of children suffering from sickle cell disease (sickle cell anaemia (SCA) and sickle cell betadegree-thalassaemia (Sbetadegree-thal.)) has been the concern of all clinicians caring for these patients. Several agents have been tried for treatment, often limited by toxic side effects. Piracetam (2-oxo-1-pyrrolidine acetamide, Nootropyl (R)), a cyclic derivative of gamma-amino butyrate, used for the treatment of psychosenescent syndromes with no known side effects, was considered as a possible therapeutic agent for sickle cell disease. Interest was focused on the use of piracetam when it was shown that it had an antisickling effect, both in vivo and in vitro. We initiated multicentre double-blind investigations in two groups of children suffering from sickle cell disease ranging in age from 3-6 to 6-12 years. The total number of patients included in the study were 87 (SCA = 79 and Hb Sbetadegree-thal. = 8) in 13 centres in 10 different regions of Saudi Arabia. Coded boxes of the drugs were received from the company (UCB) and were administered as intravenous infusion during crises and orally during the follow-up, for a period of up to 1 year. After decoding the code at the end of the study, the patients were grouped into those receiving placebo (n = 39), i.e. controls, or piracetam (n = 48), i.e. study cases. In terms of age, weight, height and severity index, number of blood transfusions received and number of hospitalization, both groups were statistically homogenous. Data analysis showed that the clinical severity of the disease, the number of crises, the extent of hospitalization and the blood transfusion requirements significantly decreased during piracetam treatment (p < 0.001), though no statistically significant changes occurred in the placebo group. However, in the levels of the haematological and biochemical parameters no significant changes were documented in both groups. In addition, the improvement in the clinical presentation of the disease continued even several months after discontinuation of the drug in the majority of the children, as judged from the low severity index value. Though our results point to the recommendation that piracetam can be used for the treatment of children suffering from sickle cell disease, both SCA asnd Sbetadegree-thal, it is advisable to conduct long-term and close follow-up treatment programmes using piracetam to establish its therapeutic Sickle cell anaemia value particularly in adults and to ascertain that there are no long-term toxic Sickle cell disease side effects.
Cerebral blood flow effects of piracetam, pentifylline, and nicotinic acid in the baboon model compared with the known effect of acetazolamide
Arzneimittel-Forschung/Drug Research (Germany), 1996, 46/9 (844-847)
In normal aging humans there is a progressive decrease of oxygen and glucose consumption with a reduction of cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A baboon model under anaesthesia using single photon emission computed tomography (SPECT) of the brain and the radiopharmaceutical hexamethylpropylene amine oxime (99mTc-HMPAO) has been developed and found to be sensitive to the effects of drugs that are known to increase CBF. In the present study, the effect of two haemorrheologically active drugs, viz a combination of pentifylline (CAS 1028-33-7) and nicotinic acid (CAS 59-67-6) vs. piracetam (CAS 7491-74-9) were compared with the known effect of acetazolamide (CAS 59-66-5) on CBF in the baboon model using the 99mTc-HMPAO split dose method. Acetazolamide (p < 0.05) and the combination of pentifylline and nicotinic acid (p <0.01) increased the CBF when compared with the control baseline. The CBF was not significantly increased upon treatment with piracetam, pentifylline alone and nicotinic acid alone, when compared with the control values for total brain ratios (p > 0.05). However, an increased regional effect was observed for piracetam. These results indicate that the above haemorrheologically active drugs exhibit specific but different effects on cerebral blood flow with possible clinical implications.
Hyperbaric oxygen therapy and piracetam decrease the early extension of deep partial-thickness burns
Burns (United Kingdom), 1996, 22/6 (468-473)
During the first 24 h, a progression of the burn wound in histological depth or extension is often noted. This can only partially be prevented by the routinely used protocols of fluid resuscitation and burn wound dressing. In a rat model of 5% TBSA burn, hyperbaric oxygen therapy (HBOT) and piracetam were evaluated for their ability to further prevent this early deepening of the burn wound. After infliction of the burn wound, the animals were treated with an accepted basic burn wound treatment consisting of mafenide 10% solution humid dressings. They were then randomized into three groups: a control group (n = 10), receiving no other treatment, a HBOT group (n = 17), receiving 60 min of HBOT (203 kPa) twice daily, and a piracetam group (n = 19), receiving piracetam (200 mg/kg IM) twice daily. On the third day of treatment, the entire burn wound was exised and examined histologically. It was found that both HBOT and piracetam had statistically significant effects on the preservation of epidermal basal membrane (P < 0.001 and P < 0.01, respectively). HBOT, but not piracetam, further had significant effects on the destruction of skin appendages (P less than or equal to 0.05 and P > 0.05, respectively) and on the degree of subepidermal inflammation, as measured by leucocyte infiltration (P<0.001 and P > 0.05, respectively). Furthermore, the HBOT group showed significantly less leucocyte infiltration than the piracetam group (P < 0.01). It was concluded that, although the clinical importance of the small effects on skin appendage and basal membrane preservation may be questionable, the effect on subepidermal leucocyte infiltration is striking and warrants further investigation of the anti-inflammatory effects of HBOT and possibly piracetam.
Cortical myoclonus in Angelman syndrome
Annals of Neurology (USA), 1996, 40/1 (39-48)
Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11-13. This region encompasses three GABA(A) receptor subunit genes (beta3, alphleft arrow over right arrow, and gamma3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uuiparental disomy for chromosome 15, 8 had a >3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 plus or minus 13 msec and had a frequency of 11 plus or minus 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 plus or minus 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.
Piracetam in the treatment of patients with brain stroke in the vascular bed of the carotid artery
Medizinische Welt (Germany), 1996, 47/5 (200-204)
Cerebrovascular affections are one of the most causes of death following cardial or malignant diseases. In patients of 75 years and more stroke mortality has overcome the mortality of coronary heart disease. Furthermore, cerebrovascular diseases often lead to a loss of independence and to a permanent need of care. The research on stroke pathophysiology brought some substances including piracetam for the treatment of cerebral ischemia, which activate the cerebral metabolism. A lot of experimental and clinical studies have shown the effectiveness of piracetam on the disturbed cerebral energy metabolism. In the present study the efficiency and tolerance of piracetam was investigated in patients suffering from cerebral ischemia.