GABA

In a concentration-dependent manner, piracetam (UCB-6215) can greatly reduce the fusogenic and destabilizing effect of Abeta 29–42. Piracetam preincubation, at a piracetam/peptide ratio of 960, for 20 minutes prior to Abeta 29-42 addition virtually eliminates the mixture of the two fluorescent probes. Piracetam/lipid preincubation virtually eliminates the peptide-induced calcein release in a dose-dependent manner (piracetam/peptide ratios ranging from 9.6 to 960)[1].

---

Piracetam (UCB-6215) inhibited the lipid-destabilising effect of the amyloid peptide Aβ C-terminal fragment in vitro. When incubated with lipid membranes, the Aβ C-terminal fragment caused membrane disruption and increased lipid fluidity, while Piracetam (UCB-6215) (0.1-10 mM) dose-dependently reversed these changes, restoring membrane stability by reducing lipid disorder [1]
In membrane preparations from aged rat and human brain tissues, Piracetam (UCB-6215) (1-5 mM) increased membrane fluidity in a concentration-dependent manner. The effect was more pronounced in aged brain membranes (which had inherently reduced fluidity) compared to young controls, with maximal fluidity enhancement of ~15% at 5 mM [2]

Age-related changes in membrane fluidity in mice, rats, and humans are demonstrated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH) in the presence of piracetam (UCB-6215) at concentrations less than 1.0 mM prior to preincubation. In some brain regions of both young and old rats, piracetam (UCB-6215) (300 mg/kg once daily) dramatically enhances membrane fluidity; however, in young rats, it has no discernible effect[2]. (UCB-6215) (300 mg/kg daily for 6 weeks) increases membrane fluidity in all brain regions except the cerebellum in old rats and only enhances active avoidance learning in these rats. Additionally, NMDA receptor density in the hippocampus and muscarinic cholinergic receptor densities in the frontal cortex, striatum, and to a lesser extent in the hippocampus of rats are improved by piracetam (UCB-6215) (300 mg/kg daily for 6 weeks)[3].

---

In aged mice (24 months old) and rats (20 months old), oral administration of Piracetam (UCB-6215) (100-400 mg/kg/day for 14 consecutive days) significantly increased membrane fluidity in the cerebral cortex and hippocampus. The effect was dose-dependent, with 400 mg/kg/day restoring membrane fluidity to levels similar to young animals (6 months old) [2]
In aged rats (22 months old), chronic oral administration of Piracetam (UCB-6215) (200 mg/kg/day for 30 days) improved cognitive performance. It enhanced spatial learning and memory in the Morris water maze test (reduced escape latency by ~35% and increased target quadrant time by ~40%) and reversed age-related deficits in passive avoidance memory. Additionally, it restored neurochemical imbalances in the aged rat brain, including increased choline acetyltransferase (ChAT) activity (by ~25%) and reduced acetylcholinesterase (AChE) activity (by ~20%) in the hippocampus and cortex [3]

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 [2].

Amyloid peptide (Abeta) is a 40/42-residue proteolytic fragment of a precursor protein (APP), implicated in the pathogenesis of Alzheimer's disease. The hypothesis that interactions between Abeta aggregates and neuronal membranes play an important role in toxicity has gained some acceptance. Previously, we showed that the C-terminal domain (e.g. amino acids 29-42) of Abeta induces membrane permeabilisation and fusion, an effect which is related to the appearance of non-bilayer structures. Conformational studies showed that this peptide has properties similar to those of the fusion peptide of viral proteins i.e. a tilted penetration into membranes. Since Piracetam interacts with lipids and has beneficial effects on several symptoms of Alzheimer's disease, we investigated in model membranes the ability of Piracetam to hinder the destabilising effect of the Abeta 29-42 peptide. Using fluorescence studies and 31P and 2H NMR spectroscopy, we have shown that Piracetam was able to significantly decrease the fusogenic and destabilising effect of Abeta 29-42, in a concentration-dependent manner. While the peptide induced lipid disorganisation and subsequent negative curvature at the membrane-water interface, the conformational analysis showed that piracetam, when preincubated with lipids, coats the phospholipid headgroups. Calculations suggest that this prevents appearance of the peptide-induced curvature. In addition, insertion of molecules with an inverted cone shape, like piracetam, into the outer membrane leaflet should make the formation of such structures energetically less favourable and therefore decrease the likelihood of membrane fusion [1].

---

Lipid membrane stability assay: Prepare artificial lipid vesicles (composed of phosphatidylcholine and phosphatidylserine) and incubate with the Aβ C-terminal fragment (10 μM) in the presence or absence of Piracetam (UCB-6215) (0.1-10 mM) at 37°C for 2 hours. Assess membrane stability by measuring leakage of a fluorescent dye encapsulated within the vesicles, using a spectrofluorometer to detect fluorescent intensity in the external buffer [1]
Brain membrane fluidity assay: Isolate cerebral cortex and hippocampus from aged rats/humans, homogenize, and prepare crude membrane fractions by differential centrifugation. Incubate membrane fractions with Piracetam (UCB-6215) (1-5 mM) at 37°C for 60 minutes. Label membranes with a lipophilic fluorescent probe and measure fluorescence polarization using a fluorometer. Membrane fluidity is inversely proportional to polarization values [2]

Dissolved in saline; 300 mg/kg; oral gavage
Male Wistar rats In order to test the hypothesis that piracetam improves cognitive functions by restoring biochemical deficits of the aging brain, we investigated the effects of piracetam treatment (300 mg/kg daily for 6 weeks) on the active avoidance performance of young and aged rats. After testing, the rats were killed and membrane fluidity and NMDA as well muscarinic cholinergic receptor densities were determined in the frontal cortex, the hippocampus, the striatum, as well as the cerebellum. Piracetam treatment improved active avoidance learning in the aged rats only and elevated membrane fluidity in all brain regions except the cerebellum in the aged animals. Moreover, we observed a positive effect of piracetam treatment on NMDA receptor density in the hippocampus and on muscarinic cholinergic receptor densities in the frontal cortex and the striatum and to a lesser extent in the hippocampus. Again, these effects were only observed in aged animals. Discrimination analysis indicated that piracetam effects on membrane fluidity in the frontal cortex, the hippocampus, and the striatum and its effects on NMDA densities in the hippocampus might be involved in its positive effects on cognitive performance. [3]

---

---

Aged animal membrane fluidity study: Aged mice (24 months) and rats (20 months) are randomly divided into control and treatment groups. Piracetam (UCB-6215) is dissolved in drinking water at concentrations corresponding to 100, 200, or 400 mg/kg/day and administered ad libitum for 14 days. Control groups receive plain drinking water. After treatment, animals are sacrificed, and cerebral cortex and hippocampus are dissected to prepare membrane fractions for fluidity analysis [2]
Aged rat cognitive and neurochemical study: Aged rats (22 months) are assigned to vehicle and treatment groups. Piracetam (UCB-6215) is suspended in 0.5% carboxymethylcellulose and administered orally at 200 mg/kg/day for 30 days. Vehicle group receives equal volume of 0.5% carboxymethylcellulose. During the last week of treatment, cognitive function is evaluated using the Morris water maze and passive avoidance test. After behavioral testing, rats are sacrificed, and brain tissues (hippocampus, cortex) are collected to measure ChAT and AChE activities [3]

Absorption, Distribution and Excretion
Piracetam exhibits linear and time-dependent pharmacokinetic characteristics with minimal inter-individual variability over a wide dose range. Following oral administration, piracetam is rapidly and extensively absorbed, reaching peak plasma concentrations within 1 hour in fasting subjects. After a single oral dose of 3.2 g of piracetam, the peak plasma concentration (Cmax) is 84 µg/mL. Food intake reduces Cmax by 17% and prolongs the time to peak concentration (Tmax) from 1 hour to 1.5 hours. Tmax in cerebrospinal fluid is reached approximately 5 hours after administration. The absolute bioavailability of oral piracetam formulations is close to 100%, with steady-state plasma concentrations reached within 3 days of administration. Piracetam is primarily excreted via the kidneys, with approximately 80-100% of the total dose excreted in the urine. Approximately 90% of the piracetam dose is excreted unchanged in the urine. The volume of distribution (Vd) is approximately 0.6 L/kg. Piracetam may cross the blood-brain barrier, as it has been detected in cerebrospinal fluid after intravenous administration. Piracetam diffuses into all tissues except adipose tissue, crosses the placental barrier, and penetrates separated erythrocyte membranes. Apparent systemic clearance is 80-90 mL/min. Piracetam is rapidly and almost completely absorbed. Peak plasma concentrations are reached within 1.5 hours after administration. Oral bioavailability (assessed by area under the curve (AUC)) is close to 100% for capsules, tablets, and solutions. Peak concentrations and AUC are proportional to the administered dose. The volume of distribution of piracetam is 0.7 L/kg, and… the clearance of this compound depends on renal creatinine clearance, which is expected to decrease in renal insufficiency. Piracetam is excreted into human milk. Piracetam crosses the blood-brain barrier and placental barrier and diffuses across renal dialysis membranes. Piracetam is almost entirely excreted in the urine, and the proportion of the dose excreted in the urine is independent of the administered dose. Metabolites/Metabolites: Since most of the administered piracetam is excreted unchanged, no major metabolic pathway for piracetam has been identified. …No metabolites of piracetam have been identified. Biological Half-Life: After oral or intravenous administration, the plasma half-life of piracetam is approximately 5 hours. The half-life in cerebrospinal fluid is 8.5 hours. …The half-life in the plasma of young adult males is 5.0 hours.

Protein Binding
Piracetam has been reported not to bind to plasma proteins. Interactions …There have been reports of concomitant use of thyroid extracts (T3 + T4) and piracetam leading to confusion, irritability, and sleep disturbances. Currently, although based on a small number of patients, no interactions have been found between piracetam and the following antiepileptic drugs: clonazepam, carbamazepine, phenytoin sodium, phenobarbital, and sodium valproate. In a single-blind study of patients with severe recurrent venous thrombosis, daily administration of 9.6 g of piracetam did not change the dose of acetocoumarin required to achieve an INR (International Normalized Ratio) of 2.5 to 3.5, but the addition of 9.6 g of piracetam daily significantly reduced INR values compared to acetocoumarin alone. Platelet aggregation, β-thromboglobulin release, fibrinogen and von Willebrand factor (VIII:C; VIII:vW:Ag; VIII:vW:RCo) levels, and whole blood and plasma viscosity.

---

Non-human toxicity values
Oral LD50 in mice: 26 g/kg

[1]. Piracetam inhibits the lipid-destabilising effect of the amyloid peptide Abeta C-terminal fragment. Biochim Biophys Acta, 2003. 1609(1): p. 28-38.

[2]. Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain. Biochem Pharmacol, 1997. 53(2): p. 135-40.

[3]. Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain. Pharmacopsychiatry, 1999. 32 Suppl 1: p. 10-6.

Therapeutic Uses
A researcher reported a case of a 30-year-old patient with advanced cerebellar degeneration caused by sickle cell anemia type 2. He presented with severe myoclonus, unresponsive to conventional treatment, but his condition significantly improved after taking piracetam at a dose of 12-18 g/day. Piracetam can be used to treat refractory myoclonus caused by spinocerebellar degeneration. Piracetam is indicated for patients with cortical myoclonus, regardless of etiology, and should be used in combination with other antimyoclonus drugs. Drug Warnings Piracetam is contraindicated in patients with severe renal impairment (renal creatinine clearance less than 20 mL/min), hepatic impairment, and in patients under 16 years of age. Piracetam is contraindicated in patients with cerebral hemorrhage and in patients with hypersensitivity to piracetam, other pyrrolidone derivatives, or any excipients. Because piracetam affects platelet aggregation, caution is advised in patients with impaired hemostasis, undergoing major surgery, or experiencing severe bleeding. Abrupt discontinuation of the drug should be avoided. This may cause myoclonic or generalized seizures in some patients with myoclonus. For more complete data on piracetam (9 of 9), please visit the HSDB record page. Pharmacodynamics: Piracetam is known to mediate a variety of pharmacodynamic effects: Neuronal effects: Piracetam modulates cholinergic, serotonergic, norepinephrine, and glutamatergic neurotransmission, although the drug does not have high affinity for any of the relevant receptors (Ki > 10 μM). Instead, piracetam increases the density of postsynaptic receptors and/or restores their function by stabilizing membrane fluidity. In the forebrain of aging mice, NMDA receptor density increased by approximately 20% after 14 days of piracetam treatment. Based on results from multiple animal and human studies, piracetam treatment enhances cognitive processes, including learning, memory, attention, and consciousness, without producing sedation or psychostimulation. Piracetam has neuroprotective effects against damage caused by hypoxia, poisoning, and electroconvulsive therapy. In two studies involving alcohol treatment and withdrawal-related neuronal loss in rats, piracetam was shown to reduce the degree of neuronal loss and increase the number of hippocampal synapses by up to 20% compared to the alcohol-treated or withdrawal groups. This suggests that piracetam can promote neural plasticity when reversible neural circuits are present. Although its mechanism of action is not fully elucidated, administration of piracetam before seizure stimulation reduced the severity of seizures and enhanced the anticonvulsant efficacy of traditional antiepileptic drugs such as carbamazepine and diazepam. Vascular effects: Piracetam increases erythrocyte deformability, reduces platelet aggregation in a dose-dependent manner, decreases erythrocyte adhesion to vascular endothelium, and reduces capillary spasm. In healthy volunteers, piracetam directly stimulates prostacyclin synthesis and reduces plasma levels of fibrinogen and von Willebrand factor (VIII:C; VIIIR:AG; VIIIR:vW) by 30% to 40%. Enhanced microcirculation is thought to be a result of multiple effects on erythrocytes, blood vessels, and blood coagulation.

---

Piracetam (UCB-6215) is a nootropic drug (cognitive enhancer) with a proven effect on membrane structure and function[2].
Its main mechanism of action involves altering the properties of lipid membranes, including increasing fluidity and stability, thereby modulating the function of membrane-bound proteins (e.g., neurotransmitter receptors, enzymes)[1][2].
It improves cognitive abilities in older animals by restoring age-related membrane fluidity and cholinergic neurotransmission defects (by modulating ChAT and AChE activity)[3].
It is highly selective for brain tissue, and its effects are primarily targeted at areas associated with learning and memory (hippocampus, cerebral cortex)[2][3].

C6H10N2O2

142.16

142.074

C, 50.69; H, 7.09; N, 19.71; O, 22.51

7491-74-9

Piracetam-d8;1329799-64-5;Piracetam-d6

4843

White to off-white solid powder

1.4±0.1 g/cm3

337.3±44.0 °C at 760 mmHg

151-152ºC

157.8±28.4 °C

0.0±1.7 mmHg at 25°C

1.603

-1.39

1

2

2

10

167

0

SIXPSGNZQPKXTG-UHFFFAOYSA-N

InChI=1S/C6H10N2O2/c1-5(9)7-8-4-2-3-6(8)10/h2-4H2,1H3,(H,7,9)

1-Acetamido-2-pyrrolidinone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (17.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (17.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: 100 mg/mL (703.43 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)