Piracetam improves memory and enhances cognitive functions

By Sergey Skudaev

Introduction

Piracetam has gained popularity as a smart drug that is taken by students to enhance their learning abilities and increase their exam scores. In Europe, piracetam is a prescribed medication that is used to treat patients with different neurologic dysfunctions and diseases including Alzheimer's disease. In the US piracetam is not approved by the Food and Drug Administration (FDA). It can be bought as a supplement.

What is piracetam?

Piracetam (2-oxo-1-pyrrolidine-acetamide) is a cyclic derivative of gamma-aminobutyric acid. It was produced by Belgium pharmacologists C.Giurgea and V. Skondia in 1963. [8]

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the brain. Neurotransmitters or neuromediators are physiologic active compounds that transmit signals from one neural cell to another. Read my article How does the neural cell work? for details.

There are many different neurotransmitters: noradrenaline, dopamine, serotonin, gamma butyric acid (GABA), glutamic acid (glutamate), acetylcholine and benzodiazepines.

The transmission of signals between neurons takes place in synapse.

Synapse structure

Figure 1. A neurotransmitter is released by ending of an axon and passively diffuses in the synaptic cleft.

When the neurotransmitter reaches the postsynaptic membrane, it binds to postsynaptic receptors and starts a chain of processes that lead to changing membrane ion currents and as a result the postsynaptic neuron becomes activated or inhibited.

The action of different neurotransmitters is ceased by different mechanisms. For example, acetylcholine is broken down by the enzyme acetylcholine esterase to acetate and choline. Noradrenaline and dopamine are broken down by the enzyme monoamine oxidase (MAO).

The mechanism of taking a neurotransmitter back into the axon ending is called reuptake. Serotonin reuptake removes serotonin from the synaptic cleft. Inhibitors of serotonin reuptake (Selective serotonin reuptake inhibitors or SSRI) increase serotonin concentration in the synaptic cleft. SSRI are used as antidepressants.

Neurons that produce noradrenalin are called noradrenergic neurons; neurons that produce acetylcholine are called cholinergic neurons and so on. Different parts of the brain have different neurotransmitters and participate in different functions. For example, it is known that cholinergic and glutamatergic receptors are related to learning abilities and memory. Impairment of the cholinergic and glutamatergic systems with aging or in Alzheimer´s disease decrease learning abilities and impairs memory.

Dopamine deficit causes Parkinson´s disease, while excessive activity of dopaminergic neurons is observed in schizophrenia. Deficiency of noradrenaline (norepinephrine) and serotonin as well as dopamine causes depression. GABA receptors cause inhibition of postsynaptic neurons and are related to sleep.


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Upregulation and Downregulation

To better understand actions of different drugs on brain functions we have to be familiar with the brain ability to change its microstructure depending on different conditions. For example, when a drug that increases activity of certain type of receptors is used for a period of time the brain may decrease the number of these receptors to alleviate the drug action. It is called downregulation. For example, flurazepam stimulates GABA receptors and is used as a sedative drug. At the same time, flurazepam decreases the number of GABA receptors. [2].

On the contrary, when a drug decreases activity certain receptors, the brain may increase number of that receptors and their sensitivity to minimize the drug inhibitory effect. It is called upregulation.

Piracetam mechanism of action

Piracetam was intended to be used as a substitution for GABA, because GABA cannot cross the Blood-Brain-Barrier. The Blood-Brain-Barrier separates cerebrospinal fluid from blood and protects our brain. Piracetam can cross the Blood-Brain-Barrier, but it appears that piracetam has no affinity with GABA receptors. Actually, piracetam has no or little affinity with any type of receptors.

However, indirectly piracetam affect cholinergic and glutamatergic receptors that are related to memory and learning abilities. Piracetam increases the density of cholinergic receptors in the frontal cortex of aged mice. [16].

Anticholinergic drug scopalamine blocks learning abilities in mice. Piracetam given with scopalamine reverse the scopalamine effect and restores learning abilities. It proves that piracetam affects cholinergic receptors. [4].

One of the mechanisms of piracetam action that it increases the reuptake of choline by the nerve ending in the cholinergic synapse. [15]

The chief excitatory neurotransmitter of the brain is glutamate. Piracetam increases the density of glutamate receptors. At the same time memory improvement observed after piracetam treatment can be blocked by an inhibitor of NMDA glutamate receptors.[9].

One of the mechanisms of piracetam´s action is improving mitochondrial function. Mitochondria are the cell organelles where conversion of food energy to energy of ATP occurs as a chain of enzyme activated chemical reactions. For example, in the Crebs cycle carbon and hydrogen of organic compounds derived from food are oxidized into CO2 and water and produced energy is stored in ATP. Many toxic compounds are oxidized by mitochondria enzymes. Piracetam improve mitochondrial dysfunction associated with oxidative stress and aging. It restores mitochondrial membrane potential and production of ATP.[13].

Muller research shows that piracetam my affect neuronal cell membranes. A cell membrane comprised of two layers of lipids. Each lipid layer has hydrophobic tail inside the membrane and hydrophilic phospholipids´s head on the inner and outer membrane surface. Piracetam interacts with phospholipids´ groups of the membrane lipid bilayers. It restores the membrane age-related alteration in the neural cells, protects cells from hypoxia and as a result improves brain functions.[5]

Piracetam protects astrocytes against hypoxic injury in cell culture. The number of apoptotic and dead cells was significantly decreased after administration of piracetam due to stimulation of mitochondrial function and the increase of intracellular ATP. In addition, piracetam increases the proliferation of astrocytes during reoxigenation.[7].

Piracetam significantly improves glucose metabolism in most cortical areas of the brain in patients with Alzheimer's disease. [11]. In rats, piracetam increased metabolism of glucose in different brain areas ranging from 16% to 28%. [10]

Piracetam improves the blood flow in the brain. Its antithrombotic action depends on its ability to normalize excessive aggregation of platelets or thrombocytes in patients with such conditions as acute stroke, transient cerebral ischemic attacks and diabetes mellitus. [6].

Patients with the alcohol withdrawal delirium were treated with piracetam. It was shown that parenteral piracetam treatment normalizes the brain metabolism and improves cognitive functions. Piracetam administered in early stages of the withdrawal syndrome prevents development of delirium. It improves permeability of cell membranes and restores biogenic amine systems.[12].

In high doses (24 g/day) piracetam has an antiseizure effect and relieves symptoms in progressive myoclonus epilepsy.[14]

Psychiatric patients treated with 4.8 or 2.4 g daily dosage of piracetam demonstrated significant improvement in IQ score, memory, socialization and cooperation. [3].

Piracetam improves performance not only in elderly or mentally impaired subjects. It is shown that piracetam enhances verbal memory in young healthy man, college students in dose of 3 x 4 capsules at 400 mg per day [17]

Piracetam is not toxic and has minimal side effects such as general excitability, irritability and insomnia. Piracetam given to dogs orally in dose of 10g/kg for one year did not cause any toxic effect.[18].

Conclusion

Piracetam improves brain functions by different mechanisms. It improves mitochondrial function, improves metabolism of glucose, and restores cell membrane alteration in the aging brain. It increases density of the cholinergic and glutamate receptors that are related to learning and memory.

Piracetam has mild anticoagulant effect and increases brain blood flow. It has anti-seizure effect and can be used for treatment of epilepsy and it helps to relieve alcohol withdrawal syndrome.

Piracetam enhances cognitive abilities in aging or mentally ill patients, as well as in young healthy men.

References

1. C. Barnas et al(1990) "High versus low-dose piracetam in alcohol organic mental disorder: a placebo controlled study". Psychopharmacology Volume 100, Number 3, 361-365.

2. Blednov Y.A. et al (2003) "Deletion of the 1 or 2 Subunit of GABA A Receptors Reduces Actions of Alcohol and Other Drugs" Pharmacology and experimental therapeutics Vol. 304, Issue 1, 30-36.

3. Chouinard, G. et al (1983) "Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment." Journal Psychopharmacology, Volume 81, Number 2, 100-106.

4 Davidson, M. et al (1987) "Reversal of scopalamine- induced amnesia and alterations in energy metabolism by the nootropic piracetam" Brain Res 424, 1-9.

5. Eckert, G.P. et al (1999) "Piracetam reverses hippocampal membrane alterations in Alzheimer's disease." Journal of Neural Transmission Volume 106, Numbers 7-8, 757-761.

6. Evers S, Grotemeyer KH.(1999) "Piracetam and platelets - a review of laboratory and clinical data." Pharmacopsychiatry Mar; 32.

7. Gabryel B. et al (2002) "Piracetam and vinpocetine exert cytoprotective activity and prevent apoptosis of astrocytes in vitro in hypoxia and reoxygenation." Neurotoxicology. 2002 May;23 (1):19-31.

8. Giurgea, C. (1973) "The nootropic approach to the pharmacology of the integrative activity of the brain" Cond. Reflex 8, 108-115.

9. Gouliaev, A. & Senning, A, (1994) "Piracetam and other structurally related nootropics" Brain Res Rev 19, 180-222.

10. Grau, M. et al, (1987) "Effect of piracetam on electro-corticogram and local cerebral glucose utilization in the rat" Gen Pharmac 18, 205-11.

11. Heiss WD et al (1988) "Effect of piracetam on cerebral glucose metabolism in Alzheimer’s disease as measured by positron emission tomography." J Cereb Blood Flow Metab. 1988 Aug; 613

12. Kalmar, S (2003) "Adjuvant therapy with parenteral piracetam in alcohol withdrawal delirium" Orvosi hetilap 144: 927-30.
URL:"http://www.ionchannels.org/showabstract.php?pmid=12809069&redirect=yes&terms=
djuvant+therapy+with+parenteral+piracetam+in+alcohol+withdrawal+delirium"

13. Keil U. et al (2006) "Piracetam improves mitochondrial dysfunction following oxidative stress." Br J Pharmacol. January; 47(2): 99–208.

14. Koskiniemi M. et al (1998) "Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo." J Neurol Neurosurg Psychiatry 1998;64:344-348

15. Pepeu, G. & Spignoli, G. (1990) "Neurochemical actions of ‘nootropic drugs'" Advances In Neurology vol. 51, R. Wurtman et al, ed. Raven Press: NY

16. Pilch, H. & Mueller, W. (1988) "Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of aged by not of young mice" Psychopharmacol 94, 74-78.

17. Stuart J. et al (1976) "Increase in the Power of Human Memory in Normal Man through the Use of Drugs." Psychopharmacology 49, 307-309

18. Tacconi, M. & Wurtman, R. (1986) "Piracetam: physiological disposition and mechanism of action" Advances in Neurology, vol. 43 S. Fahn et al, ed. Raven Press: NY.


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