- Most likely increase inter-cerebral(left and right brain hemispheres) communication by increasing activity in the corpus callosum(the link betw the two hemispheres)
- Increase brain energy metabolism
- Increase dendrite growth
- Increase density of frontal cortex acetylcholine receptors
All the above factors probably are responsible for the increase in memory, focus and attention span and potentiated by modulating of neuronal ion channels in the cholinergic system.
The cerebral cortex in humans and animals is divided into two hemispheres, the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture-oriented and simultaneous in its information processing. Research has shown that most people favor one hemisphere over the other, with the dominant hemisphere being more electrically active and the non-dominant hemisphere relatively more electrically silent, when a person is being tested or asked to solve problems or respond to information. The two cortical hemispheres are linked by a bundle of nerve fibers: the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres. In practice they act more like a wall separating them. The cerebral cortex in humans and animals is divided into two hemispheres, the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture-oriented and simultaneous in its information processing. Research has shown that most people favor one hemisphere over the other, with the dominant hemisphere being more electrically active and the non-dominant hemisphere relatively more electrically silent, when a person is being tested or asked to solve problems or respond to information. The two cortical hemispheres are linked by a bundle of nerve fibers: the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres. In practice they act more like a wall separating them.
During this same period a growing body of evidence began to show that Piracetam works in part through a multimodal cholinergic activity. Studies with both aged rats and humans which combined Piracetam with either choline or lecithin (phosphatidyl choline), found radically enhanced learning abilities in rats, and produced significant improvement in memory in Alzheimer’s patients. (30-35)Yet giving choline or lecithin alone (they are precursors for the neurotransmitter acetylcholine) in these studies provided little or no benefit, while Piracetam alone provided only modest benefit.Animal research has also shown that Piracetam increases high-affinity choline uptake, a process that occurs in cholinergic nerve endings which facilitates acetylcholine formation. (23,29) “High-affinity choline uptake rate has been shown to be directly coupled to the impulse flow through the cholinergic nerve endings and it is a good indicator of acetylcholine utilization nootropic drugs (including Piracetam) activate brain cholinergic neurons” (29) HC-3 induces both amnesia and death through blocking high-affinity choline uptake in the brain an din peripheral nerves that control breathing. Since Piracetam blocks HC-3 asphyxiation death and amnesia, this is further evidence of Piracetam’s pro-high-affinity choline uptake actions. (23,29)Scopalamine is a drug that blockades acetylcholine receptors and disrupts energy metabolism in cholinergic nerves. When rats were given Scopalamine, it prevented the learning of a passive avoidance task, and reduced glucose utilization in key cholinergic brain areas. When rats given Scopalamine were pretreated with 100/kg Piracetam, their learning performance became almost identical to rats not given Scopalamine. (36) The Piracetam treatment also reduced the Scopalamine depression of glucose-energy metabolism in the rats’ hippocampus and anterior cingulate cortex, key areas of nerve damage and glucose metabolism reduction in Alzheimer’s disease.(36)
Increase in acetylchole receptor density
German researchers added to the picture of Piracetam’s cholinergic effects in 1988 and 1991. Treatment for 2 weeks with high dose oral Piracetam in aged mice elevated the density of frontal cortex acetylcholine receptors 30-40%, restoring the levels to those of healthy young mice. A similar decline in cortex acetylcholine receptors occurs in “normal” aging in humans. (37) The same group of researchers then discovered that there is a serious decline in the functional activity of acetylcholine receptors in aged mice; with many receptors becoming “desensitized” and inactive. Oral treatment with high dose Piracetam also partially restored the activity of acetylcholine cortex nerves, as measured by the release of their “second messenger,” inositol-1-phosphate. (38)Glutamic acid (glutamate) is the chief excitatory neurotransmitter in the mammalian brain. Piracetam has little affinity for glutamate (glutamate) receptors, yet it does have various effects on glutamate neurotransmission. One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts [levels which are achieved through oral Piracetam intake] of Piracetam enhance the efficacy of AMPA-induced calcium influx [which “excites” nerve cells to fire] in cerebeller [brain] cells. Piracetam also increases the maximal density of [AMPA glutamate receptors] in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission.” (1) Further support for involvement of the glutamate system in Piracetam’s action is provided by a Chinese study which showed that the memory improving properties of Piracetam can be inhibited by ketamine, an NMDA (another major subtype of glutamate receptor) channel blocker. (1) Furthermore, high dose injected Piracetam decreases mouse brain glutamate content and the glutamate/GABA ratio, indicating an increase in excitatory nerve activity (1) At micrornolar levels,
Piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves. (1) Given that acetylcholine and glutamate are two of the most central “activating” neurotransmitters and the facilatory effects of acetylcholine/glutamate neural systems on alertness, focus, attention, memory and learning. Piracetam’s effects on acetylcholine/glutamate neurotransmission must he presumed to play a major role in its demonstrated ability to improve mental performance and memory. Although Piracetam is generally reported to have minimal or no side effects, it is interesting to note that Piracetam’s occasionally reported side effects of anxiety, insomnia, agitation, irritability and tremor (18) are identical to the symptoms of excess acetylcholine/glutamate neuroactivity.Taken together, these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal excitability [electrical activity] within specific neuronal pathways.” (23)Grau and colleagues note that “there exist papers giving data of bioelectric activity as affected by Piracetam, and suggesting that it acts as a non-specific activator of the excitability. [i.e. brain electrical activity] thus optimizing the functional state of the brain.” (25) Gouliaev and Senning similarly state “we think that the racetams exert their effect on some species [of molecule] present in the cell membrane of all excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the excitatory (electrical) response. It would therefore seem that the racetams act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any [neurotransmitter-like] activity of their own, in keeping with their very low toxicity and lack of serious side effects. The result of their action is therefore an increase in general neuronal sensitivity toward stimulation.” (1)Compared to saline controls, Piracetam rats had a 22% increase in whole brain glucose metabolism, while the increase in 12 different brain regions ranged from L6 to 28%. (25) This increase in brain energy metabolism occurred under normal oxygen conditions.
Increases brain energy metabolism
Piracetam has also been shown to increase synthesis and turnover of cytochrome b5, a key component of the electron transport chain, wherein most ATP energy is produced in mitochondria. (22) Piracetam also increases permeability of mitochondrial membranes for certain intermediaries of the Krebs cycle, a further plus for brain ATP production. (25) In his 1989 paper on cerebral ischemia in humans, Herrschaft notes that the Herman Federal Health Office has conducted controlled studies that indicate a “‘significant positive” effect of Piracetam (4.8 – 6gm/day) to increase cerebral blood flow, cerebral oxygen usage metabolic rate and cerebral glucose metabolic rate in chronic impaired human brain function – i.e. multi-infarct dementia, senile dementia of the Alzheimer type, and pseudo-dementia. (9)
B complex vitamins, NADH, lipoic acid, Co Q10, or idebenone, and magnesium will enhance Piracetam’s brain energy effects. In the clinical literature on Piracetam, dosages have ranged from 2.4 gm/day (6,11) up to 8gm/day (7,21), continued for years (7,21). Piracetam has a relatively short half-life in the blood, although there is some short-term bioaccumulation in the brain. (1,22) Piracetam is therefore usually taken 3-4 times daily. 1.6 gm, 3 times daily, or 1.2 gm 3-4 times daily is a fairly typical Piracetam dosage, although some people report noticeable improvement in memory and cognition from just 1.2 gm twice daily..
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