Digg in deep and see how Ciltep nootropic formula induce long-term potentiation
Natural Stacks’ nootropic formula, CILTEP, aims to chemically induce long-term potentiation by increasing the intracellular levels of the second messenger cyclic AMP (cAMP) through a two-pronged approach. CILTEP contains foreskolin, in the form of Coleus forskohlii extract, which stimulates the synthesis of cAMP by activating the enzyme adenylyl cyclase. On the other hand, the lutoelin from artichoke extract in CILTEP, prevents the breakdown of cAMP by inhibiting the enzyme phosphodiesterase 4 (PDE4). The elevated levels of cAMP induce long-term potentiation, the brain’s endogenous mechanism for storing memories. The effect is enhanced cognition, improved ability to learn, and better memory.
Increased levels of cAMP lead to increased activity of the enzyme tyrosine hydroxylase, which is necessary for the synthesis of the neurotransmitter dopamine. CILTEP, therefore also contains the amino acid L-phenylalanine, a precursor of dopamine, and vitamin B6, and essential cofactor in the synthesis of the neurotransmitter. The naturally enhanced levels of dopamine lead to increased alertness and energy levels, without the side effects of drugs that interfere with dopamine metabolism.
On the other hand, increased levels of cAMP lead to stimulation of the action of acetylcholinesterase, which breaks down another neurotransmitter, acetylcholine. To counteract this CILTEP contains the amino acid acetyl L-carnitine (ALCAR), which inhibits the enzyme and maintains optimum acetylcholine levels.
Long Term Potentiation as the Basis of Learning and Memory
Long-term potentiation is believed by neuroscientists to be the biochemical basis of many, if not all, types of memory. The phenomenon was first observed in 1966 and has been studied extensively ever since. It is a particularly persistent form of synaptic plasticity. The basic observation is that stimulating neurons synchronously causes the synapse between them to become better at conducting signals in the future. The connection between the neurons is basically strengthened.
Central to the understanding of LTP is the existence of synapses. Nerve cells are not continuous throughout the body; instead signals are passed from one neuron to another across a synapse. The presynaptic neuron releases neurotransmitters into the junction, the neurotransmitter molecules cross the synapse and bind to receptors in the plasma membrane of the postsynaptic neuron. Once in the second neuron, the neurotransmitter can either excite it, or inhibit it depending on its chemical nature.
It is thought that when a synapse is excited repeatedly, the presynaptic neuron forms more synaptic vesicles with neurotransmitter. At the same time the post synaptic neuron produces more receptor molecules in its membrane. This causes the connection between the neurons to become stronger, so that even a weak signal causes a strong reaction. Because this strengthening of the synapse can last a very long time, it is called long-term potentiation.
CILTEP Targets the Second Messenger cAMP
Although scientists don’t completely understand the detailed mechanisms of LTP, there is great interest in learning how to artificially manipulate it to improve the brain’s capacity to learn and to remember. It is known that cyclic AMP (cAMP) plays a crucial part in LTP.
cAMP (cyclic adenosine monophosphate) is a small molecule that is known as a second messenger. It is involved in signal transduction with several hormones and neurotransmitters, which cannot enter the cell. The hormones bind to their G-protein coupled receptors on the outside side of the plasma membrane. This causes a change in the receptor that activates the enzyme adenylyl cyclase, bound to the plasma membrane inside the cell. Once activated, adenylyl cyclase converts ATP into cAMP. cAMP then exerts its various functions inside the cell, depending on the cell type.
Many of the functions of ATP are transduced through its activation of protein kinase A. Protein kinases are a class of regulatory proteins which activate other proteins by phosphorylating them, transferring a phosphate group to serine and threonine amino acids on the proteins. In the absence of cAMP, protein kinase A is inactive, since the catalytic subunits are bound to regulatory subunits. When present cAMP binds to the protein, this causes a structural change which results in the regulatory subunit being released, and the activation of the kinase.
Apart from the activation of PKA, cAMP has several other regulatory functions. In the brain it can also regulate ion channels in the prefrontal complex, which affects higher order thinking.
CILTEP Increases Intracellular cAMP Levels in Neurons.
Because of its involvement in LTP, enhancing cAMP levels inside the neurons of the hippocampus has long been a major aim of scientists aiming to improve human memory and cognition. However, many of the synthetic chemicals trialed cause unpleasant side effects. CILTEP was developed by Abelard Lindsay, the Director of Research and Development at Natural Stacks. He focused on elevating the intracellular concentration of cAMP in neurons using only natural botanical extracts, which are safer and have fewer side effects than synthetic chemicals.
CILTEP elevates cAMP levels through two mechanisms. On the one hand, it targets phosphodiesterase 4 (PDE-4), the enzyme that breaks down cAMP. On the other hand it uses botanical extracts that activates adenylyl cyclase, the enzyme that produces cAMP from ATP. This two pronged approach is extremely efficient at increasing cAMP inside brain neuron cells, and producing the nootropic effects of CILTEP.
The inhibition of Phosphodiesterases is being intensely studied by neuroscientists since results in animal studies show their importance in cognition. There are 11 different PDE enzymes, and current research is attempting to figure out which ones are important in cognition. The data available now suggests that PDE-4 is important in the brain. In animal studies the effects of PDE-4 inhibitors on memory and information processing yielded very positive results.
CILTEP contains the all-natural artichoke extract, a rich source of the bioactive phytochemical lutoelin, a well characterised PDE-4 inhibitor. Luteolin has significant nootropic effects, not only improved memory and cognition, but also increased alertness. It also appears to have a neuroprotective and neuroregenerative action.
The second ingredient in CILTEP that elevates cAMP levels is foreskolin, in the form of an extract from the roots of Coleus forskohlii. Foreskolin is a very well characterised activator of adenylyl cyclase, and is used by scientists extensively to raise intracellular cAMP levels. The dual action of artichoke extract and foreskolin makes CILTEP an incredibly effective nootropic.
Acetyl L-Carnitine to Maintain Optimal Acetylcholine Levels
During the years he spent trying out CILTEP, Abelard Lindsay added three additional ingredients to the stack, to achieve optimal levels of neurotrasmitters. Although the foreskolin-artichoke extract combination is completely natural and safe, one undesirable side effect of elevating cAMP levels, and the resulting activation of the CREB protein, is an increased concentration of acetylcholinesterase. Acetylcholinesterase is an enzyme that breaks down the neurotransmitter acetylcholine. ALCAR (acetyl L- carnitine), a naturally occurring amino acid was added to the stack to counteract the elevation of acetylcholinesterase and maintain optimal acetylcholine concentrations for energy and short-term memory.
L-Phenylalanine to Support Increased Dopamine Synthesis
On the other hand, a positive side effect of increased cAMP levels, is increased transcription of the gene coding for tyrosine hydroxylase. One of the outcomes of cAMP signalling is the phosphorylation, and therefore activation, of the CREB protein. CREB stands for cAMP Response Element Binding protein. As the name suggests, when activated the CREB protein binds to specific DNA sequences, called cAMP Response Elements, and acts as a transcription enhancer increasing the level of mRNA transcribed from the target genes of cAMP.
Tyrosine hydroxylase is a cAMP and CREB protein target gene. It is also the enzyme involved in the synthesis of the neurotransmitter dopamine. In this way, elevated cAMP levels increase the neurons’ capacity for making dopamine. Dopamine is a neurotransmitter that plays a significant role in motivation, the reward system, and cognitive function.
Neurons that use dopamine as a neurotransmitter are known as dopaminergic neurons. The largest group of dopaminergic cells in the human brain is known as the ventral tegmental area, in the midbrain. The neurons from the VTA connect with the prefrontal cortex and other areas of the brain involved in reward systems and motivation. Animals in which the dopaminergic neurons of the VTA are deactivated do not seek food, for example. If left to their own devices they would starve to death, even if food is nearby. However when they are forced to eat, they appear to derive pleasure from the food. Dopamine is therefore the neurotransmitter at the centre of motivation and pursuing goals with determination.
To make sure that your body is able to gain maximum dopamine production from the increased levels of tyrosine hydroxylase, L-phenylalanine was added to the CILTEP stack. L-phenylalanine is an essential amino acid, meaning that the body cannot synthesise it and it must be obtained from the diet. Phenylalanine is not only a residue present in many proteins, but it is also a precursor of dopamine. The synthesis of dopamine starts with the amino acid, which is converted to L-tyrosine. This in turn is the precursor of L-DOPA, and finally dopamine is made from L-DOPA.
What is important to notice is that CILTEP does not interfere with the natural metabolism of dopamine the way other drugs, such as Adderall or Ritalin, do. The enzyme necessary for its synthesis is naturally elevated because of the enhanced levels of cAMP, and the naturally occurring amino acid is simply added to the stack to ensure there is sufficient dopamine precursor for the extra enzyme to work with.
Vitamin B6 for Optimal Dopamine Synthesis
Vitamin B6 is a water soluble vitamin belonging to the B-complex. It is an essential cofactor for many enzymatic reactions, and is necessary for amino acid metabolism, as well as producing glucose from glycogen.
One of the roles of B6 is as a cofactor of DOPA carboxylase, which catalyses the formation of dopamine from L-DOPA, the last step in dopamine synthesis. Vitamin B6 is added to the CILTEP stack to support increased production of the neurotransmitter in the environment of elevated tyrosine hydroxylase levels resulting from increased cAMP.
CILTEP was inspired by decades of research into memory formation through the process of long-term potentiation. The dual actions of the cAMP elevating foreskolin, and the PDE-4 inhibitor luteolin from artichoke extract result in chemically induced LTP. Users of CILTEP observe remarkable improvement in cognitive function, memory and ability to absorb new information. The increased cAMP levels increase the neurons ability to produce the neurotransmitter dopamine, and CILTEP supports improved dopamine metabolism by including its precursor, the amino acid L-phenylalanine in the stack. The enhanced dopamine metabolism increases mental alertness and motivation. CILTEP also contains acetyl L-carnitine to mitigate the effects of cAMP on cholinesterase and keep acetylcholine concentrations optimal. Users find CILTEP to be a surprisingly effective and fast acting nootropic, allowing them to experience visible improvements in cognition, memory, energy levels, mental focus and determination for 8-14 hours after taking the supplement. Since the ingredients of CILTEP are all natural botanicals, no negative side effects have been reported.
Long-term potentiation as a model of memory:
PDE inhibitors and cognitive enhancement:
Better memory in PDE4 knockdown mice.
The diagram showing the final stage of LTP is by Tomwsulcer and is in the public domain.The three dimensional structure of cAMP is by Benhah-bmm27 and is in the public domain.The image of artichoke is by China Crisis and is used under the Creative Commons Share-Alike 2.5 generic licence.The image of Coleus forskohlii is by mauroguanandi and is used here under the Creative Commons 2.0 generic licence.The chemical structure of dopamine is by Harbin, and is in the public domain.