16 replies to this topic

[brotherx]

Hi,

just came across the following article - FYI

"Effects of piracetam and meclofenoxate on the brain NMDA and nicotinic receptors in mice with different exploratory efficacy in the cross maze test]
[Article in Russian]

Kovalev GI, Firstova IuIu, Salimov RM.

A population of outbred mice of the ICR strain was divided into two subpopulations according to their high (EH mice) or low (EL mice) exploratory efficacy in the closed cross maze test. In addition, the EH and EL mice differed in the number of binding sites of (i) [G-3H]-MK-801 with NMDA receptors from hippocampus and (ii) [G-3H]-nicotine with nicotine cholinoreceptors (nACh) from neocortex. A subchronic administration of the cognition enhancer piracetam (200 mg/kg, once per day for 5 days) increased by 70% the number of binding sites of NMDA receptors in the EL mice. At the same time, this treatment decreased the density of neocortical nACh receptors in both EL and EH mice (by 55% and 40%, respectively). A subchronic administration of the cognition enhancer and anti-oxidant meclofenoxate (100 mg/kg, once per day for 5 days) also decreased the density of neocortical nACh receptors in both EL and EH mice (by 48% and 20%, respectively). However, meclofenoxate also increased by 41% the number of binding sites of NMDA receptors in the EH mice."

Cheers

Alex

[jackinbox]

Hi,

just came across the following article - FYI

"Effects of piracetam and meclofenoxate on the brain NMDA and nicotinic receptors in mice with different exploratory efficacy in the cross maze test]
[Article in Russian]

Kovalev GI, Firstova IuIu, Salimov RM.

A population of outbred mice of the ICR strain was divided into two subpopulations according to their high (EH mice) or low (EL mice) exploratory efficacy in the closed cross maze test. In addition, the EH and EL mice differed in the number of binding sites of (i) [G-3H]-MK-801 with NMDA receptors from hippocampus and (ii) [G-3H]-nicotine with nicotine cholinoreceptors (nACh) from neocortex. A subchronic administration of the cognition enhancer piracetam (200 mg/kg, once per day for 5 days) increased by 70% the number of binding sites of NMDA receptors in the EL mice. At the same time, this treatment decreased the density of neocortical nACh receptors in both EL and EH mice (by 55% and 40%, respectively). A subchronic administration of the cognition enhancer and anti-oxidant meclofenoxate (100 mg/kg, once per day for 5 days) also decreased the density of neocortical nACh receptors in both EL and EH mice (by 48% and 20%, respectively). However, meclofenoxate also increased by 41% the number of binding sites of NMDA receptors in the EH mice."

Cheers

Alex

Is that good or bad news?

[Galantamine]

Is that good or bad news?

It appears to be bad news.

Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs).

Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).

Edited by TheDiesel, 01 September 2008 - 05:18 PM.

[Galantamine]

The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid_25-35 I.c.v.-injected mice : Involvement of dopaminergic systems

http://cat.inist.fr/...cpsidt=18968876

[luv2increase]

edit:

it reduced the density of receptors and not the number of receptors


Is this bad, who knows?


All the human studies shows that it induced cognitive enhancement in humans and animal models so go figure. It is too bad they didn't do cognitive tests as well. It would have shown that the piracetam and meclofenoxate (centrophenoxine) treatment mice had better cognitive abilities after treatment. If it didn't show this, it would defy all studies showing this.

It may just be a good thing that the density is decreased....

Edited by luv2increase, 01 September 2008 - 07:16 PM.

[brotherx]

This is not an easy one - here are some definitions and abstracts that might help to bring some light into the discussion.

Definition NMDA receptor:


The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl D-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell.

Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent.

source: wiki http://en.wikipedia....i/NMDA_receptor

---
Definition Nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors, or nAChRs, are Cholinergic receptors that form ligand-gated ion channels in cells' plasma membranes. Like the other type of acetylcholine receptors, muscarinic acetylcholine receptors (mAChRs), their opening is triggered by the neurotransmitter acetylcholine (ACh), but they are also opened by nicotine.[1][2] Also in contrast to muscarinic ACh receptors, nicotinic receptors do not operate with a second messenger, but open themselves forming an ion channel. Their action is inhibited by curare.

Nicotinic acetylcholine receptors are present in many tissues in the body. The neuronal receptors are found in the central nervous system and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction.


Receptor desensitization

Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor[8] Prolonged or repeat exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. nAChR function can be modulated by phosphorylation[9] by the activation of second messenger-dependent protein kinases. Phosphorylation of the nAChR by PKA[8] and PKC[10] have been shown to phosphorylate nAChR resulting in its desensitization. It has been reported that after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization

source:Wiki http://en.wikipedia....holine_receptor
----


Mol Chem Neuropathol. 1996 May-Aug;28(1-3):3-11.Links
Nicotinic receptors in the brain. Molecular biology, function, and therapeutics.
Vidal C.

Institut Pasteur, Paris, France.

Although the psychological and physiological effects of nicotine have long suggested that nicotine exerts specific actions in the brain, the identification of neuronal nicotinic receptors (nAChRs) only began in the past few years with the development of molecular genetics. It is now clear that neuronal nAChRs form a family of highly heterogenous receptor subtypes, as evidenced by the number of genes encoding nAChR subunits, the diversity of immunopurified receptor proteins, and the multiple functional types of ligand-gated ion channels. Neuronal nAChRs have discrete localizations within the brain, and are involved in modulating neuronal firing and transmitter release. Cumulative evidence from animal and human studies indicates that nicotinic systems play a major role in higher cognitive functions and dysfunctions. In particular, the loss of cortical nAChRs is a neuro-chemical hallmark of Alzheimer (AD) and Parkinson (PD) diseases. In addition, nicotine improves memory and attention in Ad and PD. Our recent studies using electrophysiological biochemical and behavioral approaches suggest that the prefrontal cortex is a major target site for the cognitive actions of nicotine.

PMID: 8871936 [PubMed - indexed for MEDLINE]

----------


The nicotinic acetylcholine receptor, smoking, and Alzheimer's disease.
Sabbagh MN, Lukas RJ, Sparks DL, Reid RT.

The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. marwan.sabbagh@sunhealth.org

Cholinergic dysfunction is one of the cornerstones of Alzheimer's disease (AD) pathology. Reviewed here is evidence evaluating relationships between smoking, nicotine exposure, nicotinic cholinergic signaling, and AD. Epidemiological studies initially indicating a lower incidence of AD in smokers now suggest conflicting results. Clinicopathological findings also are mixed as to how smoking behavior affects manifestation of AD markers. Studies that show nicotine-induced increases in nicotinic acetylcholine receptors (nAChR) and protection against age-related nAChR decline contrast, perhaps in a functionally relevant way, to losses of nAChR in AD. Although epidemiological, clinicopathological, and functional studies in humans do not present a cohesive picture, much in vitro data suggests neuroprotective properties of nicotine when used in models of neurodegenerative disorders. Studies of nicotine and nicotinic agonist effects on cognitive function in the non-demented and in AD are not compelling. More work is needed to ascertain whether acute or repetitive activation of nAChR with acute or intermittent exposure to nicotine or the persistent inactivation of nAChR with chronic nicotine exposure is a therapeutic objective and/or explains any pro-cognitive effects of those drugs. Other studies show complex interactions between nAChR, nicotinic agonists, and agents implicated in AD etiology. Thus, while controversies still exist, ongoing research is illuminating how nicotinic receptor changes and functions may be relevant to clinical, pathological and neurochemical changes that occur in AD.


-----

Desensitization of nicotinic ACh receptors: shaping cholinergic signaling.
Giniatullin R, Nistri A, Yakel JL.

Neurobiology Sector and INFM Unit, International School for Advanced Studies (SISSA), Via Beirut 4, 34014, Trieste, Italy.

Nicotinic ACh receptors (nAChRs) can undergo desensitization, a reversible reduction in response during sustained agonist application. Although the mechanism of desensitization remains incompletely understood, recent investigations have elucidated new properties underlying desensitization, indicating that it might be important to control synaptic efficacy, responses to cholinergic agents, and certain nAChR-related disease states. Thus, studying how different nAChR subunits contribute to desensitization might help to explain variations in responsiveness to drugs, and might thus improve their therapeutic applications. Agonist-specific desensitization, desensitization arising from resting receptors, natural mutations dramatically altering desensitization, and the possibility that recovery from desensitization is an important process for modulating receptor function, together provide a new framework for considering desensitization as a target to shape cholinergic signaling.

----

Desensitization of neuronal nicotinic receptors.
Quick MW, Lester RA.

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a well-defined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge. Copyright 2002 Wiley Periodicals, Inc.

----

Cheers Alex

edit:

it reduced the density of receptors and not the number of receptors


Is this bad, who knows?


All the human studies shows that it induced cognitive enhancement in humans and animal models so go figure. It is too bad they didn't do cognitive tests as well. It would have shown that the piracetam and meclofenoxate (centrophenoxine) treatment mice had better cognitive abilities after treatment. If it didn't show this, it would defy all studies showing this.

It may just be a good thing that the density is decreased....

[Galantamine]

edit:

it reduced the density of receptors and not the number of receptors

Unless there is a mistranslation, it means the same thing. It is not refering to the density of the protein subunits.

[Galantamine]

http://books.google....result#PPA41,M1

[luv2increase]

edit:

it reduced the density of receptors and not the number of receptors

Unless there is a mistranslation, it means the same thing. It is not refering to the density of the protein subunits.

I understand where you are coming and looked at the diagram as well. I cannot understand though as to why for the NMDA receptor, they call it a loss of receptors but for the nicotine receptors, they call is a lower density. If it is the same researcher and his own writing, why do it in a way that distinguishes the two?

[luv2increase]

The more NMDA receptor binding sites the merrier. They are important for cognition. I guess this situation may be one of an opportunity cost. One will improve in one area (NMDA) while declining in another (nicotine). Maybe one way of overcoming this would be to take nicotine concurrently with the above to counteract the decrease of nicotine receptors. This way, one would get the best of both worlds.

[Galantamine]

The more NMDA receptor binding sites the merrier. They are important for cognition. I guess this situation may be one of an opportunity cost. One will improve in one area (NMDA) while declining in another (nicotine). Maybe one way of overcoming this would be to take nicotine concurrently with the above to counteract the decrease of nicotine receptors. This way, one would get the best of both worlds.

I like the way you think!

One also needs to keep in mind the distinct area's of discussion. According to this article, there is an increase in receptor density in the hippocampus (limbic system), while a concomitant decrease in receptor density in the neocortical region. The hippocampus is obviously a very important region for memory formation (as well as memory extinction), as well as spatial memory and so forth, while the cortext is responsible for higher thinking, and access to already stored memories (frontal/temporal).

It's already been demonstrated that a nicotine agonist can increase nAch receptor density in both regions, which is quite beneficial for overall memory (working included), while also working against the (somewhat idiopathic) development of AD and parkinsons. There are downsides to this, obviously, including dependence, tolerance, and so forth (stimulating nAchR's also induce BDNF elevation, which is also possible with choline esters).

But it's also important to keep in mind that nAchR's in this area are not fully understood, and that brain-mechanisms can be very tricky and unorthodox. A good example is, as you know, the mechanism behind the SSRI's. When supplementing with one, a pharmacokinetic elevation in serotonin is immediately evident, however a therapuetic effect is not observed for a number of weeks. Biologically, the receptors are actually downregulated, decreasing in density, however becoming more efficient (through tranduction mechanisms including cAMP). It's possible, though probably not likely, that a mechanism similar to this is happening when supplementing with the nootropics in question (I'd like to see this study repeated).

[brotherx]

Gents,

good discussion so far.

Below you'll 1st find an related article - and then the explanation of mecamylamine and its effects on NAchR.

": Eksp Klin Farmakol. 2008 May-Jun;71(3):3-5.Links
[Effects of nicotinic cholinoreceptor ligands and nootropic drugs on the spontaneous exploratory activity in a labyrinth in mice]

[Article in Russian]

Salimov RM, Kovalev GI.
We have studied the effects of nicotine (0.125, 0.25, and 0.5 mg/kg) and mecamylamine (0.5, 1.5, and 3 mg/kg) in comparison to reference cognition-enhancing drugs piracetam (100 and 300 mg/kg) and meclofenoxate (20, 50, and 100 mg/kg) administered to male C57BL mice intraperitoneally 30 min prior to behavioral test. The behavioral drug effect was evaluated as influencing the activity in visiting arms of a closed plus-maze. Piracetam (300 mg/kg) and meclofenoxate (100 mg/kg) improved the exploratory activity. Mecamylamine (0.5 mg/kg) also improved the exploratory activity, while nicotine (0.5 mg/kg) deteriorated it."
Source: pubmed

Definition of meclofenoxate

"Mecamylamine is a nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to it blocking α3β4 nicotinic receptors in the brain.
In a recent double-blind, placebo controlled trial in patients with major depression, mecamylamine appears to have efficacy as an augmentation therapy. This was the first substantive evidence that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties."
Source: Wiki


Cheers

Alex

The more NMDA receptor binding sites the merrier. They are important for cognition. I guess this situation may be one of an opportunity cost. One will improve in one area (NMDA) while declining in another (nicotine). Maybe one way of overcoming this would be to take nicotine concurrently with the above to counteract the decrease of nicotine receptors. This way, one would get the best of both worlds."

I like the way you think!

One also needs to keep in mind the distinct area's of discussion. According to this article, there is an increase in receptor density in the hippocampus (limbic system), while a concomitant decrease in receptor density in the neocortical region. The hippocampus is obviously a very important region for memory formation (as well as memory extinction), as well as spatial memory and so forth, while the cortext is responsible for higher thinking, and access to already stored memories (frontal/temporal).

It's already been demonstrated that a nicotine agonist can increase nAch receptor density in both regions, which is quite beneficial for overall memory (working included), while also working against the (somewhat idiopathic) development of AD and parkinsons. There are downsides to this, obviously, including dependence, tolerance, and so forth (stimulating nAchR's also induce BDNF elevation, which is also possible with choline esters).

But it's also important to keep in mind that nAchR's in this area are not fully understood, and that brain-mechanisms can be very tricky and unorthodox. A good example is, as you know, the mechanism behind the SSRI's. When supplementing with one, a pharmacokinetic elevation in serotonin is immediately evident, however a therapuetic effect is not observed for a number of weeks. Biologically, the receptors are actually downregulated, decreasing in density, however becoming more efficient (through tranduction mechanisms including cAMP). It's possible, though probably not likely, that a mechanism similar to this is happening when supplementing with the nootropics in question (I'd like to see this study repeated).

[luv2increase]

Definition of meclofenoxate

"Mecamylamine is a nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to it blocking α3β4 nicotinic receptors in the brain.
In a recent double-blind, placebo controlled trial in patients with major depression, mecamylamine appears to have efficacy as an augmentation therapy. This was the first substantive evidence that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties."
Source: Wiki

You said "definition of meclofenoxate", but the definition was for "mecamylamine". They are not the same substances. Meclofenoxate is centrophenoxine.


Your sourced study was a bit interesting, but it was only for "exploratory behavior". I don't really know how this could relate to cognitive functioning. If you think about it, it could translate that the mice had a hard time concentrating on one thing thus wanted to explore more. This may be bad for ADD which is why nicotine has been known to help those with ADD. Just some food for thought.

[brotherx]

You are absolutely right - that was a spelling error.

Cheers

Alex

Definition of meclofenoxate

"Mecamylamine is a nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to it blocking α3β4 nicotinic receptors in the brain.
In a recent double-blind, placebo controlled trial in patients with major depression, mecamylamine appears to have efficacy as an augmentation therapy. This was the first substantive evidence that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties."
Source: Wiki

You said "definition of meclofenoxate", but the definition was for "mecamylamine". They are not the same substances. Meclofenoxate is centrophenoxine.


Your sourced study was a bit interesting, but it was only for "exploratory behavior". I don't really know how this could relate to cognitive functioning. If you think about it, it could translate that the mice had a hard time concentrating on one thing thus wanted to explore more. This may be bad for ADD which is why nicotine has been known to help those with ADD. Just some food for thought.

[brotherx]

Hi luv2increase,

both studies were performed by Salimov RM & Kovalev GI.
So there might be a connection.

Cheers

Alex

Definition of meclofenoxate

"Mecamylamine is a nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.
Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to it blocking α3β4 nicotinic receptors in the brain.
In a recent double-blind, placebo controlled trial in patients with major depression, mecamylamine appears to have efficacy as an augmentation therapy. This was the first substantive evidence that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties."
Source: Wiki

You said "definition of meclofenoxate", but the definition was for "mecamylamine". They are not the same substances. Meclofenoxate is centrophenoxine.


Your sourced study was a bit interesting, but it was only for "exploratory behavior". I don't really know how this could relate to cognitive functioning. If you think about it, it could translate that the mice had a hard time concentrating on one thing thus wanted to explore more. This may be bad for ADD which is why nicotine has been known to help those with ADD. Just some food for thought.

[solarfingers]

The more NMDA receptor binding sites the merrier. They are important for cognition. I guess this situation may be one of an opportunity cost. One will improve in one area (NMDA) while declining in another (nicotine). Maybe one way of overcoming this would be to take nicotine concurrently with the above to counteract the decrease of nicotine receptors. This way, one would get the best of both worlds.

"Nicotinic receptors can be opened not only by acetylcholine but also by nicotine - hence the name 'nicotinic.'"

It would make sense that both piracetam and meclofenoxate both use-up a great deal of acetylcholine.

This would result in a drop in nACh receptors by lack of usage. The appropriate response would be to supplement with choline and ALCAR. Also, vitamin B complex is critical to the synthesis of acetylcholine. Ginkgo biloba purportedly stimulates the brain to absorb acetylcholine.

Read more: http://www.livestron.../#ixzz2Vl5ggn8k

[brainslugged]

I have always been under the impression that racetams increase cholinergic activity, and that is why there are anticholinergic-like effects sometimes, not from reduction of choline activity, but from depletion of choline.

http://www.ncbi.nlm..../pubmed/3594455

nACh receptors, I think, are reduced because of downregulation. Regular activity on nACh receptors does decrease density if I recall correctly. It is only nicotine that paradoxically upregulates them from use.

I am unsure about the mechanisms by which it increases NMDA density, but greater NMDA density is normally considered a good thing, and, in this case, it doesn't look like activity is even being decreased on them, but they are being sensitized by a 2ndary mechanism.