49 replies to this topic

[VERITAS INCORRUPTUS]

It may not be so much nicotine itself that is the culprit, it is smoking that is so abusive as a form so prone to such severe over-administration of nicotine (severe chronic intake via inhalation) and causes the harm and addiction. Know anyone who abuses nicotine replacements or that they are imposing negative health effects?

RAS may indeed help, but the damage to multiple pathways from such chronic overstimulation can take a very long time to repair as it may cause extreme corruption to the receptor or some form of highly compromised degree of desensitization.

Try to use some low dose nicotine gum or such in the meantime to help aid the dysfunctional deficits if you desire a means to feeling better and reduce imposing cravings. It should be of benefit and no negative consequence if used therapeutically.It may somewhat couterintuitive on the surface, but I believe this is a very valid approach. There are other very valid means as well, but this is quick and simple.

Edited by VERITAS INCORRUPTUS, 23 March 2014 - 05:34 PM.

[Phoenicis]

Thanks for your reply, I think you're right. For now I intend to stay away from nicotine all together in the hope that this will facilitate repair response. Additional efforts aside from taking rasagiline will be to start exericising again regularly, challenging my brain with new topics like learning to program python.

I intend to do 3 months on rasagiline with a two week break every month.

My stack will include 200mg EPA 400mg DHA, 5000iu vitamin d3, B12, Non-heme iron, turmeric (curcumin) with black pepper, and resveratrol with quercetin.

If all else fails I may consider vaping nicotine or the patches, but I want that to be a last resort because addicition sucks.

Edited by Phoenicis, 23 March 2014 - 06:14 PM.

[VERITAS INCORRUPTUS]

^ Patch would be superior from a therapeautic perspective

[Phoenicis]

Monoamine oxidase inhibition for tobacco pharmacotherapy

TP George, AH Weinberger - Clinical Pharmacology & Therapeutics, 2008 - nature.com

"There has been a considerable amount of work dealing with the genetics of MAO-A and MAO-B [...] and two known genetic polymorphisms in MAO-A and MAO-B genes may influence smoking behavior: a variable number of tandem repeat polymorphism in the promoter region of MAO-A, and a single nucleotide polymorphism in the MAO-B gene’s coding region comprised of an A→G transition, leading to lowerenzyme activity and increased levels of synaptic monoamine concentrations. However, only the MAO-A variable number1 [...] of tandem repeat polymorphism appears to have functional con-sequences for smoking behavior."
[...]
"Several clinical and neuroimaging reports suggest that cigarette smoke contains components that inhibit both MAO iso-forms. Humanex vivostudies have suggested that smokers have reduced levels of platelet MAO-A and MAO-B activity whencompared with non-smokers.15–17 Consistent with these results, positron emission tomography studies using labeled clorgylineand selegiline have shown that binding of these ligands to brain and peripheral organs is reduced in smokers when comparedwith non-smokers.18,19 Both clinical studies, assaying platelet MAO inhibition and positron emission tomography imaging, suggest that this inhibition persists for >30 days, consistentwith the irreversible inhibition produced by these agents.15,20 This inhibition of MAO by smoking is not related to the direct effects of nicotine. Interestingly,in vitrostudies have identifiedseveral components, namely the alkaloids harman (a specificcompetitive MAO-A inhibitor; IC50= 0.34μM) and norhar-man (nonspecific competitive inhibitor of MAO-A and MAO-B,with IC50s of 6.5 and 4.7μM, respectively) as contributing to the inhibitory effects of tobacco smoke on MAO isoforms.21 Besides harman alkaloids, other components of tobacco smoke may also inhibit MAO-A and MAO-B.22,23 In the light of the observation that: (i) MAO inhibition leads to increases in synaptic monoamines which are also increasedby nicotinic acetylcholine receptor activation; and (ii) cigarette smoke possesses components that inhibit MAO isoforms, we(and others) have reasoned that MAOIs may be promising candidates for developing medications to aid smokers to stop tobacco use."
[...]
"Inhibition of monoamine metabolism by MAO inhibitors leads to increased synaptic levels of dopamine, serotonin, and norepinephrine. There is also a compensatory decrease in the respective monoamine metabolites (homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxymandelic acid), which are produced by the sequential actions of MAO and catechol-O-methyl transferase. Overall, the increase in monoaminelevels is hypothesized to lead to a decrease in the craving for nicotine in tobacco, and thereby in a reduction in the urge to smoke. This process facilitates smoking cessation."
[...]
"MAO subtype-selective inhibitors may represent a novel class of medications that can be developed as adjuncts tobehavioral therapies aimed at quitting cigarette smoking. Initial proof-of-concept studies in human subjects support the case for further development of these agents. Given the evidence that both MAO-A and MAO-B genes show genetic variationsthat may alter the functioning of the corresponding enzymes, there will be considerable interest in the application of pharma-cogenetic methods to tailor antismoking therapy using agentsthat target these MAO isoforms."
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
The journal quoted above also has a great diagram showing the mechanism of how MAOIs can treat tabacco addiction, I would encourage anyone interested in these pathways to get the full text version of this article!

It seems that rasagiline hasn't yet been tested extensively in this regard (unless anyone knows otherwise), but selegiline has been tested with some good results, although I have also found some mixed studies.

• Effects of selegiline (L-deprenyl) during smoking and short-term abstinence
  
  EJ Houtsmuller, JA Thornton, ML Stitzer - Psychopharmacology, 2002 - Springer

• Monoamine oxidase polymorphisms and smoking behaviour in Japanese

H Ito, N Hamajima, K Matsuo, K Okuma… - Pharmacogenetics …, 2003 - journals.lww.com

• A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation
  
  …,A Termine, PI Jatlow, TR Kosten, SS O'Malley - … psychiatry, 2003 - Elsevier

• A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation

R Biberman, R Neumann, I Katzir, Y Gerber - Addiction, 2003 - Wiley Online Library

I think the major thing that could set rasagiline apart from selegiline is the fact that it's MAO A gene expression mechanism leads to increased GDNF. Perhaps it would make sense to cycle the two for alternating GDNF and BDNF.

Edited by Phoenicis, 23 March 2014 - 08:26 PM.

[VERITAS INCORRUPTUS]

Tobacco is a very complex plant, especially the 'poisonous variety' as purveyed by BIG CIG.
There are as well MAOB specific inhibitors within tobacco.
You can thank BIG CIG (and BIG PHARMA) for the disgusting nature of what has transpired with the scourge that is smoking...

As an aside to the thread relative to nicotine, its effects, and addictive nature (inherent) itself; here is an anecdotal report from another thread looking more directly at nicotinic receptors:

I concur nicotine itself might not be harmful on itself, I'm schizo, was a heavy cigs smoker, on one hand it was good for only 15/30 min. concentration on the other hand it affected my symptoms like DP/DR and mentally it slowed me down.. After comparing it with vaping, cigs are the axis of evil!! After switching to vaping Nicotine (since Jan 8th) liquids I have some nootropics effects, well, I can't really say nootropic but some symptoms really improved (I'm more of the old me and feeling fresh and young!), mental clarity, I'm way more talkative, my brainspeed to take up information and process it improved, short term memory works better, anxiety improved, depression improved, verbal memory improved (maybe other cognitive things but can't really tell because I'm also taking Clonazepam), it works anti-stress and off course not only mentally, all the physical downsides of smoking are gone! I craved cigs after normal daily events, eating, gaming, reading, stressful events, (almost the whole day) with vaping the whole craving to a drug like a junkie is gone and I don't even find it necessary to increase my intake of vaping over the past several months!

[LexLux]

So upon reviewing this recent study again this is a revised summary of the Rasagiline GDNF pathway (based on what happened in a petri dishes):

What appears to be happening with RAS in SH-SY5Y cell (in a petri dish) is as follows:

Rasagiline Induces MAO A transcriptionally via R1-Sp1 pathway (reduced repressors R1), wheras Selegiline induces MAO A via a non-defined pathway. Rasagiline decreases R1 and increases MAO-A

BUT

Increased MAO-A expression by rasagiline and selegiline have never been reported in the brain of experiemntal animals and further, "[a]fter chronic treatment, rasagiline and selegiline reduced MAO-A activity...(Lamensdorf et al 1996)"

The good news is that this seems to conflict with what was reported here:

"Type A MAO (MAO-A) was found to mediate the induction of Bcl-2 by [rasagiline and selegiline] in MAO-A-expressing neuroblastoma SH-SY5Y cells. Rasagiline and selegiline increased the mRNA and protein levels of glial cell line-derived neurotrophic factor (GDNF) and neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3)] in SH-SY5Y cells. Rasagiline increased GDNF more markedly than neurotrophins, and vice versa selegiline increased neurotrophins. The distinct induction of GDNF and neurotrophins by MAO inhibitors was also confirmed in non-human primates. Rasagiline was systematically administered in Japanese monkeys (n=4) for 4 weeks by daily subcutaneous injection, and the cerebrospinal fluid (CSF) was taken once a week. The NTF levels were quantified by the EIA assay. Rasagiline at 0.25 mg/day increased GDNF significantly, followed by BDNF, NGF and NT-3. On the contrary, selegiline increased BDNF in the CSF from parkinsonian patients treated with selegiline."

and those findings were reported again recently here: http://www.ncbi.nlm....pubmed/22892822

So there appears to be some evidence that this increase in GDNF happens in animals, not just in a petri dish.

In any case, we should look more carefully at the mechanism to question whether there are any potential downsides.

___________________________________________
The author has retracted this statement due to errors:

"Both selegiline and rasagiline supress mitochondrial apoptotic signaling and up-regulation anti-apoptotic bcl-2 and bcl-xL as well as prosurvival neurotrophic factors, including GDNF and BDNF. Further Rasagiline increases GDNF more markedly than BDNF and NGF (vice versa for selegiline)."

_____________
Correction:


"Rasagiline and (-)deprenyl (selegiline), irreversible type B monoamine oxidase (MAO-B) inhibitors, protect neuronal cells through gene induction of pro-survival Bcl-2 and neurotrophic factors in the cellular models of neurodegenerative disorders. In this paper, the role of MAO in the up-regulation of neuroprotective Bcl-2 gene by these inhibitors was studied using type A MAO (MAO-A) expressing wild SH-SY5Y cells and the transfection-enforced MAO-B overexpressed cells. Rasagiline and (-)deprenyl, and also befloxatone, a reversible MAO-A inhibitor, increased Bcl-2 mRNA and protein in SH-SY5Y cells. Silencing MAO-A expression with short interfering (si) RNA suppressed Bcl-2 induction by rasagiline, but not by (-)deprenyl. MAO-B overexpression inhibited Bcl-2 induction by rasagiline and befloxatone, but did not affect that by (-)deprenyl, suggesting the different mechanisms behind Bcl-2 gene induction by these MAO-B inhibitors. The novel role of MAO-A in Bcl-2 induction by rasagiline is discussed with regard to the molecular mechanism underlying neuroprotection by the MAO inhibitors."
(Inaba-Hasegawa K1, Akao Y, Maruyama W, Naoi M, Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase. J Neural Transm, 2012 Apr;119(4):405-14. doi: 10.1007/s00702-011-0730-6. Epub 2011 Nov 8.)

Bcl-2 induction is important because it inhibits apoptosis which may be desirable for parkinsons patients, but what about cancer patients? "Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer."

"Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer."

One of the main reasons why curcumin is so appealing as a cancer fighting agent is it's ability to reduce Bcl-2 expression, leading to apoptosis in cancer cells: http://www.ncbi.nlm....pubmed/21595920

I am not an expert on this, or even involved in the medical field and my only intention is to question whether there a potential issue here. A deceased member of this community in fact died with a brain tumor. I read that he was taking deprenyl/selegiline somewhere in that thread.

More here http://www.groupsrv....bout168764.html

I wonder whether it could be detrimental for healthy people to take these MAOs chronically, given that they mess with Bcl-2 homeostasis?

Edited by cryonicsculture, 02 April 2014 - 07:31 PM.

[LexLux]

Pretty sure the study referred to as to GDNF elevation in Japanese monkeys is the one I have provided the link to the abstract as above. Searching a see no link for a full text format. If you do I would like to have that link to that specific study. Thanks

Here again:
http://www.abstracts...a2-eebfa14cd9f1

Perhaps it was never formally published and was just presented as this refers to a presentation and I do not see a journal referenced as to publication.
eh....
Only means appears to try to contact the author.
I sent word, and generally I do hear back

the results of the 'monkey study' can be viewed on pg 86 figure two of this study:

''70th Birthday Professor Riederer'' induction of glial cell line-derived and brain-derived neurotrophic factors by rasagiline and (-)deprenyl: a way to a disease-modifying therapy? Maruyama W¹, Naoi M. J Neural Transm. 2013 Jan;120(1):83-9. doi: 10.1007/s00702-012-0876-x. Epub 2012 Aug 15.

http://www.ncbi.nlm....pubmed/22892822

"Effects of systematic administration of rasagiline on NFT levels in the CSF from Japanese monkeys. Rasagiline (2, 0.25 and0.1 mg/day) and saline as control were subcutaneously administered in Japanese monkeys (n=4 for each groups), and the lumbar CSF was taken from anesthetized monkeys four times, once in every week[...] NTF levels were quantified by the EIA"
[...]
"rasagiline at 0.25 mg/day significantly increased GDNF levels. Rasagiline at 0.25 and 0.1 mg/day induced also NGF, BDNFand NT-3, but at 1 mg/day did not increase these four NTF levels in the CSF. Increased levels of NTF, caused by ra-sagiline, returned to the basal values after 1 week’s washout"
The graphs also showed that 2mg consistently failed to increase NTFs.

This roughly what their results looked like, the figures are estimates based on the graphs (do not rely on these figures, this is merely for academic discussion purposes and I am not qualified as health care practitioner):

GDNF:

at 0.25mg Rasalgiline/day the peak was 75pg/ml at week 1 and this dropped to 40 pg/ml in weeks 2 and 3, before rising to 50 at week 4.
at 0.1mg Rasagiline/day GDNF peaked at around 20pg/ml at week one and gradually declined to control by week 4.

BDNF:

at 0.25 mg/day 5pg/ml was seen for week 1, there was a dip to 0 at week 2 and a spike to 10 at week 3 followed by a drop to control at week 4.
at 0.1 mg/day the increase and decrease was more gradual and similar peak was seen at week 3 at 7pg/ml

NGF:

at 0.25 mg/day week 1 showed a spike at 100 pg/ml which dropped to control levels by week 2 and stayed there for the rest of the experiment
at 0.1 mg/day no better than control

NT-3:

at 0.25 mg/day - week 1 - 100, week 2 - 50, week 3 - 60, week 4 - 200 (but looks like control is the same)
at 0.1 mg/day no better than control, flat at 0ish

Remember folks this was subcutaneously in monkeys, this isn't for humans!

Edited by LexLux, 24 March 2014 - 03:19 AM.

[LexLux]

So upon reviewing this recent study again this is a revised summary of the Rasagiline GDNF pathway (based on what happened in a petri dishes):

What appears to be happening with RAS in SH-SY5Y cell (in a petri dish) is as follows:

Rasagiline Induces MAO A transcriptionally via R1-Sp1 pathway (reduced repressors R1), wheras Selegiline induces MAO A via a non-defined pathway. Rasagiline decreases R1 and increases MAO-A

BUT

Increased MAO-A expression by rasagiline and selegiline have never been reported in the brain of experiemntal animals and further, "[a]fter chronic treatment, rasagiline and selegiline reduced MAO-A activity...(Lamensdorf et al 1996)"

The good news is that this seems to conflict with what was reported here:

"Type A MAO (MAO-A) was found to mediate the induction of Bcl-2 by [rasagiline and selegiline] in MAO-A-expressing neuroblastoma SH-SY5Y cells. Rasagiline and selegiline increased the mRNA and protein levels of glial cell line-derived neurotrophic factor (GDNF) and neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3)] in SH-SY5Y cells. Rasagiline increased GDNF more markedly than neurotrophins, and vice versa selegiline increased neurotrophins. The distinct induction of GDNF and neurotrophins by MAO inhibitors was also confirmed in non-human primates. Rasagiline was systematically administered in Japanese monkeys (n=4) for 4 weeks by daily subcutaneous injection, and the cerebrospinal fluid (CSF) was taken once a week. The NTF levels were quantified by the EIA assay. Rasagiline at 0.25 mg/day increased GDNF significantly, followed by BDNF, NGF and NT-3. On the contrary, selegiline increased BDNF in the CSF from parkinsonian patients treated with selegiline."

and those findings were reported again recently here: http://www.ncbi.nlm....pubmed/22892822

So there appears to be some evidence that this increase in GDNF happens in animals, not just in a petri dish.

In any case, we should look more carefully at the mechanism to question whether there are any potential downsides. "Both selegiline and rasagiline supress mitochondrial apoptotic signaling and up-regulation anti-apoptotic bcl-2 and bcl-xL as well as prosurvival neurotrophic factors, including GDNF and BDNF. Further Rasagiline increases GDNF more markedly than BDNF and NGF (vice versa for selegiline)."

Bcl-2 induction is important because it inhibits apoptosis which may be desirable for parkinsons patients, but what about cancer patients? "Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer."

"Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer."

One of the main reasons why curcumin is so appealing as a cancer fighting agent is it's ability to reduce Bcl-2 expression, leading to apoptosis in cancer cells: http://www.ncbi.nlm....pubmed/21595920

I am not an expert on this, or even involved in the medical field and my only intention is to question whether there a potential issue here. A deceased member of this community in fact died with a brain tumor. I read that he was taking deprenyl/selegiline somewhere in that thread.

More here http://www.groupsrv....bout168764.html

I wonder whether it could be detrimental for healthy people to take these MAOs chronically, given that they mess with Bcl-2 homeostasis?

From his personal supplement regimen: http://www.antiaging...pplement-regime

"One of my favorite nootropics is liquid Deprenyl Citrate. I had used Jumex ® (Deprenyl HCL) intermittently over the years, but found that it didn't agree with me. It often made me irritable, anxious, "uptight" and even depressed at times. About 5 years ago Dr. Ward Dean convinced me to try the liquid Deprenyl, and much to my surprise I found it to be qualitatively different from Jumex. I find it to be an excellent mood elevator, psychoenergizer, and motivation-enhancer. It has improved my fine neuromuscular control, and seems to be a dopaminergic neuroprotector. I take 1-3 drops sublingually upon arising every morning. It may not be a coincidence that I've written more in the past few years than the previous decade."

[VERITAS INCORRUPTUS]

One word: Homeostasis
Think about it

Okay, one other: Mutations... lol

[LexLux]

If apoptosis is suppressed via bcl-2 Induction consistently for years (like that guy) wouldn't cancer cells/tumors grow much more quickly? I just question the chronic use of these drugs as a life extension medication in healthy individuals.

Also wouldn't curcumin counteract bcl-2 induction if it were taken at the same time as RAS/SEL since it reduces bcl-2 expression?

One final question lol - I wonder if RAS/SEL would have any long term benefits since NTFs returned to baseline after a 1 week washout (homeostasis?)?

Edited by LexLux, 24 March 2014 - 06:58 PM.

[VERITAS INCORRUPTUS]

Most any direct pathway which induces proliferation/renewal/repair (growth) also has potential for induction/proliferation of cancer.

This can be a dissertation, into areas of cancer, apoptosis, homeostasis, senescence, etc etc etc...
But one needs to give thought to the basis of homeostasis/homeostatic mechanisms as a general rule; action/reaction. 'Supraphysiological' states, mutation, and other noteworthy considerations.

One last quick point on the subject is how the inducers of proliferation and growth trend toward baseline after a few weeks.

Curcumin is an amazing compound, but very difficult to pinpoint in just what manner it will impact physiology as it has an affinity for so many pathways. Curcumin induces growth and repair as well through many distinct pathways. Only a study perhaps would be able to truly determine what X dose of curcumin would inhibit what X dose of RAS/SEL induction of bcl-2 and NTFs. Obviously the curcumin would need to be assessed as well directly in vivo due to bioavailability issues.

RAS/SEL may best be engaged intermittently to foster growth and repair; yet allow natural processes to resume for a period. If one gets into the minutiae of supplementation or any areas that effect physiology it can become extremely overwhelming due to the complexity.

Trying to achieve enhanced/supraphysiological states trends to have some risk:reward, as a general rule. As well try to 'push' the body - and it will resist - the harder and futher, the more resistance (homeostasis at work).

If he was deriving a viable benefit it may have been correcting a deficit that served well to be compensated. It is so complex and individualized. We cannot measure to see what is beneficial and feel is many times a good indicator, but still not necessarily reliable.

If one overall perceives a course is providing benefit it is a good indicator to proceed; however, if the body starts to say otherwise do we always perceive it or are attuned to it. Again, it is so complex. The more we know can sometimes make things all the more complicated in just how we approach these areas; the more we know, the more we know we don't know.

Is the agent/agents being used strictly therapeutically to correct a known imbalance or to achieve a 'supraphysiological' condition is one last thing that is at base of consideration - again homeostasis.

I can go on and on of course. Even so far as to delving into the realm that would be of a philosophical nature...
There are as well of course so many schools of thought...

Sorry I cannot provide any direct answers, solutions to these 'riddles'; as sometimes they are just not viable to derive.
I hope this in some way helped - perhaps with some fuller and deeper understanding, especially at base levels of that which may best be considered; or perhaps maybe just to clarify how difficult such things are to clarify

Edited by VERITAS INCORRUPTUS, 24 March 2014 - 07:16 PM.

[VERITAS INCORRUPTUS]

Let me as well clarify, as it is of practical relevance that may have not been able to have been derived from the above, although such is implied. This is to answer LexLux last question.

Within pushing the body to any supraphysiological state, when it is not directly correcting an imbalance, it is generally best to cycle such courses. Will it do harm if one does not; perhaps not as the body is generally going to just maintain the homeostatic environment, although it can be set to a superior level than where it was.

Sometimes there must as well be something akin to a two steps forward one step back progression toward a superior physiological state, that which again will within means only be coaxed so far.

Again, can go on for ages...I guess anyone who does not perceive the main bases of these points they can asked for clarification; though many times it is better trying to give thought oneself to truly learn and grow...hopefully this all leaves one without too much distress and better yet a little eustress perhaps

[Phoenicis]

This is all very interesting, as stated in the study bellow, Bcl-2 also plays a functional role in lung cancer and nicotine induces cell (and cancer) survival in part via Bcl2 phosphorylation:

http://www.ncbi.nlm....pubmed/12421819

A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis.
Mai H¹, May WS, Gao F, Jin Z, Deng X.

Abstract
"Nicotine is not only a major component in tobacco but is also a survival agonist that inhibits apoptosis induced by diverse stimuli including chemotherapeutic drugs. However, the intracellular mechanism(s) involved in nicotine suppression of apoptosis is unclear. Bcl2 is a potent antiapoptotic protein and tumor promotor that is expressed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. It is possible that nicotine may regulate Bcl2 to stimulate cell survival. Here we report that nicotine can induce Bcl2 phosphorylation exclusively at the serine 70 site in association with prolonged survival of SCLC H82 cells expressing wild-type but not the phosphorylation-deficient S70A mutant Bcl2 after treatment with chemotherapeutic agents (i.e. cisplatin or VP-16). Nicotine induces activation of PKC alpha and the MAPKs ERK1 and ERK2, which are physiological Bcl2 kinases. Furthermore, ET-18-OCH3, a specific phospholipase C (PLC) inhibitor, blocks nicotine-stimulated Bcl2 phosphorylation and promotes apoptosis, suggesting that PLC may be involved in nicotine activation of Bcl2 kinases. Using a genetic approach, the gain-of-function S70E mutant, which mimics Ser(70) site phosphorylation in the flexible loop domain, potently enhances chemoresistance in SCLC cells. Thus, nicotine-induced cell survival results, at least in part, from a mechanism that involves Bcl2 phosphorylation. Therefore, novel therapeutic strategies for lung cancer in which Bcl2 is expressed may be used to abrogate the anti-apoptotic activity of Bcl2 by inhibiting multiple upstream nicotine-activated pathways."

V.I. - I was just wondering out of interest - are you be considering using GDNF enhancement via RAS as a part of wider strategy of NTF brain enhancement? I'm primarily seeing it as a tool for addictive substances but maybe you see some other utility in it?

The NTFs discussed so far are: GDNF, BDNF, NGF, NT-3. How each these can be used systematically remains a mystery to me. Any threads/studies on using these in a synergistic manner?

Edited by Phoenicis, 24 March 2014 - 08:34 PM.

[VERITAS INCORRUPTUS]

Remember smoking tobacco release a profound abundance of chemicals, many toxic or potentially toxic. Nicotine is onlhy a factor. It is as well highly neuroprotective - because it induces neurogenesis. Modest nicotine intake, outside the poisin that is modern tobacco from BIG CIG, is largely actually beneficial.

Nicotine itself is generally not addictive within administration outside of inhalation; particularly that involving the inhlation of smoking tobacco. It is a profound chemical, but abused certainly contributes to creating a gross imbalance and toxicity; at those levels the overstimulation of bcl-2 is likely not the main significant factor of health concern, though it can certainly play a part in fostering cancer; undeniably within the abuse the lungs take from the slew of carcinogens imposed upon these delicate and highly reactive tissues and cells.

RAS and SEL induce all the NTFs, to varying degrees and ratios. These factors are largely synergistic along with other neurogenic factors that are as well induced. There is no way to create induction of some optimized ratio for some penultimate synergy of course

Again, best not to overthink it all, LOL

Low dose NIC is also potentially of benefit for neuroprotection, particularly its effect on agonism of alpha7 nAChR, but as well within moderate agonist activity at alpha2beta4.
When NIC is abused there is an overexpression of alpha2beta4 receptors, which is generally the opposite of overexposure to an agonistic ligand. This causes a sharply disharmonic skew within dopaminergic(reward) dynamics, hence with abuse certainly comes addiction. As well the overstimulation at alpha7 from abuse corrupts this pathway as well.

[Phoenicis]

Allow me to pick your brain for these two last questions:

Note, the Japanese monkey study denoted s.c. administration of substrates, which I somehow missed. So note that the conversion is inaccurate as to relates to oral administration. RAS oral bioavailability is approximately 35%, so the adjusted oral dose would actually be higher by a factor of almost 3x equating to 0.75mg/d p.o.. Japanese monkeys weigh approximately 10kg. As such, this would create a p.o. dose for Japanese monkeys at a basis of 0.075mg/kg/d.

The conversion based on body surface is approximately 2:1. This would actually make the human dose equivalent via p.o. (oral) route at ~0.038mg/kg/d as relates to dose that expressed significant GDNF expression in Japanese monkeys. This would equate to approximately 2.28mg for a 60kg individual. It is very much within the therapeutic range and below the range of inducing MAO-A enzymatic inhibition.

So, optimal dosing is likely between 2-4mg for the neurotrophic gene induction in humans for RAS. At too high a dose induction is negated and neurotoxicity might actually occur via other factors RAS induces at these levels. The level of increased dosage in which there is seen a full negation of neurotrophic gene induction and potentiating neurotoxicity is shown to be at approximately at a dose of 800% of the given dose in monkeys above that which expressed significant GDNF (2mg/d vs. 0.25mg/d). To note, this would equate to a human dose range of approximately 15-20mg.

[...]

To reiterate, nuerotrophic factors are promoted by RAS and SEL via MAO-A induction (binding sans inhibition). Such is MAO-A dependent, but at levels significantly lower than that which will create MAO-A enzymatic inhibition. Effective dosing for enhancing neuotrophic gene expression are within a therapeutic range of 1-2mg/d and perhaps optimal at dosages of 2-4mg/day.

Given the data from the monkey study just posted, how do you think a dosage of 1mg/day for humans would convert to the monkey study. I tried to do the calculation above but seem unable to get a reliable outcome. Surely it's better than the 0.1 concentration the that experiment right?

I will extrapolate I have derived it should be superior in both efficacy and optimal overall safety for fostering GDNF gene induction to administer for a one week period alternating with a one week washout, though it is NOT unsafe to use in a continual fashion by any conventional measures.

This alternating basis is derived from extrapolations I am deriving from reviewing several studies on NTF and in noting the peak levels of GDNF and NGF are seen at the one week point. Though note peak levels of BDNF are seen at week 3 of continual daily dosage and peak levels of NT-3 are seen at week 4. It may perhaps be superior protocol to alternate RAS and SEL on a weekly basis.
.

Do you still think 1 week admin followed by 1 week washout would be most effective given the results of the 'monkey experiment'?

[VERITAS INCORRUPTUS]

I would suggest an optimal dosing regimen for GDNF induction using RAS to be 1-2 weeks on 1-2 weeks off.

There are more sophisticated dosing schemes that may be more optimized, but those would be hypothetical and likely not of too substantially a greater benefit. Such as a mild loading and tapering with subsequent washouts. These might provide the greatest area under the curve concentration for period usage.

Most would do well and would be a rational basis for maintaining a compliance of a reasonably uncomplicated nature to do 2mg/d in two-week alternating on/off cycles. A higher dose (4mg/d) for 1 week with a two-week washout may be best for greatest total AUC.

[VERITAS INCORRUPTUS]

Here again is the ballpark dose conversion if you missed it:

Note, the Japanese monkey study denoted s.c. administration of substrates, which I somehow missed. So note that the conversion is inaccurate as to relates to oral administration. RAS oral bioavailability is approximately 35%, so the adjusted oral dose would actually be higher by a factor of almost 3x equating to 0.75mg/d p.o.. Japanese monkeys weigh approximately 10kg. As such, this would create a p.o. dose for Japanese monkeys at a basis of 0.075mg/kg/d.

The conversion based on body surface is approximately 2:1. This would actually make the human dose equivalent via p.o. (oral) route at ~0.038mg/kg/d as relates to dose that expressed significant GDNF expression in Japanese monkeys. This would equate to approximately 2.28mg for a 60kg individual. It is very much within the therapeutic range and below the range of inducing MAO-A enzymatic inhibition.

So, optimal dosing is likely between 2-4mg for the neurotrophic gene induction in humans for RAS. At too high a dose induction is negated and neurotoxicity might actually occur via other factors RAS induces at these levels. The level of increased dosage in which there is seen a full negation of neurotrophic gene induction and potentiating neurotoxicity is shown to be at approximately at a dose of 800% of the given dose in monkeys above that which expressed significant GDNF (2mg/d vs. 0.25mg/d). To note, this would equate to a human dose range of approximately 15-20mg.

[LexLux]

I found this to be interesting, this is the study that led to the FDA easing food and medication restrictions on Rasagiline for the 1mg/day recommended dosage. Other dosages were also looked at (see bellow).

http://www.ncbi.nlm....pubmed/20445015

Clinical pharmacology tyramine challenge study to determine the selectivity of the monoamine oxidase type B (MAO-B) inhibitor rasagiline, Goren T¹, Adar L, Sasson N, Weiss YM, 2010 Dec J Clin Pharmacol. ;50(12):1420-8. doi: 10.1177/0091270010369674. Epub 2010 May 5.
Author information

Abstract

"Rasagiline is a selective, monoamine oxidase (MAO)-B inhibitor indicated for treatment of Parkinson's disease. This double-blind, placebo-controlled study determined the tyramine sensitivity factor (TSF) and degree of MAO-A inhibition (ie, reduction in plasma dihydroxyphenylglycol) in healthy volunteers who received phenelzine (15 mg, 3 times daily; positive control), selegiline (5 mg, twice daily), or rasagiline (1-6 mg, once daily) for 14 days or rasagiline 2 mg/d for 30 days. The selegiline/rasagiline groups were randomized to placebo or active drug. TSF was highest with phenelzine (17.3) and lowest with placebo (1.5). TSF with selegiline was 2.5. TSFs for rasagiline were as follows: 2.0 for 1 mg/d; 3.3 and 2.4 for 2 mg/d administered for 14 and 30 days, respectively; 4.5 for 4 mg/d; and 5.1 for 6 mg/d. Plasma dihydroxyphenylglycol concentrations suggested that rasagiline 1 mg/d had no effect, whereas rasagiline 2 mg/d had only minimal effect. In contrast, rasagiline 4 and 6 mg/d reduced dihydroxyphenylglycol to a degree approaching that achieved by the positive control phenelzine. Results demonstrate that rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/d). These data allowed removal of dietary tyramine restriction from rasagiline US labeling."

Edited by LexLux, 26 March 2014 - 04:22 PM.

[YOLF]

Attention:
This post has been updated with a correction:
http://www.longecity...post__p__651447

[Flex]

Found this, maybe You will find it interresting:

 

http://www.ncbi.nlm....pubmed/24755275

Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism

..At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt)...

 

 

 

 

Edited by Flex, 30 May 2014 - 10:32 AM.