49 replies to this topic

[LexLux]

Hi, I was wondering if anyone knew the dosage at which Rasagiline increases glial cell derived neurotrophic factor? Would it need to be inhibiting MAO A?

Edited by LexLux, 17 March 2014 - 03:13 AM.

[Morphy]

MAO A inhibition is worthless and does not contribute to GDNF. See here: http://www.rasagiline.com/review.htm

"Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases."

As for dosage, it's unclear. You can expect 0.5-1g/day to be effective. Maybe even less than that if you think you're middle-aged or younger.

[LexLux]

This is why I was asking -

http://www.ncbi.nlm....pubmed/23739004

"Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms.

In Parkinson's disease, cell death of dopamine neurons in the substantia nigra progresses and neuroprotective therapy is required to halt neuronal loss. In cellular and animal models, selegiline [(-)deprenyl] and rasagiline, inhibitors of type B monoamine oxidase (MAO)-B, protect neuronal cells from programmed cell death. In this paper, the authors review their recent results on the molecular mechanisms by which MAO inhibitors prevent the cell death through the induction of antiapoptotic, prosurvival genes. MAO-A mediates the induction of antiapoptotic bcl-2 and mao-a itself by rasagiline, whereas a different mechanism is associated with selegiline. Rasagiline and selegiline preferentially increase GDNF and BDNF in nonhuman primates and Parkinsonian patients, respectively. Enhanced neurotrophic factors might be applicable to monitor the neurorescuing activity of neuroprotection.

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

"Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neuronal cells in animal and cellular models of neurodegenerative disorders. Molecular mechanism behind their neuroprotective action has been clarified to be the regulation of mitochondrial death signal pathway and the induction of pro-protective anti-apoptotic Bcl-2 and neurotrophic factors (NTFs). Type A MAO (MAO-A) was found to mediate the induction of Bcl-2 by these MAO-B inhibitors 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. The role of MAO-A and MAO-B in the induction of neurotrophins was investigated in wild SH-SY5Y cells and MAO-B-expressing glioblastoma U118MG cells. The effects of these MAO-B inhibitors on mRNA levels of neurotrophins were measured by use of real-time RT-PCR method. Rasagiline increased BDNF mRNA in wild SH-SY5Y cells, which was suppressed by treatment with siRNA against MAO-A, whereas selegiline increased BDNF mRNA in wild and siRNA treated cells. Selegiline and rasagiline induced BDNF mRNA in U118MG cells, and selegiline was more potent than rasagiline. These results suggest that NTF gene induction of rasagiline may depend on MAO-A, whereas selegiline may not in SH-SY5Y cells. In U118MG cells, these MAO-B inhibitors induce prosurvival NTFs through different signal pathway. The distinct signal pathway activated by rasagiline and selegiline may account for the preferential induction of GDNF and neurotrophins in animal and human experiments. The molecular mechanisms of the signal pathways should be further investigated to clarify the selective induction of these two NTF classes by rasagiline and selegiline."

does that mean they were inhibiting MAO A?

Edited by LexLux, 17 March 2014 - 02:33 PM.

[Morphy]

I believe for the drugs selegiline and rasagiline there is a potential for MAO-A inhibition, although very slight even at recommended dosages. Are you concerned with it?

[LexLux]

Im curious about the GDNF and am confused about the dosage required to achieve this. The study and lecture quoted above seem to say that MAO A mediates the induction of bcl-2, it doesn't say "MAO A inhibition" though does it? After all Rasagiline is a selective MAO B inhibitor up to 1mg daily right?

Edited by LexLux, 17 March 2014 - 03:22 PM.

[Morphy]

The dosage should be regular (1-2 mg/day) to achieve GDNF, but I would not worry about any MAO-A inhibition unless you're going above 2mg/day. As I recall, 1mg of rasagiline = ~ 5mg of selegiline. Like selegiline, rasagiline has the potential to inhibit MAO-A at doses greater than 2mg/day.

[VERITAS INCORRUPTUS]

The selectivity perhaps is an issue if we are addressing this study relating the MAOA-I capacity as specific to the GDNF effect.
Notably, RAS has a 100x specificity for MAOB>MAOA
http://www.ncbi.nlm....pubmed/15027867
I believe RAS and SEL have almost equal (oral) potency at MAOB. RAS is favorable solely in regard to the lack of production of amphetamine/methamphetamine. I believe SEL may be about 500x MAOB>MAOA selective.

The above study lacks aspects to provide definitive insight as I see it as regards GDNF and BDNF enhancement.
I wish it could have been conducted to be more definitive. I could explain further my concerns, but that is really not warranted here for your purposes...so...

As to actually engaging a practical application relevance, please note the following, which I believe will shed a direct light as regards your desired intentions to foster GDNF enhancement.

The conversion for a Japanese monkey that displayed strong GDNF enhancement would correlate to a human dosing of approximately .12mg/kg/d
As such one is looking at approximately 8.4mg/d for a 70kg human.
I would as such suggest it may be of benefit to utilize a dose range more in line of 5-10mg for optimal GDNF enhancement.

This is a safe dose to use, though I would perhaps not recommend to do so on a daily basis. I as well think neurotrophic factor enhancement is best perhaps not used chronically in an ED fashion. EOD or ETD is a good basis IMO.

Hope this helps. Best of Success

[LexLux]

Thanks for the response, I was always under the impression that RAS was more MAOB specific than SEL. Even at 5 mg we're talking about MAO A inhibition arent we? I'm no expert. but I guess at the doses you're talking about, dietary tyrosine restriction would be absolutely necessary? May also be a good to carry some Nifedipine in case of hypertension? So after talking this EOD/ETD for like 3 weeks it would be about 2-3 weeks before your body produces more MAO and like 2 months before it is completely replaced right?

"I could explain further my concerns, but that is really not warranted here for your purposes...so..." feel free to elobaorate

Edited by LexLux, 19 March 2014 - 02:11 PM.

[Morphy]

The selectivity perhaps is an issue if we are addressing this study relating the MAOA-I capacity as specific to the GDNF effect.
Notably, RAS has a 100x specificity for MAOB>MAOA
http://www.ncbi.nlm....pubmed/15027867
I believe RAS and SEL have almost equal (oral) potency at MAOB. RAS is favorable solely in regard to the lack of production of amphetamine/methamphetamine. I believe SEL may be about 500x MAOB>MAOA selective.

The above study lacks aspects to provide definitive insight as I see it as regards GDNF and BDNF enhancement.
I wish it could have been conducted to be more definitive. I could explain further my concerns, but that is really not warranted here for your purposes...so...

As to actually engaging a practical application relevance, please note the following, which I believe will shed a direct light as regards your desired intentions to foster GDNF enhancement.

The conversion for a Japanese monkey that displayed strong GDNF enhancement would correlate to a human dosing of approximately .12mg/kg/d
As such one is looking at approximately 8.4mg/d for a 70kg human.
I would as such suggest it may be of benefit to utilize a dose range more in line of 5-10mg for optimal GDNF enhancement.

This is a safe dose to use, though I would perhaps not recommend to do so on a daily basis. I as well think neurotrophic factor enhancement is best perhaps not used chronically in an ED fashion. EOD or ETD is a good basis IMO.

Hope this helps. Best of Success

Great response. Would you mind further validating that claim? Please, spare us the curiosity and enlighten us as to how you came up with 0.12mg/kg/day.

Are you sure 5-10mg is safe? That's like the equivalent of 25-50mg of selegiline. Without the amphetamine/methamphetamine effect, but still.

[VERITAS INCORRUPTUS]

I'll be happy to further elaborate of the issues relevant to the practical application concerns.

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.

The conversion for Japanese monkeys to a human equivalency dosage is slightly greater than a 2:1 basis. As such 0.25mg/kg/d = ~0.12mg/kg/d. This is in the range of 5-10mg for most humans as to normal body weight. In that this dose provided a significant increase, a somewhat lower dose basis may be effective.

For those sensitivity to hypertension there should be some attention paid toward the MAO-A inhibition as there is a degree of loss of selectivity in this range of dosing. Two to three milligrams of RAS is generally considered to be highly specific for MAOB. There is a degree of MAO-A inhibition within the noted 5-10mg range, so one should exert some awareness to the potential suppression of MAO-A.

[LexLux]

It turns out that the studies I cited earlier were not talking about MAO A inhibition, but rather were looking at Rasagiline's interraction with MAO A as part of it's Bcl 2 induction mechanism. Sorry if I confused anyobne else. I just read the full version of this study:

Inaba-Hasegawa K1, Akao Y, Maruyama W, Naoi M. 2012 Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase J Neural Transm. Apr; 119(4) : 405-14. doi: 10.1007/s00702-011-0730-6. Epub 2011 Nov 8.

http://www.ncbi.nlm....pubmed/22065207

This clears up my earlier confusion and supports staying away from MAO A inhibition. In this paper researchers wanted to find out what role MAO A plays in Bcl 2 induction (as possibly required for increaed GDNF). They used an RNA interference approach to inhibit MAO A expression in wild SH cells and then exposed these cells to rasagiline. Their results show that cells with reduced MAO A expression also showed a suppressed rasagiline dependant increase in Bcl-2 mRNA.

"In addition, neuroprotection by these MAO-B inhibitors does not depend on the inhibition of MAO-B activity. Rasagiline induces Bcl-2 and GDNF even at 10 -12M(Naoi and Maruyama 2009), whereas the Ki values of MAO-A and MAO-B are in the order of 10 -6M (Bindaet al.2005). Therefore, it should be clarified whether rasagiline and related MAO-B inhibitors require MAO itself to induce pro-survival genes, including Bcl-2,GDNF,BDNF, other neurotrophic factors and antioxidant enzymes."

I do not think it would be good idea to irreversibly inhibit MAO A given these other findings:

"Our results show that befloxatone up-regulated neuro- protective Bcl-2, whereas clorgyline induced apoptosis in SH-Y5Y cells. Moclobemide (Chiou et al. 2006) and N- propargylamine (Yi et al.2006 b) reversibly inhibit MAO-A and increase Bcl-2, as in the case of befloxatone. These results suggest that the reversible binding to MAO-A might change MAO-A conformation, activate signal path- way and induce neuroprotective genes. On the other hand, clorgyline binds to MAO-A irreversibly and covalently, and alters the environment of aromatic residues more profoundly than reversible MAO-A inhibitors (Hynson et al.2004), leading to apoptosis."

In another paper:

Inaba-Hasegawa K¹, Akao Y, Maruyama W, Naoi M, 2013 Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells, Mar;120(3):435-44. doi: 10.1007/s00702-012-0899-3. Epub 2012 Sep 12.

http://www.ncbi.nlm....pubmed/22968599

these same researchers also stated that while:

"Rasagiline and selegiline are selective inhibitors of MAO-B, but they bind to MAO-A, as shown by the inhibition of MAO-A activity at the high concentrations or longer treatment. Rasagiline adducts with the FAD moiety of both MAO types, even the affinity to MAO-A is less than 1/100th of that to MAO-B (Hubalek et al. 2004; Ed-mondson et al. 2007). Our presented results present that the binding of MAO-B inhibitors to MAO-A, not to MAO-B, may initiate MAO-A induction, which does not depend on inhibition of the catalytic activity of either MAO types."

and they went on to say that:


"It remains to be clarified whether MAO-A induction by these MAO-B inhibitors may regulate signal pathway, either in a way to accelerate cell death by activating death signaling, or to protect neurons by inducing pro-survival and anti-apoptotic genes. In addition, we should be cautious to apply our results observed in neuroblastoma SH-SY5Y cells to neurodegenerative process in the human brain, and we should reconfirm our results at least in animal subclinical models. Nevertheless, understanding of the regulation mechanism mediated by MAO-A to induce pro-survival genes and finding of new compounds with affinity to MAO-A will bring us a new way to develop novel classes of neuroprotective agents for PD and related neurodegenerative disorders"

So I am definitely concerned about MAO-A induction by rasagiline, as it remains to be seen whether this might even accelarate cell death as proposed above.

Edited by LexLux, 19 March 2014 - 06:22 PM.

[VERITAS INCORRUPTUS]

What doses were assayed in the Japanese monkeys other than the significantt effect on GDNF noted as derived from a .25mg/kg dose?
I would hope they assayed other doses.

This would be the clearest picture of in vivo GDNF enhancement respective to dose.

[LexLux]

What doses were assayed in the Japanese monkeys other than the significantt effect on GDNF noted as derived from a .25mg/kg dose?
I would hope they assayed other doses.

This would be the clearest picture of in vivo GDNF enhancement respective to dose.

Ill have a look, could you cite your source on MAO B selectivity of rasagiline Vs. selegiline?

Edited by LexLux, 19 March 2014 - 06:26 PM.

[LexLux]

I think this was the study, although I don't have access to a full version:

http://www.ncbi.nlm..../pubmed/9564628

My opinion is that this would not be the best reference for a dose in humans because the papers I referenced earlier shows that rasagiline depends on MAO A mediation as a part of its mechanism to increase GDNF. At higher doses RAS could lose it's specificity and I would be worried about other side effects. In the paper above, another irreversiable MAO A inhibitor was shown to cause cell death:

"On the other hand, clorgyline binds to MAO-A irreversibly and covalently, and alters the environment of aromatic residues more profoundly than reversible MAO-A inhibitors (Hynson et al.2004), leading to apoptosis."

The mechanism for rasagiline MAO A induction does not seem to be that well understood yet.

Edited by LexLux, 19 March 2014 - 06:53 PM.

[LexLux]

so I think the recommended dosage would be the most I would use.

[normalizing]

interesting read. yes, rasagiline is not well understood as of yet and i have no idea how you can afford such expensive drug to begin with to experiment. in any case, please keep updates on how you do with it im quite curious.

[VERITAS INCORRUPTUS]

so I think the recommended dosage would be the most I would use.

Indeed, I would surmise the GDNF enhancement is dependent on MAO-A inhibition. Researching further into MAO-Ai and GDNF this becomes more clearly evident.
To be most prudent one would best use only occasionally (which may be what is superior when regards neurotrophic enhancement) and be aware to not imbibe anything contraindicated with MAO-Ai usage. Other than that, there is no concern for safety I can see otherwise. Thus, if one desires such an effect, just proceed within the proper caution.

[LexLux]

so I think the recommended dosage would be the most I would use.

Indeed, I would surmise the GDNF enhancement is dependent on MAO-A inhibition. Researching further into MAO-Ai and GDNF this becomes more clearly evident.
To be most prudent one would best use only occasionally (which may be what is superior when regards neurotrophic enhancement) and be aware to not imbibe anything contraindicated with MAO-Ai usage. Other than that, there is no concern for safety I can see otherwise. Thus, if one desires such an effect, just proceed within the proper caution.

to be clear MAO-A inhibition is not required for GDNF enhancement from rasagiline. There are many studies that demonstrate that in this case MAO-A mediates bcl-2 induction and thus the GDNF increase. 'Mediates' means that MAO-A plays a role in the bcl-2 induction and should not be inhibited.

Edited by LexLux, 20 March 2014 - 05:04 PM.

[VERITAS INCORRUPTUS]

so I think the recommended dosage would be the most I would use.

Indeed, I would surmise the GDNF enhancement is dependent on MAO-A inhibition. Researching further into MAO-Ai and GDNF this becomes more clearly evident.
To be most prudent one would best use only occasionally (which may be what is superior when regards neurotrophic enhancement) and be aware to not imbibe anything contraindicated with MAO-Ai usage. Other than that, there is no concern for safety I can see otherwise. Thus, if one desires such an effect, just proceed within the proper caution.

to be clear MAO-A inhibition is not required for GDNF enhancement from rasagiline. There are many studies that demonstrate that in this case MAO-A mediates bcl-2 induction and thus the GDNF increase. 'Mediates' means that MAO-A plays a role in the bcl-2 induction and should not be inhibited.

Mediates implies here, as I understand, that it is the factor that is required for the effect. I believe this is essential within the pathway RAS displays the overall efficacy within GDNF elevation. It indicates that within RAS action to induce MAO-A inhibition, that such elicits the pathways to effect bcl-2, which in turn creates elevation of GDNF.

An agent that can directly act upon bcl-2 could as well create this effect. For RAS it appears such is caused downstream of MAO-A inhibitory modulation.

Perhaps simplified: RAS > MAO-Ai > bcl-2 induction > GDNF elevation

Yes, it appeared in one study cited that induction of bcl-2 that is responsible for the GDNF elevation was seen at a far lower dose of RAS then that will elicit MAO-A inhibition. The monkey study however does denote a dosage that would appear to be in a range that MAO-A inhibition would occur. Other studies appear to correlate that it MAO-A inhibition is upstream mechanism of action within this pathway to foster GDNF elevation.

That is why I initially asked if lower doses were assayed in the monkeys, as in theory from the above as regards bcl-2 potency and GDNF expression a far lower dose would then be indicated to be effective. However, I do not think substantially lower doses will elicit such as the dose is correlative to MAO-A inhibition.

This is as well why I denoted earlier such was not wholly clear, as sometimes there is conflicting data.

This study I believe clearly does reveal though that MAO-Ai is indeed required for the effect from RAS.

Expert Rev Neurother. 2013 Jun;13(6):671-84. doi: 10.1586/ern.13.60.
Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms.
Naoi M1, Maruyama W, Inaba-Hasegawa K.

In Parkinson's disease, cell death of dopamine neurons in the substantia nigra progresses and neuroprotective therapy is required to halt neuronal loss. In cellular and animal models, selegiline [(-)deprenyl] and rasagiline, inhibitors of type B monoamine oxidase (MAO)-B, protect neuronal cells from programmed cell death. In this paper, the authors review their recent results on the molecular mechanisms by which MAO inhibitors prevent the cell death through the induction of antiapoptotic, prosurvival genes. MAO-A mediates the induction of antiapoptotic bcl-2 and mao-a itself by rasagiline, whereas a different mechanism is associated with selegiline. Rasagiline and selegiline preferentially increase GDNF and BDNF in nonhuman primates and Parkinsonian patients, respectively. Enhanced neurotrophic factors might be applicable to monitor the neurorescuing activity of neuroprotection.

Edited by VERITAS INCORRUPTUS, 20 March 2014 - 05:47 PM.

[LexLux]

I see what you're saying, it does indeed seem that there is some binding to MAO A but I was under the impression that does not this inhibit it?

"Our presented results present that the binding of MAO-B inhibitors to MAO-A, not to MAO-B, may initiate MAO-A induction, which does not depend on inhibition of the catalytic activity of either MAO types.""

from the full text version of:

"J Neural Transm. 2013 Mar;120(3):435-44. doi: 10.1007/s00702-012-0899-3. Epub 2012 Sep 12.

http://www.ncbi.nlm....pubmed/22968599
Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells.

Inaba-Hasegawa K¹, Akao Y, Maruyama W, Naoi M.

Abstract


Type B monoamine oxidase (MAO-B) is proposed to be involved in the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, through oxidative stress and synthesis of neurotoxins. MAO-B inhibitors, rasagiline and selegiline [(-)deprenyl], protect neuronal cells by direct intervention in mitochondrial death signaling and induction of pro-survival Bcl-2 and neurotrophic factors. Recently, type A MAO (MAO-A) was found to mediate the induction of anti-apoptotic Bcl-2 by rasagiline, whereas MAO-A increases in neuronal death and also serves as a target of neurotoxins. These controversial results suggest that MAO-A may play a decisive role in neuronal survival and death. This paper reports that rasagiline and selegiline increased the mRNA, protein and catalytic activity of MAO-A in SH-SY5Y cells. Silencing MAO-A expression with small interfering (si)RNA suppressed rasagiline-dependent MAO-A expression, but MAO-B overexpression in SH-SY5Y cells did not affect, suggesting that MAO-A, not MAO-B, might be associated with MAO-A upregulation. Rasagiline reduced R1, a MAO-A specific repressor, but selegiline did not. Mithramycin-A, an inhibitor of Sp1 binding, and actinomycin-D, a transcriptional inhibitor, reduced the rasagiline-dependent upregulation of MAO-A mRNA, indicating that rasagiline induced MAO-A transcriptionally through R1-Sp1 pathway, whereas selegiline by another non-defined pathway. These results are discussed in relation to the role of MAO-A and these MAO-B inhibitors in neuronal death and neuroprotection."

Edited by LexLux, 20 March 2014 - 06:28 PM.

[VERITAS INCORRUPTUS]

I see your point as well.

Practically speaking, the monkey study should be reviewed for the doses assayed and if such also denoted MAO-A inhibition to best see if the dose specifically correlative to MAO-A inhibition.


I am looking to get some full texts.
Can't find any way to a full text for the 'monkey study'...???
http://www.abstracts...a2-eebfa14cd9f1

To be 100% clear on just what is what here I actually think requires another study, as per what I alluded to earlier.

To note on in vivo specificity:
Here I believe we see RAS as ED50 as specific to MAO-Ai in vivo within the brain as only 15x and in liver 50x. SEL displays 100x and 50x respectively (brain/liver).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572573/#!po=40.9091
The specificity curves are also demonstrated herein, which is needed for fuller insight. I believe 80% inhibition is required for effectiveness. I had those figures in another study but cannot locate now.

After having reviewed quite a few studies I believe I could likely derive a firm hypothesis with supported citations, but it is getting exhausting to pursue and to detail. LOL

Edited by VERITAS INCORRUPTUS, 20 March 2014 - 06:59 PM.

[LexLux]

I see your point as well.

Practically speaking, the monkey study should be reviewed for the doses assayed and if such also denoted MAO-A inhibition to best see if the dose specifically correlative to MAO-A inhibition.


I am looking to get some full texts.
Can't find any way to a full text for the 'monkey study'...???
http://www.abstracts...a2-eebfa14cd9f1

To be 100% clear on just what is what here I actually think requires another study, as per what I alluded to earlier.

To note on in vivo specificity:
Here I believe we see RAS as ED50 as specific to MAO-Ai in vivo within the brain as only 15x and in liver 50x. SEL displays 100x and 50x respectively (brain/liver).
http://www.ncbi.nlm....73/#!po=40.9091
The specificity curves are also demonstrated herein, which is needed for fuller insight. I believe 80% inhibition is required for effectiveness. I had those figures in another study but cannot locate now.

After having reviewed quite a few studies I believe I could likely derive a firm hypothesis with supported citations, but it is getting exhausting to pursue and to detail. LOL

thanks I think this is the monkey study but not 100% sure: http://link.springer...-7091-6499-0_28

Edited by LexLux, 20 March 2014 - 08:30 PM.

[VERITAS INCORRUPTUS]

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

Edited by VERITAS INCORRUPTUS, 20 March 2014 - 09:07 PM.

[VERITAS INCORRUPTUS]

Upon further evaluation of all the relevant full texts I can feel confident to assert these conclusions. There was some data that appeared to be in conflict and that which is elaborated within the totality of all the relevant studies not prior available.

Rasagiline (RAS) binds to MAO-A to induces GDNF and Bcl-2 via this binding, but it does not inhibit the enzymatic activity at these levels. As such, RAS has a very viable therapeutic index to promote this effect.

The pathway is as determined (but further elaborated):
RAS > MAO-A binding (sans enzymatic inhibition) > bcl-2 induction > Pro-survival NTF gene induction elevating GDNF significantly

Again, both RAS and SEL, MAO-B specific inhibitors, increase neuroprotective gene induction at concentrations significanty lower than those required for the inhibition of enzymatic activity, of which gene induction does not depend on inhibition itself. This gene induction by RAS and SEL is mitigated by binding MAO-A.

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.

The full text of this study is not yet published, as it is still in preparation; it was just given as an initial abstract and presentation.

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.

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.

The oral bioavailability of rasagiline is 35%, it reaches Tmax after 0.5–1 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2)..

Edited by VERITAS INCORRUPTUS, 21 March 2014 - 03:50 PM.

[LexLux]

[...]
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.

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.

The oral bioavailability of rasagiline is 35%, it reaches Tmax after 0.5–1 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2)..

Thanks for taking the time to write this up. I do want to ask where you got the idea to use selegiline and rasagiline in alternating weeks. The Rx list website on drug interactions between RAS and SELsays to wait at least 14 days after stopping one MAOI before starting another. Is there also a study that shows at which dosage rasagiline will start to inhibit MAO A? I heard that SEL and RAS build up fairly quickly in the system, so I think the washout period sounds sensible. I do question whether 1 week would be sufficient since it take the body like 2 weeks to start making new MAO and 2 months to fully replace the inhibited enzymes right?

Edited by LexLux, 21 March 2014 - 06:42 PM.

[VERITAS INCORRUPTUS]

RAS and SEL do not 'build up' so to speak, as they have relatively modest half-lives; though in that they are irreversible suicide inhibitors they have a duration of action of regarding enzymatic inhibition that surpass the actual typical half-lives and binding times (inhibition duration) of reversible inhibitors.

Within this, in practical terms, this is not an issue. I recall clearly a study that showed MAO-A inhibition fully terminated at the 24hr point with a dose higher than within therapeutic range. I apologize that I cannot cite as I am going off recall and have recenetly assessed well over a dozen papers that pertain to this area.

If you are unaware, in general, BIG PHARMA and AMA are typically ignorant of much outside their limited scope. The guidelines as so denoted are a conservatively derived guidance that applies no rational approach or basis. There is absolutely no valid reason whatsoever one could not immediately alternate bewteen SEL and RAS. It is highly similar to simply using one or the other continuously.

Actually, variance is superior with agents that both have high safety profiles and similar mechanisms of action, but have somewhat different overall effect of enough of a nature to derive the benefit from each and to modulate pathways in a slightly different fashion. A washout is most conservative and potentially of greatest benefit to indiviudals who are not using these agents for correction of deficiencies; those using for enhancing health and wellness, not those treating a condition. Though even within treating a condition it may be superior, however, most who are doing such cannot generally properly express the discipline of coordinating such a form of administration, as well as the pharmaceutical is obviously not going to be prescribed with such a basis.

This is a very good study to answer some of your concerns. There are several relevant issues addressed in a clearly reviewed manner. Note, indeed it requires two weeks for a total washout of the MAO-B inhibitory effect for RAS after using a dose that provides total inhibition within duration of administration.

http://ccs01.vo.ca-c...les/LA4Park.pdf

It is up to the determination of the individual what dosing protocol that which to engage if not being used for treating an underlying condition. I do not believe anyone can definitively define what an absolute most efficacious dosing protocol would be for a healthy individual wishing to promote optimal well-being.

I doubt a two-week washout is necessary or even perhaps optimal, but it is more conservative. For those who read and can actually digest this thread they can determine what they are comfortable with with a very full understanding of all that relates to this area.

To reiterate regarding MAO-A inhibtion, MAO-A inhibition should not be of practica concern within the proper doses used for these benefits. The doses that would engage relevant MAO-A inhibition are significantly higher, and again, this inhibition does not persist at all through a 24hr period; the specificity for MAO-B inhibition is more than substantial within these dosages.

A determination of actual true in vivo MAO-A inhibition is in process. As I understand, within clinical samples, the effects of SEL and RAS on the enzymatic activity of MAO-A and MAO-B will soon be published by Professor P. Riederer's group in J Neural Transm.

Edited by VERITAS INCORRUPTUS, 21 March 2014 - 07:42 PM.

[LexLux]

RAS and SEL do not 'build up' so to speak, as they have relatively modest half-lives; though in that they are irreversible suicide inhibitors they have a duration of action of regarding enzymatic inhibition that surpass the actual typical half-lives and binding times (inhibition duration) of reversible inhibitors.

Within this, in practical terms, this is not an issue. I recall clearly a study that showed MAO-A inhibition fully terminated at the 24hr point with a dose higher than within therapeutic range. I apologize that I cannot cite as I am going off recall and have recenetly assessed well over a dozen papers that pertain to this area.

If you are unaware, in general, BIG PHARMA and AMA are typically ignorant of much outside their limited scope. The guidelines as so denoted are a conservatively derived guidance that applies no rational approach or basis. There is absolutely no valid reason whatsoever one could not immediately alternate bewteen SEL and RAS. It is highly similar to simply using one or the other continuously.

Actually, variance is superior with agents that both have high safety profiles and similar mechanisms of action, but have somewhat different overall effect of enough of a nature to derive the benefit from each and to modulate pathways in a slightly different fashion. A washout is most conservative and potentially of greatest benefit to indiviudals who are not using these agents for correction of deficiencies; those using for enhancing health and wellness, not those treating a condition. Though even within treating a condition it may be superior, however, most who are doing such cannot generally properly express the discipline of coordinating such a form of administration, as well as the pharmaceutical is obviously not going to be prescribed with such a basis.

This is a very good study to answer some of your concerns. There are several relevant issues addressed in a clearly reviewed manner. Note, indeed it requires two weeks for a total washout of the MAO-B inhibitory effect for RAS after using a dose that provides total inhibition within duration of administration.

http://ccs01.vo.ca-c...les/LA4Park.pdf

It is up to the determination of the individual what dosing protocol that which to engage if not being used for treating an underlying condition. I do not believe anyone can definitively define what an absolute most efficacious dosing protocol would be for a healthy individual wishing to promote optimal well-being.

I doubt a two-week washout is necessary or even perhaps optimal, but it is more conservative. For those who read and can actually digest this thread they can determine what they are comfortable with with a very full understanding of all that relates to this area.

To reiterate regarding MAO-A inhibtion, MAO-A inhibition should not be of practica concern within the proper doses used for these benefits. The doses that would engage relevant MAO-A inhibition are significantly higher, and again, this inhibition does not persist at all through a 24hr period; the specificity for MAO-B inhibition is more than substantial within these dosages.

A determination of actual true in vivo MAO-A inhibition is in process. As I understand, within clinical samples, the effects of SEL and RAS on the enzymatic activity of MAO-A and MAO-B will soon be published by Professor P. Riederer's group in J Neural Transm.

Thanks so much for your input, let us know when you hear back regarding the 'monkey study'. Also will you be taking any SEL or RAS personally?

Edited by LexLux, 21 March 2014 - 10:04 PM.

[Phoenicis]

So I thought I'd add what you posted in the Brain Repair thread regarding the use of GDNF in treating addictions so that people reading this thread understand why GDNF is interesting. Personally I'm wondering if it could help with any damage caused to my dopamine pathways by nicotine?


"BDNF vs GDNF depends "on the drug type, the brain site, the addiction phase (initiation, maintenance, or abstinence/relapse), and the time interval between site-specific BDNF or GDNF injections and the reward- and relapse-related behavioral assessments"

Role of BDNF and GDNF in drug reward and relapse: a review
Udi E. Ghitza, Haifeng Zhai, Ping Wu, Mikko Airavaara, Yavin Shaham, Lin Lu
Neurosci Biobehav Rev. Author manuscript; available in PMC 2011 November 1.

• "In the case of alcohol, activating BDNF or GDNF signaling consistently decreases alcohol self-administration and alcohol intake, but the brain sites involved in these effects are different"
• "In the case of cocaine, an unexpected potential conclusion is that VTA BDNF and GDNF have opposite effects on the initial cocaine rewarding effects: facilitation by BDNF (Bahi et al., 2008; Graham et al., 2007; Graham et al., 2009) and inhibition by GDNF (Messer et al., 2000)"
• "[BDNF] profoundly increased systemic cocaine-induced potentiation of responding for a conditioned cue previously paired with water in thirsty rats"
• "Three to seven days after the last injection, BDNF-exposed rats self-administered more cocaine over a range of cocaine doses (an upward shift in the dose-response curve), suggesting increases in cocaine's rewarding effects." yikes!
• "The data reviewed above indicate that BDNF within the mesocorticolimbic dopamine system is a positive modulator of psychostimulant and opiate reward."
• "Drug relapse - Activation of BDNF-TrkB signaling in both the VTA and accumbens strongly potentiates extinction responding, and reinstatement induced by cocaine priming, cocaine cue, and intermittent footshock stress (Graham et al., 2007; Lu et al., 2004a)."

• This study had mixed results for drug relapse for GDNF, other studies had positive findings. It seems to depend on the drug and also on the "phase in the addiction cycle" (also see this study)

GDNF seems to work well for cocaine:

Role of Ventral Tegmental Area Glial Cell Line–Derived Neurotrophic Factor in Incubation of Cocaine Craving
Lin Lu, Xi Wang, Ping Wu, Chunmei Xu, Mei Zhao, Marisela Morales, Brandon K. Harvey, Barry J. Hoffer, Yavin Shaham
Biol Psychiatry. Author manuscript; available in PMC 2011 August 4.

"On the basis of earlier studies (13–15), we previously studied mesolimbic brain-derived neurotrophic factor’s (BDNF’s) role in incubation of cocaine craving. BDNF colocalizes with midbrain (ventral tegmental area [VTA] and substantia nigra [SN]) dopamine neurons (16) and supports their function (17,18). We found that BDNF levels in the VTA (the cell-body region of mesolimbic dopamine neurons), nucleus accumbens, and amygdala progressively increase over the first 90 withdrawal days (11). We also found that a single BDNF injection into the VTA at the end of the cocaine self-administration period enhances cue-induced drug seeking for up to 30 days after withdrawal (19). These findings implicate mesolimbic BDNF in incubation of cocaine craving (for a discussion of BDNF’s role in this incubation see Lu et al.) (19).
Another growth factor that is important for the survival and function of midbrain dopamine neurons is glial cell line–derived neurotrophic factor (GDNF) (20,21), a member of the GDNF-subfamily of ligands (22). Although there is evidence that stimulating mesolimbic BDNF potentiates rodents’ response to cocaine and cocaine cues (13,23–26), opposite effects were found for GDNF (27–30). GDNF VTA injections decrease, whereas local anti-GDNF antibodies injections increase, cocaine’s rewarding effects in a conditioned place preference (CPP) procedure (31). Additionally, striatal transplantation of simian virus-40 glial cells that produce GDNF or local injections of GDNF-conjugated nanoparticles decrease cocaine self-administration (32,33)."

Excessive alcohol consumption is blocked by glial cell line–derived neurotrophic factor
Sebastien Carnicella, Ryoji Amamoto, Dorit Ron
Alcohol. Author manuscript; available in PMC 2009 December 7

GDNF — A potential target to treat addiction
Sebastien Carnicella, Dorit Ron
Pharmacol Ther. Author manuscript; available in PMC 2013 June 14.

"The present reviewed data suggest that GDNF negatively regulates the actions of drugs of abuse, as reducing endogenous GDNF levels or inhibition of the GDNF pathway increases several biochemical and behavioral adaptations to psychostimulants, opioids and ethanol, whereas GDNF administration in the mesolimbic system results in opposite effects. The mechanisms of action of GDNF to counter these adaptations associated with addiction are currently unknown. The rapid MAPK-mediated effect of GDNF on dopaminergic neurons (Yang et al., 2001) in combination with GDNF's long-term actions to alter the level of TH (He & Ron, 2008) are possible candidates. These changes mediated by GDNF could lead to synaptic remodeling and change the responsiveness of the mesolimbic dopaminergic system and by doing so, counter the incentive and/or rewarding value of, and the neuroadaptations induced by, drugs of abuse. For example, it is plausible that activation of the MAPK signaling pathway by GDNF reverses the decrease in VTA dopaminergic cell size resulting from the downregulation of the insulin receptor substrate 2 (IRS2)-Akt signaling pathway, observed after chronic morphine administration (Russo et al., 2007). Other growth factors such as the brain derived neurotrophic factor (BDNF) activate similar signaling pathways as GDNF (Papoutian & Reichardt, 2001). Interestingly, BDNF was shown to modulate biochemical and behavioral adaptation to drugs of abuse. For example, intra-VTA infusion of BDNF prevents the upregulation of TH levels induced by chronic morphine and cocaine administration (Berhow et al., 1995). BDNF has been shown to potentiate cocaine-seeking behaviors in the mesolimbic system (Lu et al., 2004; Graham et al., 2007), but to negatively regulate ethanol-drinking behaviors within the dorsal striatum (McGough et al., 2004; Jeanblanc et al., 2006). Interestingly, recently Esposito et al. (2008) found a direct crosstalk between the BDNF and the GDNF signaling pathway in neuroblastoma cell lines. It would therefore be of great interest to determine if such cross talk exists in the brain and whether it contributes to the action of these two growth factors.
Importantly, a growing number of studies support the possibility that GDNF-mimetics may be potent and selective agents to treat addiction.

GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse

Sebastien Carnicella, Viktor Kharazia, Jerome Jeanblanc, Patricia H. Janak, Dorit Ron
Proc Natl Acad Sci U S A. 2008 June 10; 105(23): 8114–8119. Published online 2008 June 9. doi: 10.1073/pnas.0711755105

GDNF is an Endogenous Negative Regulator of Ethanol-Mediated Reward and of Ethanol Consumption After a Period of Abstinence
Sebastien Carnicella, Somayeh Ahmadiantehrani, Patricia H. Janak, Dorit Ron
Alcohol Clin Exp Res. Author manuscript; available in PMC 2009 December 7.


Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption

Dao-Yao He, Nancy N. H. McGough, Ajay Ravindranathan, Jerome Jeanblanc, Marian L. Logrip, Khanhky Phamluong, Patricia H. Janak, Dorit Ron
J Neurosci. Author manuscript; available in PMC 2006 January 19.

Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking
Segev Barak, Sebastien Carnicella, Quinn V. Yowell, Dorit Ron
J Neurosci. Author manuscript; available in PMC 2012 January 6."

Edited by Phoenicis, 22 March 2014 - 12:37 PM.

[VERITAS INCORRUPTUS]

^
As to the above, GDNF induction should bear some worth for the dysfunctional dopaminergic and acetylcholinergic implications of nicotine. As there is no perceived downside to this pathway one certainly can engage it to assess the efficacy for various conditions in which such a course should derive benefit.

Are you still smoking?
Are you suffering from MDD or similar?
Do you still sense reasonably strong cravings if you have been nicotine abstinent?

[Phoenicis]

I started smoking when I was 15 and quit cold turkey at 20, started again a year later and quit again after a year. Currently I don't have strong cravings all the time, but things don't feel the same. I sometimes feel 'numb' to reward sensations and I find it more difficult to concentrate. When I think of smoking I do still get the positive memories.

My current partner smokes, I'm not sure for how long but she wants to quit and has been asking me about rasagiline ever since I mentioned I might be trying it. She says she might order some for herself so we can try it at the same time. If we do go ahead and try it (at 1mg/day as recommended by the manufacturer) I will post a log.

So I think I found the brain area and it seems it might be similar to cocaine?:

Nicotine Potentiation of Excitatory Inputs to Ventral Tegmental Area Dopamine Neurons

• http://www.jneurosci...31/18/6710.full

Nicotine and cocaine leave similar mark on brain after first contact: Memory-like effects in brain reward pathway could contribute to drug addiction

• http://www.uchospita...3-nicotine.html

Edited by Phoenicis, 23 March 2014 - 03:48 PM.