54 replies to this topic

[LexLux]

BDNF vs GDNF depends on the type of drug:

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.

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. FDA-approved drugs such as cabergoline open new and promising avenues for the development of therapeutic approaches to treat addiction."

Cabergoline Decreases Alcohol Drinking and Seeking Behaviors Via Glial Cell Line-Derived Neurotrophic Factor
Sebastien Carnicella, Somayeh Ahmadiantehrani, Dao-Yao He, Carsten K. Nielsen, Selena E. Bartlett, Patricia H. Janak, Dorit Ron
Biol Psychiatry. Author manuscript; available in PMC 2010 July 1.

Edited by LexLux, 22 March 2014 - 01:55 AM.

[Flex]

Thx, Good to Know

[LexLux]

To be more specific, 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)

some more:

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 LexLux, 22 March 2014 - 03:08 AM.

[Phoenicis]

Alas cabergoline's side effects look daunting, but it's interesting. Rasagiline looks more tolerable to me, I wonder what the difference in GDNF is?

Edited by Phoenicis, 22 March 2014 - 03:30 AM.

[celebes]

An increase in rewarding effects is a good thing... as long as you stay off cocaine. Better than going through life anhedonic. Unless GDNF's effect only applies to artificial and not natural rewards for some reason. But why would that be? Raising baseline satisfaction as opposed to thrill-seeking? Interesting, though. I imagined GDNF would increase motivation generally.


Edit: I see that GDNF rescues DA levels in withdrawal. That points to it being thrill-seeking/reinstatement related.

Edited by celebes, 22 March 2014 - 06:57 AM.

[Phoenicis]

Do you guys think GDNF help with damage caused to dopamine pathways by nicotine abuse? What about withdrawal for someone quitting smoking? I know selegiline was tested for that (with mixed results), but that's mainly BDNF inducing.

[Jeoshua]

Damage caused to dopamine pathways by nicotine abuse? What are you on, about?

[Phoenicis]

Nicotine Potentiation of Excitatory Inputs to Ventral Tegmental Area Dopamine Neurons

• http://www.jneurosci.org/content/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, 22 March 2014 - 03:24 PM.

[Jeoshua]

That doesn't sound like damage, to me. That just sounds like activity. I mean, inducing long term potentiation and synaptic plasticity in the ventral tegmental area is not damage. In fact, it's the closest thing on this thread that I've seen to something that really has a measurable effect on rewiring the brain. Certainly there are issues with this, but I just can't agree that this is at all "damage".

[Phoenicis]

Well it could be considered damage in that once the rewiring is done, those pathways no longer function the as they did before, without nicotine. If I as a contractor (which Im not) mistakenly rewire your home's US power sockets with European sockets, would I be causing damage? Most definitely. Perhaps an even better example would be replacing your locks, those reward pathways get locked up by nicotine's rewiring.

Edited by Phoenicis, 22 March 2014 - 04:41 PM.

[Flex]

I heard about it, but afaik this happens not untill about 15+ Years of Nicotine abuse.

Sry can´t provide any evidence on my claim, I read it somewhere but dont remeber where to find.

In addition it isn´t easy to find, since I get mostly benefical results regarding Parkinson and Alzheimer -.-

Edited by Flex, 23 March 2014 - 03:17 AM.

[Flex]

Found this one regarding Gdnf

http://www.ncbi.nlm....pubmed/15585109
Regulated delivery of glial cell line-derived neurotrophic factor into rat striatum, using a tetracycline-dependent lentiviral vector.
Georgievska B¹, Jakobsson J, Persson E, Ericson C, Kirik D, Lundberg C.

Abstract
In this study, a tetracycline-regulated lentiviral vector system, based on the tetracycline-dependent transactivator rtTA2(S)-M2, was developed for controlled expression of glial cell line-derived neurotrophic factor (GDNF) in the rat brain. Expression of the marker gene green fluorescent protein (GFP) and GDNF was tightly regulated in a dose-dependent manner in neural cell lines in vitro. Injection of high-titer lentiviral vectors into the rat striatum resulted in a 7-fold induction of GDNF tissue levels (1060 pg/mg tissue), when doxycycline (a tetracycline analog) was added to the drinking water. However, low levels of GDNF (150 pg/mg tissue) were also detected in animals that did not receive doxycycline, indicating a significant background leakage from the vector system in vivo. The level of basal expression was markedly reduced when a 10-fold lower dose of the tetracycline-regulated GDNF vector was injected into the striatum (3-11 pg/mg tissue), and doxycycline-induced GDNF tissue levels obtained in these animals were about 190 pg/mg tissue. Doxycycline-induced expression of GDNF resulted in a significant downregulation of the tyrosine hydroxylase (TH) protein in the intact striatum. Removal of doxycycline from the drinking water rapidly (within 3 days) turned off transgenic GDNF mRNA expression and GDNF protein levels in the tissue were completely reduced by 2 weeks, demonstrating the dynamics of the system in vivo. Accordingly, TH protein expression returned to normal by 2-8 weeks after removal of doxycycline, indicating that GDNF-induced downregulation of TH is a reversible event.

http://www.ncbi.nlm....pubmed/16584838
Doxycycline-regulated co-expression of GDNF and TH in PC12 cells.
Wang JJ¹, Zhang T, Niu DB, Wang K, Li KR, Xue B, Wang XM.

Abstract
Current gene therapy models for Parkinson's disease (PD) have adapted two treatment strategies. One is to restore dopamine (DA) production by delivering the genes of DA-synthesizing enzymes such as tyrosine hydroxylase (TH) to the striatum to relieve motor symptoms of PD. Another is to block or slow down progressive degenerative changes by delivering neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) to protect the remained neurons. To test the assumption that the combination of the two strategies may have a compound or synergistic effect, we had constructed tetracycline-inducible (tet-off) AAV vector carrying GDNF and TH. After co-transfection of PC12 cells with this vector and the inducer plasmid, the expression of GDNF and TH protected these cells from 1-methyl-4-phenyl-pyridinium-induced injury, and significantly increased the content of dopamine in GDNF/TH-expressing cells compared with the control. Furthermore, mRNA expression of GDNF and TH could be effectively and reversibly regulated by doxycycline (Dox) and the function of GDNF and TH could be repressed by Dox. These results suggest that the tet-off AAV vector carrying GDNF and TH may be a useful tool for gene therapy in the treatment of PD.
----------------------------------

The Gdnf related anti addictive effect seems, at least for me, to be mediated by downregulation of TH Expression.
Does that in turn mean, that Bdnf enhances addiction just via increasing of monoamine contend ?

Btw,I dont want to be responsible if someone gets a treatment ressistant bacterial infection, due careless handling with Antibiotics.

Edited by Flex, 23 March 2014 - 03:35 AM.

[abcmanomandriepunt1]

Great topic!
some cheap additions :

Green tea http://www.sciencedi...006291X14002095 http://www.ncbi.nlm....pubmed/20936703
Rosemary http://www.ncbi.nlm....pubmed/14600414

and there's a connection between BDNF and iodine so i take kelp to ensure i'm not deficient :
Kelp (iodine) http://www.ncbi.nlm....pubmed/23328070

[Logic]

NSI-189
http://www.longecity.../page__st__1770

Cerebrolysin
http://www.longecity...1-cerebrolysin/

Threonate
http://www.longecity...osteoarthritis/

Various Mushrooms
site search this

[GreenLemon]

10. Sertraline is an antidepressant that increases BDNF. (Link)
11. Risperidone increases BDNF levels and augments antidepressant treatment. (Link)



while this may be great.... the thing is, well from peoples experience long term use of sertarline and they have memory problems..... and rispdal, well they felt like their brain was reduced in size.........

so this is quite interesting, because well. it shows us that just because of one study we should not start taking random drugs or herbs because clearly... well the point is don't judge a drug/herb/etc from one study

??

[abcmanomandriepunt1]

They raise BDNF or other neurotrophic factors in certain areas in the brain, but decrease it in others. Quick search already found a decrease in the hippocampus where memory is located.

[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 leads to increased GDNF. Perhaps it would make sense to cycle the two for alternating GDNF and BDNF.

Edited by Phoenicis, 23 March 2014 - 08:20 PM.

[Flex]

Do you still smoke ?

Here is some interresting stuff regarding substitution.

http://en.wikipedia.org/wiki/Anatabine
its in https://www.cigrx.com/order-now and
https://store.anatab...-unflavored-300
or
http://en.wikipedia.org/wiki/Cytisine
sold under: Tabex

Edited by Flex, 23 March 2014 - 09:24 PM.

[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 reason 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

Now 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 - 07:33 PM.

[LexLux]

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."

[YOLF]

Attention:

This post has been updated with a correction:
http://www.longecity...post__p__651440

[Flex]

thx

[Flex]

I´ve made antoher thread which at least shares some of the subjects from here:

 

Newly natural compounds that I´ve found with interresting effects

http://www.longecity...ts/#entry681626

[abelard lindsay]

The best thing I've found for brain repair is very high dose ALCAR.  I used to get sciatic pain and numbness in my foot and taking 3 to 4 grams of ALCAR would always help reverse that.

 

http://www.ncbi.nlm....pubmed/14615246

 

 

Br J Plast Surg. 2003 Dec;56(8):732-9.

Primary sensory neuronal rescue with systemic acetyl-L-carnitine following peripheral axotomy. A dose-response analysis.

Wilson AD1, Hart A, Brannstrom T, Wiberg M, Terenghi G.

Author information

 

Abstract

The loss of a large proportion of primary sensory neurons after peripheral nerve axotomy is well documented. As a consequence of this loss, the innervation density attained on completion of regeneration will never be normal, regardless of how well the individual surviving neurons regenerate. Acetyl-L-carnitine (ALCAR), an endogenous peptide in man, has been demonstrated to protect sensory neurons, thereby avoiding loss after peripheral nerve injury. In this study we examined the dose-response effect of ALCAR on the primary sensory neurons in the rat dorsal root ganglia (DRG) 2 weeks after sciatic nerve axotomy. Six groups of adult rats (n=5) underwent unilateral sciatic nerve axotomy, without repair, followed by 2 weeks systemic treatment with one of five doses of ALCAR (range 0.5-50 mg/kg/day), or normal saline. L4 and L5 dorsal root ganglia were then harvested bilaterally and sensory neuronal cell counts obtained using the optical disector technique. ALCAR eliminated neuronal loss at higher doses (50 and 10 mg/kg/day), while lower doses did result in loss (12% at 5 mg/kg/day, p<0.05; 19% at 1 mg/kg/day, p<0.001; 23% at 0.5 mg/kg/day, p<0.001) compared to contralateral control ganglia. Treatment with normal saline resulted in a 25% (p<0.001) loss, demonstrating no protective effect in accordance with previous studies.ALCAR preserves the sensory neuronal cell population after axotomy in a dose-responsive manner and as such, has potential for improving 

 

[Flex]

Thank You.

I knew that Acetyl-carnitine increases the action of NGF to 100 fold to treated cells. But Your posted study has nevertheless astonished me.

 

Btw I´ve read recently that Acetyl-carnitine is very benefical to those who are stress sensitive:

 

...The researchers found that the highly stress-susceptible mice had less of an important molecule known as mGlu2 in a stress-involved region of the brain known as the hippocampus. The mGlu2 decrease, they determined, resulted from an epigenetic change, which affects the expression of genes, in this case the gene that codes for mGlu2.

“If you think of the genetic code as words in a book, the book must be opened in order for you to read it. These epigenetic changes, which affect histone proteins associated with DNA, effectively close the book, so the code for mGlu2 cannot be read,” says first author Carla Nasca, a postdoc in the lab and a fellow of the American Foundation for Suicide Prevention. Previously, she and colleagues implicated mGlu2 in depression when they showed that a promising potential treatment known as acetyl carnitine rapidly alleviated depression-like symptoms in rats and mice by reversing these epigenetic changes to mGlu2 and causing its levels to increase....

http://newswire.rock...ating-for-some/