Psycho-Babble Medication Thread 834421

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does selegiline really mitigate DAergic cell loss?

Posted by iforgotmypassword on June 13, 2008, at 5:08:48

does it really stop natural dopaminergic brain cell loss over time (13% each decade of adult life?), or mitigate it to any degree?

this seems to be possibly implied on BLTC's neat selegiline page http://www.selegiline.com, and it seems to be a commonly held belief. is there documented basis, or hard research? was this effect on dopaminergic brain cells noted in the mice that selegiline was observed to extend the lives of? anything else?

there is a LOT on the selegiline page, but i have a lot of trouble reading properly, i am still in the process of that. so i am asking other people, just in case, for both new information and possible clarification of the impressions that i have already accumulated.

this is very interesting to me as my problems seem tied to buggered DAergic projections from the VTA. i am guessing it is more tied to it's mesocortical projections into the PFC. but it's projections into the NAc also seem relevant, as i have a hunch that dopaminergic effect in that NAc that lamotrigine has (thanks for sharing this, was it SLS? thank you whoever did?) that may be what makes it helpful to me, as i have restarted it. i am staying at 100mg, and i feel quite a bit more woken up. less stiff and akathitic, and my thinking is more dislodged, executive function notably better, but of course as usual far from ideal. but an improvement i am quite thankful for. it seems important that i take lorazepam to allow it to help me periodically.

anyway, the idea of keeping away the 13% (or what specific percentage) on average of DAergic cell loss each decade of adult life. does anyone have more on this? solid support of the idea that it does this?

(this issue, in this last paragraph above, is the main question(s) focused on it my post.)

thanks. as usual sorry for any incoherence. i think i did well this morning actually tho! at least in comparison to my usual, i think my fluency level goes along with DAergic function, thanks lamotrigine.

 

Re: does selegiline really mitigate DAergic cell l iforgotmypassword

Posted by SLS on June 13, 2008, at 7:16:49

In reply to does selegiline really mitigate DAergic cell loss?, posted by iforgotmypassword on June 13, 2008, at 5:08:48

Hi.

I think Linkadge or Undopaminergic would be the people most capable of answering your question.

I will say this, though. There were studies performed at least 10 years ago refuting the notions that selegiline is an anti-apoptopic (anti-cell death) and anti-oxidant. This contradicts the more recent publications that conclude that selegiline is neuroprotective of dopaminergic neurons. I would tend to give more credence to the later studies because they have the advantage using more technologically advanced investigative equipment and protocols.

One putative anti-oxidant, N-Acetylcysteine (NAC), enhances the production of dopaminergic neurons and may confer a mitigation of apoptosis. It has been demonstrated to be neuroprotective of dopaminergic neurons.


- Scott

 

Re: does selegiline really mitigate DAergic cell l

Posted by okydoky on June 13, 2008, at 13:12:12

In reply to Re: does selegiline really mitigate DAergic cell l iforgotmypassword, posted by SLS on June 13, 2008, at 7:16:49

I don't completely understand all this. I had purchased Selegiline because of the studies I read pertaining to its neuroprotection and perhaps even reversing some of the damage. Does the same thing pertain to NAC? As much as I can understand anyway. I did not find such information about NAC, at least it was not as easily obtainable and understandable for me.

oky

 

Re: does selegiline really mitigate DAergic cell l okydoky

Posted by SLS on June 13, 2008, at 17:24:24

In reply to Re: does selegiline really mitigate DAergic cell l, posted by okydoky on June 13, 2008, at 13:12:12

> I don't completely understand all this. I had purchased Selegiline because of the studies I read pertaining to its neuroprotection and perhaps even reversing some of the damage. Does the same thing pertain to NAC? As much as I can understand anyway. I did not find such information about NAC, at least it was not as easily obtainable and understandable for me.

What convinces you that you need neuroprotection against dopamine neuronal degeneration?


http://www.google.com/search?hl=en&q=n-acetyl+cysteine+neuroprotective&btnG=Google+Search


- Scott

 

Re: does selegiline really mitigate DAergic cell l SLS

Posted by Phillipa on June 13, 2008, at 17:35:18

In reply to Re: does selegiline really mitigate DAergic cell l okydoky, posted by SLS on June 13, 2008, at 17:24:24

Heals nerve injuries. Wonder if it also applies to the deadened feeling of plastic surgery site as numb. Phillipa

 

Re: does selegiline really mitigate DAergic cell l

Posted by blueboy on June 14, 2008, at 8:56:00

In reply to does selegiline really mitigate DAergic cell loss?, posted by iforgotmypassword on June 13, 2008, at 5:08:48

> does it really stop natural dopaminergic brain cell loss over time (13% each decade of adult life?), or mitigate it to any degree?
>

My pdoc doesn't buy it. The research, IIRC, is sparse and possibly conflicting. On the other hand, he was willing to prescribe a sub-therapeutic dose to me, since there didn't appear to be any danger of drug/food reactions, from the single MAOI effect at low doses.

Also an IIRC, I think the effect has only been shown in rats.

 

Re: does selegiline really mitigate DAergic cell l SLS

Posted by okydoky on June 14, 2008, at 12:14:32

In reply to Re: does selegiline really mitigate DAergic cell l okydoky, posted by SLS on June 13, 2008, at 17:24:24

Scott,

I had done this search. I guess I was not reading research or abstracts like I did for Selegiline and Stablon.

Stuff like "blueboy" might have been alluding to.

I complained of learning problems and memory stuff for several years. No one (family and gp) believed me. It was obvious even to an employer who ended up having to fire me because of it. She did not understand why I could learn the stuff so easily and the next day not have any recall. That was very simple stuff. She came out and asked me because she thought it was so strange.

Anyway my gp finally took me seriously and had an MRI done which showed a few small white spots on my brain. He said it was nothing but since I had such complaints sent me to a neurologist. I had about three hours of testing. The report said I had several cognitive deficits as compared to persons my age range and socio-economic background. To include word retrieval, spatial memory, learning problems of some sort and several others I do not recall I cried for days. Knowing it myself was one thing having it in my face was another. I am supposed to have gone back already for a yearly to see if there is further decompensation. I do not think I will ever go back. It all makes me feel like my life is over. I wanted to finish school or at least take more classes. Since I began to notice these difficulties about 8 years ago I tried to take one class it was a disaster. I am not able to learn and retain enough to go back to school. Another ambition bites the dust.

I have learned to compensate mostly for everyday things this affects although I constantly loose things am easily confused etc But some of this could be the depression.

The neurologists report suggested cocaine use and Parnate. This was wrong I think because I went back to school and worked with no problem during and after the cocaine use and Parnate.

oky

 

Re: does selegiline really mitigate DAergic cell loss?

Posted by undopaminergic on June 14, 2008, at 17:45:49

In reply to does selegiline really mitigate DAergic cell loss?, posted by iforgotmypassword on June 13, 2008, at 5:08:48

There is a lot that could be said about selegiline - if nothing else, it is certainly a substance with much history. It has been glorified beyond reason as well as wrongly and unfairly maligned, by different entities at different times.

I haven't extensively reviewed the literature on selegiline for some time, so there are gaps in my knowledge about it and possible misrecollections, so some of the following may need verification.

The compound was originally discovered as a constituent of the Ephedra plant in the 1960s by Dr. Joszef Knoll of the Semmelweis University in Hungary, and named L-deprenyl. L-deprenyl is the naturally occurring steroisomer of deprenyl, but some chemical procedures for its preparation result in the synthesis of racemic deprenyl, which consists of equal parts L- and D-deprenyl. On the other hand, the term selegiline, which was introduced later, always refers exclusively to L-deprenyl, and the two terms are used synonymously.

The original intended medical application for selegiline was for depression, but apparently those efforts were abandoned.

At some point, it was discovered that selegiline was a monoamine oxidase (MAO) inhibitor with an atypical profile, and along with another atypical MAO-inhibitor - the structurally related clorgyline - selegiline was instrumental in the discovery of the existence of two distinct isoforms of the MAO enzyme, which eventually came to be referred to as MAO-A and MAO-B.

I'm not sure how selegiline came to be used for the treatment of Parkinson's disease, other than the fact that it was a MAO-inhibitor - a class of drugs known to slow the metabolism of the neurotransmitter known to be deficient in Parkinson's disease - dopamine.

At some point, apparent neuroprotective properties of selegiline started to become evident. It was shown to extend the lifespan of rats, and some studies indicated that it slowed the progression of Parkinson's disease.

Furthermore, selegiline was shown to antagonise the toxicity of MPTP to dopaminergic neurons. MPTP was a neurotoxic contaminant accidentally synthesised as part of the preparation of pethidine (meperidine) by opioid addicts, some of whom - upon exposure to the toxin - rapidly developed Parkinson's disease (PD) of extreme severity, resulting in paralysis. MPTP-induced PD became a major animal model of the disease, and the protective effect of selegiline against MPTP-toxicity in lab animals contributed to creating great - and unrealistic - expectations regarding the potential of selegiline as an anti-parkinsonian drug.

There was a famous study called DATATOP that investigated selegiline's effect on PD patients in the US, and its positive results convinced many that a treatment that retards the progression of PD had finally been found.

Some time later, another study was made in the UK, to compare the conventional anti-parkinsonian treatment L-DOPA against the combination of L-DOPA with selegiline. At some point, significantly increased mortality was discovered in the group of patients treated with the selegiline-combination, and the researchers found it alarming enough to terminate the selegiline experiment prematurely. This unexpected discovery cast a dark shadow over selegiline that lasts to this day.

In addition to the negative publicity of the UK selegiline-study, the issue of some of the drug's metabolites - L-amphetamine and L-methamphetamine - have been a never-ending source of controversy. Although amphetamines are proven to be neurotoxic to dopaminergic nerve terminals beyond reasonable doubt at doses higher than those typically used therapeutically for the treatment of ADHD, narcolepsy and many other conditions, the trace amounts of amphetamines formed from selegiline's metabolism at typical doses for PD are of highly questionable relevance. However, the mere presence of any trace of amphetamines is sufficient to instill fear and uncertainty into many people.

It's my impression that with selegiline at normal doses of 5-10 mg/day, its amphetamine-metabolites may contribute to some of its cardiovascular effects, and also slightly to its psychopharmacological profile. At these doses, the neuroprotective effects of selegiline - and its desmethylselegiline metabolite - are likely to outweigh any deleterious effects of the amphetamines. In support of this hypothesis, it has been reported that certain doses of selegiline in the low range are the most effective in extending the life span of lab animals, whereas higher doses are less effective or indeed shorten it.

As to the findings of the UK selegiline study, they are inconsistent with the body of research on selegiline as a whole. The best theory proposed so far to explain the increased mortality in selegiline-treated PD patients is that there was a bad batch of the selegiline product employed. I've seen speculation that suggests that an unidentified neurotoxic contaminant was present.

Some of selegiline's neuroprotective actions seem to be accounted for partly by its MAO-B inhibition, and partly by its chemical structure - more specifically its propargyl-group. The desmethylselegiline metabolite has neuroprotective activity in some experiments where selegiline has none, and is probably an important contributory factor to selegiline's beneficial effects.

For context, it may be useful to mention rasagiline - a newer MAO-B inhibitor that shares selegiline's structural propargyl-feature, but lacks amphetamine metabolites. This agent is less well studied, but everything I've read about it so far - except its higher price - has been very positive, which is not entirely surprising, considering that a lot of the reports on rasagiline's properties were written or co-authored by its creator, Dr. Youdim of Israel.

Also for context, dopamine reuptake inhibitors - such as cocaine and methylphenidate - may be of interest, as they are more potent in protecting dopaminergic neurons from neurotoxins that enter the neuron by means of the dopamine transporter, which is blocked by the reuptake inhibitors. MPTP is one such neurotoxin.

 

Re: does selegiline really mitigate DAergic cell loss? undopaminergic

Posted by okydoky on June 14, 2008, at 18:02:11

In reply to Re: does selegiline really mitigate DAergic cell loss?, posted by undopaminergic on June 14, 2008, at 17:45:49

Thank you so much. I wish I could understand it all better. Are different substances neuroprotective in differnet ways or for different reasons. I.E. protectoin from certain neurotoxins or something else? I ask as I have been taking Ritalin for many years and have progressive cognitive defects beyong waht is "normal" for my age.

 

Re: does selegiline really mitigate DAergic cell l okydoky

Posted by SLS on June 15, 2008, at 5:21:26

In reply to Re: does selegiline really mitigate DAergic cell loss? undopaminergic, posted by okydoky on June 14, 2008, at 18:02:11

> Thank you so much. I wish I could understand it all better. Are different substances neuroprotective in differnet ways or for different reasons. I.E. protectoin from certain neurotoxins or something else? I ask as I have been taking Ritalin for many years and have progressive cognitive defects beyong waht is "normal" for my age.

It is the depression that is producing your dementia. It will resolve gradually as you respond to an antidepressant treatment robustly. The degree of dementia in depression is increased as one ages with the disorder inadequately treated. In fact, melancholy seems to be replaced by dementia in the elderly, thus the errant diagnoses of what is now known as depression-induced "pseudodementia". My personal opinion is that the hippocampus loses tissue volume as the result of atrophy due to a pathological reduction in its activation by efferent pathways. To compound matters, chronically elevated cortisol also results in the loss of hippocampal tissue volume.

Yes, the impairments in depression of cognition, concentration, and memory do indeed qualify for the use of the word "dementia" (not to be confused by the disease, Alzheimer's Dementia. "Dementia" is a generic term describing such functional impairments.


- Scott

 

Re: does selegiline really mitigate DAergic cell l undopaminergic

Posted by SLS on June 15, 2008, at 5:31:51

In reply to Re: does selegiline really mitigate DAergic cell loss?, posted by undopaminergic on June 14, 2008, at 17:45:49

Wow!

What an excellent treatise on selegiline!

I don't know how you have come to possess so much knowledge, but your presentation was wonderful. I have followed the development of L-deprenyl since 1983 when it was first being developed as an antidepressant.

How in the world did you know about clorgyline and the propargyl class of MAOIs? Clorgyline is the most efficacious antidepressant that presently exists. Unfortunately, the patent on it ran out long ago, and two cardiac-related deaths were reported at the NIH. While I was a research patient at the NIH, clorgyline was the physician's "ace in the whole" as they called it. At the moment, clorgyline is no longer being manufactured for human consumption. However, as a biological probe, it is the de facto marker of MAOI-A enzyme concentration.

Again, I would like to offer you praise for your post composition, as it is worded extremely well and is extremely accurate.

Thanks.


- Scott

 

Re: does selegiline really mitigate DAergic cell l

Posted by linkadge on June 15, 2008, at 18:32:51

In reply to Re: does selegiline really mitigate DAergic cell l undopaminergic, posted by SLS on June 15, 2008, at 5:31:51

The neuroproective effects of selegiline are likely independant of its MAO-B inhibitory effects. There are a several other MAO-B inhibitors which do not share the neuroprotective effects of selegiline. Selegiline has some intrinsic antioxidant regulatory effects which may be more responsible for the neuroprotective effects. The amphetamine metabolites of selegiline may detract from its neurotrotective effects. Along these lines, Rasigiline might be preferable as it is devoid of amphetamine metabolites.

One thing I found interesting was that MAO-B inhbitors like selegiline appear to upregulate the dopamine transporter, perhaps as a compensatory pathway for dopamine metabolism. I don't know how this figures into its ability to protect against the neurotoxin MPTP. I would have thought that increased activity of DAT would enhance the entry toxins like MPTP into cells.

Selegiline is not entirely safe. In Parkinson's there is a risk of cardiovascular complications with higher doses. It can be activating and highly anxiogenic for some. Selegiline can really help some forms of depression (perhaps associated with low PEA), while it can exaserbate other forms of depression. I heard a case report of it exaserbating psychotic depression.

While it is clear that MAO-B metabolizes PEA, there is some dispute of the extend to which MAO-B actually metabolizes dopamine.

I think agents like melatonin are probably a safer way to get similar neuroprotective effects. I.e. I wouldn't use selegline purely as a neuroprotectant.


Linkadge

 

Re: does selegiline really mitigate DAergic cell l SLS

Posted by okydoky on June 17, 2008, at 12:43:44

In reply to Re: does selegiline really mitigate DAergic cell l okydoky, posted by SLS on June 15, 2008, at 5:21:26

>
> It is the depression that is producing your dementia. It will resolve gradually as you respond to an antidepressant treatment robustly. The degree of dementia in depression is increased as one ages with the disorder inadequately treated. In fact, melancholy seems to be replaced by dementia in the elderly, thus the errant diagnoses of what is now known as depression-induced "pseudodementia". My personal opinion is that the hippocampus loses tissue volume as the result of atrophy due to a pathological reduction in its activation by efferent pathways. To compound matters, chronically elevated cortisol also results in the loss of hippocampal tissue volume.
>
> Yes, the impairments in depression of cognition, concentration, and memory do indeed qualify for the use of the word "dementia" (not to be confused by the disease, Alzheimer's Dementia. "Dementia" is a generic term describing such functional impairments.
>
>
> - Scott

I wanted to thank you for the post. Got to it finally as I am further depressed and in a brain fog from taking Lyrica.


If I wanted to look for research about this would I look under "pseudodementia"?


oky

 

Re: does selegiline really mitigate DAergic cell l

Posted by undopaminergic on June 20, 2008, at 12:19:17

In reply to Re: does selegiline really mitigate DAergic cell l undopaminergic, posted by SLS on June 15, 2008, at 5:31:51

> It is the depression that is producing your dementia. It will resolve gradually as you respond to an antidepressant treatment robustly. The degree of dementia in depression is increased as one ages with the disorder inadequately treated. In fact, melancholy seems to be replaced by dementia in the elderly, thus the errant diagnoses of what is now known as depression-induced "pseudodementia". My personal opinion is that the hippocampus loses tissue volume as the result of atrophy due to a pathological reduction in its activation by efferent pathways. To compound matters, chronically elevated cortisol also results in the loss of hippocampal tissue volume.
>

Another interesting action of mu-opioid agonists is that they lower cortisol levels. In contrast, the more potent noradrenaline reuptake inhibitors, such as reboxetine and atomoxetine seem to have a strong tendency to raise cortisol, whereas the effect of methylphenidate is less pronounced, and selective serotonin reuptake inhibitors have a neutral impact, although one study reported a greater elevation of waking salivary cortisol by citalopram in comparison with reboxetine, which they claimed was indistinguishable from placebo - I wonder if they mixed up the two drugs.

> Wow!
>
> What an excellent treatise on selegiline!
>
> I don't know how you have come to possess so much knowledge, but your presentation was wonderful. I have followed the development of L-deprenyl since 1983 when it was first being developed as an antidepressant.
>
> Again, I would like to offer you praise for your post composition, as it is worded extremely well and is extremely accurate.
>

Thanks for your display of appreciation, but you are exaggerating its magnificence. It leaves much room for improvement, but for a story improvised mostly from memory, it's pretty good.

> How in the world did you know about clorgyline and the propargyl class of MAOIs?
>

I researched selegiline extensively many years ago, perhaps in conjunction with starting to take it regularly, first as monotherapy and later with PEA. I've updated my knowledge of it from time to time, sometimes prompted by internal or external cues, but at other times accidentally, while researching other topics. I learned about clorgyline as a side-effect of reading about selegiline and other aspects of MAO inhibition.

> Clorgyline is the most efficacious antidepressant that presently exists.
>

You've said so before as well, but I'm not convinced. In the context where I read about clorgyline, it was often compared to selegiline or other drugs, and I don't recall ever being impressed with any of its effects. Even so, due to its potent monoamine oxidase inhibitory action, I don't doubt that it's an effective antidepressant when given in sufficient doses, but what makes you think it's more efficacious than other MAOIs?

> At the moment, clorgyline is no longer being manufactured for human consumption. However, as a biological probe, it is the de facto marker of MAOI-A enzyme concentration.
>

I imagine clorgyline is available from multiple suppliers at high purity. If I really believed it was as good as you appear to do, I would be seeking to acquire it soon.

 

Re: does selegiline really mitigate DAergic cell l undopaminergic

Posted by SLS on June 20, 2008, at 13:17:09

In reply to Re: does selegiline really mitigate DAergic cell l, posted by undopaminergic on June 20, 2008, at 12:19:17

> Thanks for your display of appreciation, but you are exaggerating its magnificence.

Sorry UD. I guess I am too easily impressed. :-)

For some reason, the investigators at the NIH got spooked when two of their patients died of cardiovascular events. I think its effectiveness is due to both its irreversibility and its selectivity for the MAO-A enzyme. I have read that MAO-A is responsible for breaking down dopamine and norepinephrine in some areas of the brain. However, perhaps more important, is that clorgyline inhibits the reuptake of dopamine in various areas.

The usual dosage of clorgyline lies between 8 and 10mg. I went up to 15mg. They justified this high-dosage treatment by telling me that I was "very sick", and that they wanted to use their "ace-in-the-hole" compound, as it had demonstrated unusually high efficacy in their experiences. I was almost treatment-REFRACTORY at that time. Nothing budged my depression. Nardil and Parnate combined with TCA no longer worked. The ONLY drug that broke through the wall of resistance during this period of time was clorgyline. I remained partially responsive to clorgyline for quite a few months. However, when I asked William Potter if we could add desipramine, he refused. My doctor at home would not take responsibility for administering polypharmacy with clorgyline, so I decided to discontinue it in order to move on to other things.

I am relating to you what the investigative staff at the department of clinical pharmacology, NIMH, NIH told me. They thought it was more potent as an antidepressant than Nardil or Parnate.

Clorgyline and selegiline both have some interesting neuroprotective properties. Perhaps it lies in their propargyl structure that these two drugs exert these properties.


- Scott


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