"Too Much Testosterone Kills Brain Cells"

[Prada]

http://abcnews.go.com/Health/wireSto...2497054&page=1

Reuters

Sep 27, 2006 — By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - Too much testosterone can kill brain cells, researchers said on Tuesday in a finding that may help explain why steroid abuse can cause behavior changes like aggressiveness and suicidal tendencies.

Tests on brain cells in lab dishes showed that while a little of the male hormone is good, too much of it causes cells to self-destruct in a process similar to that seen in brain illnesses such as Alzheimer's.

"Too little testosterone is bad, too much is bad but the right amount is perfect," said Barbara Ehrlich of Yale University in Connecticut, who led the study.

Testosterone is key to the development, differentiation and growth of cells and is produced by both men and women, although men produce about 20 times more of the hormone.

It can also be abused, and recent scandals have involved athletes who use the hormone, or steroids that turn into testosterone in the body, for an unfair advantage.

"Other people have shown that high levels of steroid can cause behavioral changes," Ehrlich said in a telephone interview.

"We can show that when you have high levels of steroids, you have high testosterone and that can destroy the nerve cells. We know that when you lose brain cells you lose function."

Ehrlich's team tried the same thing with the "female" hormone estrogen, just to be fair.

"We were surprised, but it actually looks like estrogen is neuroprotective. If anything, there is less cell death in the presence of estrogen," she said.

Writing in the Journal of Biological Chemistry, Ehrlich and colleagues said their findings meant people should think twice about supplementing with testosterone, even if it does build muscle mass and aid recovery after exercise.

"These effects of testosterone on neurons will have long term effects on brain function," they wrote.

"Next time a muscle-bound guy in a sports car cuts you off on the highway, don't get mad just take a deep breath and realize that it might not be his fault," Ehrlich said in a statement.

The cells die via a process called apoptosis, also known as cell suicide or programmed cell death.

"Apoptosis is an important thing for the brain — the brain needs to weed out some of the cells. But when it happens too frequently, you lose too many cells and causes problems."

A similar process is seen in Alzheimer's disease, the most common cause of dementia in the United States, affecting an estimated 4.5 million Americans, and Huntington's disease, another fatal brain illness.

"Our results suggest that the responses to elevated testosterone can be compared with these pathophysiological conditions," the researchers wrote.

.
. .

"Next time a muscle-bound guy in a sports car cuts you off on the highway, don't get mad just take a deep breath and realize that it might not be his fault," Ehrlich said in a statement."

WTF?

[Red Ketchup]

Wooohooo!

We now have a "license to be stupid"!!!

Red

[Logan13]

good post, just wish they had a numerical value to what was "just enough" and what was "too much" testosterone ..... too vague as it is now to be of any use to us.

[Mike Dura]

I was just going to post this. You beat me too it. It is an interesting thread. And like Logan said, specific numbers would be helpful.

http://abcnews.go.com/Health/wireSto...2497054&page=1







WTF?

[Kärnfysikern]

Well its just a in vitro experiment so I wouldnt be overly concerned

Here is the abstract of the study if anyone can make any sense out of it. I sure as hell cant I can provide the whole thing if anyone is interested, I have online acess to that journal through my university.

Elevated Testosterone Induces Apoptosis in Neuronal Cells
J. Biol. Chem., Vol. 281, Issue 35, 25492-25501, September 1, 2006

Testosterone plays a crucial role in neuronal function, but elevated concentrations can have deleterious effects. Here we show that supraphysiological levels of testosterone (micromolar range) initiate the apoptotic cascade. We used three criteria, annexin V labeling, caspase activity, and DNA fragmentation, to determine that apoptotic pathways were activated by testosterone. Micromolar, but not nanomolar, testosterone concentrations increased the response in all three assays of apoptosis. In addition, testosterone induced different concentration-dependent Ca2+ signaling patterns: at low concentrations of testosterone (100 nM), Ca2+ oscillations were produced, whereas high concentrations (1-10 µM) induced a sustained Ca2+ increase. Elevated testosterone concentrations increase cell death, and this effect was abolished in the presence of either inhibitors of caspases or the inositol 1,4,5-trisphosphate receptor (InsP3R)-mediated Ca2+ release. Knockdown of InsP3R type 1 with specific small interfering RNA also abolished the testosterone-induced cell death and the prolonged Ca2+ signals. In contrast, knockdown of InsP3R type 3 modified neither the apoptotic response nor the Ca2+ signals. These results support our hypothesis that elevated testosterone alters InsP3R type 1-mediated intracellular Ca2+ signaling and that the prolonged Ca2+ signals lead to apoptotic cell death. These effects of testosterone on neurons will have long term effects on brain function.

[Prada]

Yeah its is rather ambigious, nonetheless I like that they clarify that to little testosterone is harmfull as well. This is just an article hence they know the target reader will fail to comprehend the quantitative data derived from the research albeit I too would appreciate the full research.

What I can solely comprehend from that article is that they are saying that supraphysiological levels of testosterone (now at what level is the level of test present in the body considered supraphysiological or "above the norm" is beyond me) will commence or trigger the apoptosis or death of neurological cells. Pretty much synonymous to the article I posted except its quite more explicit in explaining how this apoptosis is triggered and occurs. Again how to quantify micro versus nanomolar as far as concentration of test beats me.

I always found that steroid abusing BBs suffered from dementia.........at a supraphysiological level.

[Farang]

Thanks for the offer Johan. However I'm a new member and having problems with sending PMs
- When I try to send a PM, I get "user account may not have sufficient privileges to access this page".

If you sent the full report to my email address: [email protected] , I would be very greatful. Cheers mate!

[Farang]

I heared about this on Fox news (American Al-Jezeera).

I am a sports scientist, so I am interested in the findings. However I need to look at the research. Looks like BS though.

A few thoughts though:

"We were surprised, but it actually looks like estrogen is neuroprotective. If anything, there is less cell death in the presence of estrogen,"

-Of course most steroids make you produce more estrogen - does this counter balance the effect? (sarcastically) - maybe this is a reason to drop the tamoxifen during a cycle!


"Tests on brain cells in lab dishes"
:aaok****t

-This wasn't even a study on living humans. How can you make claims over experiments conducted in petri-dishes (bizzare!)


"Apoptosis is an important thing for the brain - the brain needs to weed out some of the cells. But when it happens too frequently, you lose too many cells and causes problems."

"These effects of testosterone on neurons will have long term effects on brain function,"

Brain cells are being recycled all the time. The study didn't show there was permanent damage. It was not a protracted study and did not follow subject brain states over a prolonged period (during which testosterone would be normalised). It did not show brain regenerating effects on cessation of steroid use (of which we know occurs with other drugs).

How the hell can they make these claims when they did not test for them- idiots!

The study did not even measure the effects of other circulating hormones/ brain interactions in LIVING humans, with feedback mechanisms.

"Next time a muscle-bound guy in a sports car cuts you off on the highway, don't get mad -- just take a deep breath and realize that it might not be his fault," Ehrlich said in a statement.

What a wanker. It is so called scientist like this that make me sick. He is obviously not profesional making these kind of comments (and a skinny twat). These kind of wild claims (on anything form nutrition to cancer) are made all the time, with thinking being revised or completely reversed due to unsubstantiated so called science. These characters send out PR photos of themselves and contact news agencies in order to try to get exposure, improve personal self estime, to try and attract funding for their dubious endeavours, or just because they are ego-maniacs.

"A similar process is seen in Alzheimer's disease, the most common cause of dementia in the United States, affecting an estimated 4.5 million Americans, and Huntington's disease, another fatal brain illness."

This is complete nonsense! - Alzheimers occurs as a result of a build up of plaque in the brain, which inturn restricts blood flow; kills off brain cells and shrinks regions of the brain.

"Our results suggest that the responses to elevated testosterone can be compared with these pathophysiological conditions,"

Our results on the effect of testosterone in a petri dish

- what a buch of total tossers!

In addition. As someone who has written and papers and done some exercise physiology based lab tests, you will almost always get conflicting results when you look at multiple studies - sometimes giving completely the reverse opinion. Infact you can write papers to make say some kind off nutritional supplent, say, Gingseng look as if it greatly increases cardiovascular performance. You would just have to include the rogue studies that found this (huge numbers do not support such a claim) and exclude others.

There was no mention of a control being used, or the competence of testers, facilities or environmental factors.

This is just one study! - The scientific community will only accept something as a truth, if it has reproducable effects in hundreds of studies - even then some will argue.

I doubt the professionalism of this buch of muppets making stupid statements to the press. They obviously are out to get a bit of glory and 15 minutes of fame.

I suspect that they started out with the preconcieved idea that this effect would occur. This happens a lot, with testers WANTING an effect to occur. In my experience, you must have no pre-conceived ideas before conducting experiments/assesing data - otherwise it can have an effect on your findings



O.K. got the paper now;

Just a few thoughts:

"Micromolar, but not nanomolar, testosterone concentrations increased the response in all three assays of apoptosis".

This study was not conducted on living humans. Therefore- they know how much additional testosterone (whether micro or macromolar).


The abstract quoted:
Caspase-3-induced truncation of type 1 inositol trisphosphate receptor accelerates apoptotic cell death and induces inositol trisphosphate-independent calcium release during apoptosis.


However in a Belgian study Inositol 1,4,5-trisphosphate receptor-deficient (IP3RKO) B-lymphocytes were used to investigate the functional relevance of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) and its cleavage by caspase-3 in apoptosis.

Interestingly:

Expression of caspase-3-non-cleavable mutant receptor, however, dramatically slowed down the rate of apoptosis and prevented both Ca2+ overload and secondary necrosis. (Assafa et al. 2004)

It seems that the brain has a feedback mechanism!

This could not be tested for in a petri dish!


whereas high concentrations (1-10 µM) induced a sustained Ca2+ increase.I

In agreement with Asafa's observations, "caspase inhibitors impeded apoptosis and the associated rise in [Ca2+]i. Both the staurosporine- and B-cell receptor-induced apoptosis and increase in [Ca2+] could be induced in nominally Ca2+-free and serum-free culture media, suggesting that the apoptosis-related rise in [Ca2+] was primarily because of the release from internal stores rather than of influx through the plasma membrane".

-Internal stores are FINITE, thus the continual release of CA2+ would only be short term (if at all).

In other words

(Assefa et al. 2004)


Elevated testosterone concentrations increase cell death, and this effect was abolished in the presence of either inhibitors of caspases or the inositol 1,4,5-trisphosphate receptor (InsP3R)-mediated Ca2+ release

Yes, as we have previously established, this is a natural phenomena that occurs in the brain of a LIVING person. You have shown that your findings mean nothing in your own abstract.

These results support our hypothesis that elevated testosterone alters InsP3R type 1-mediated intracellular Ca2+ signaling and that the prolonged Ca2+ signals lead to apoptotic cell death.

No they don't - you just said that the effect was "abolished in the presence of inhibitors od capases/inositol 1,4,5-triphosphate (InsP3R)- mediated CA2+ release - this is a natural phenomenon in human brains - the feedback mechanism (via the previously mentioned caspase-3-non-cleavable mutant receptor!)

I have spent a small amount of time to easily disprove these claims. I can't be bothered to research more, but I'm sure I could uncover a whole host of information which could show this sensationalist crap up.

This study may be valid ,so as to show short term effects. However the noted feedback mechanism would negate effects in the longterm. There may be a downgrade of the feedback mechanism with prolonged use (those who abuse steroids and do not come off) - but that would have to be substantiated with relevant proof from relevant studies.

As an aside:

Actual values of concentrations of testosterone need to be measured in human beings over sustained periods, as it is not known how much testosterone can breach the plasma barrier.

[Prada]

You need a minimum of posts to PM....

[Mike Dura]

I wouldn't make the claim of being a sports scientists but as a generalist who has taken basic courses in biology, neurons, or specialized cells of the nervous system (brain and spinal chord), do not regenerate. A neuronal death is permanent. Where there is a hint of regeneration, it's of a limited nature. That's what I recall.

[QUOTE=Farang]I heared about this on Fox news (American Al-Jezeera).
Brain cells are being recycled all the time.

[Phreak101]

[QUOTE=Mike Dura]I wouldn't make the claim of being a sports scientists but as a generalist who has taken basic courses in biology, neurons, or specialized cells of the nervous system (brain and spinal chord), do not regenerate. A neuronal death is permanent. Where there is a hint of regeneration, it's of a limited nature. That's what I recall.

I heared about this on Fox news (American Al-Jezeera).
Brain cells are being recycled all the time.

There is a difference between recycling and regenerating though, no?

[Mike Dura]

Yeah, good point. That escaped my attention. What is that difference though? It would seem that recycling means the cell is depleted. If that's the case, than his statement is irrelevant because they are talking about cell death. A cell death is a cell death and that's peramant

[QUOTE=Phreak101]

I wouldn't make the claim of being a sports scientists but as a generalist who has taken basic courses in biology, neurons, or specialized cells of the nervous system (brain and spinal chord), do not regenerate. A neuronal death is permanent. Where there is a hint of regeneration, it's of a limited nature. That's what I recall.



There is a difference between recycling and regenerating though, no?

[singern]

At first I wanted to post a response to this, but I just cant remember what I was going to say.

[Farang]

A BRIEF DECRIPTION OF THE MECHANISM OF BRAIN CELLS:

A human brain has roughly 10 billion neurons. A neuron or nerve cell processes and transmits information from the nervous system. Neurons (most) comprise
soma, dendrites, axons and terminals buttons. Neurons are polarised with an electical charge. They contain neucleolus and chromosomes (made up of long strings of DNA). These messenger RNA, assisting protein synthesis.
Neurons are possitively charged (a mechanism of flowing pottasium ions), and thus retain a negatively charge ions in the cell. When pottasium ions are stimmulated, they cause an influx, thus effecting a possitive charge, or an action potential. After this event, the ions are exchanged at the nodes of Ranvier, with high sodiium concentrations pumping out potassium and sodium ions (sodium-potasium pump). The event occurs in 1/1000th of a second and restores the negative charge.
I could go into more setail about chemical mechanisms, but it would be getting away from the point. Although it is important to note that Neuro-dilators, neuro modulatos and Hormones are released by the brain.

Note hormones can stimulate bothe sides of the cell membrane and the cell neucleus. Thus they can alter behaviour - this does not mean that in excess (say in the case of increased testosterone ) they KILL brain cells. They attatch to a binding site, like a lock and key mechanism. They "key" being known as a ligand. For this reason and others that I mentioned in relation to caspase-3-non-cleavable mutant receptors, I do not think cell death occurs at all.
Should there be a disturbance in neural communication, the vesicle of a neuron collapses in on itself and mixes with the cell membrane, leading to the cell later being retrieved and recylced.

THIS IS LIKELY TO OCCUR.

The vesicles (that are filled with neurotransmitters) are then readily availiable to be re-used.

Brain cells use a shuttle system in order to effect more or less receptors for a transmitting signal, aiding neural pathways, via synapse communication, to be formed and to MAINTAIN function (by assisting the creation of other pathways) following cell death (if any).

Regulatory signals in the brain manage the number of receptors. The recycling of these receptors PREVENT THE WEAKENING OF SYNAPSES THAT OCCUR IN NEURODEGENERATIVE STATES.

Unlike "drugs" Testosterone does not shut off recycling. As testosterone, as a hormone, is integral in neuronal communication; an increase should INCREASE cellular recycling! Testosterone does not cause any degradation and it does not decrease the activity of the receptors.

P.s. Freak101 - I didn't mean to sound pompous by saying I was a "Sports Scientist" - just to indicate that I did know something about what I was talking about. I got a first in Sport and Exercise science form the university of Westminster (did half my masters and was doing well, but had to move to Thailand for family reasons- will finish off later).
I have an interest in all branches of science, and used to teach science in a Thai school (O.k. not so advanced!)

Anyway, hope this cleared up any misunderstandings.

[Farang]

Me again. Just to say that if anyone is still worried, I can recommend a harmless drug that can improve your health and could perhaps be used to negate any SUPPOSED damage. It also improves mood, enhances LDL cholesterol oxidation and gives vascular protection. It acts as an antioxidant, of which it is particularly active in the brain. It is cardio-protetive and an antiatherogenic).

THE DRUG: DEPRENYL (also known as Seligiline or L-Deprenyl)


I shall highlight a couple of passages from Sabelli et al. 1996 –

“Such an action could contribute to reported extension of life span associated with long-term administration of the drug.”

“Prophylactic use of low doses of l-deprenyl may accord protection against vascular and neurodegenerative diseases associated with aging.”

-If you believe “The Idiot Formally Known as Ehlrich” (T.I.F.K.E.),it is certainly something those of us on gear could do with! – with the additional added benefits mentioned above!


Please exercise caution though, as you MUST NOT EAT FOODS HIGH IN TYRAMINE – see below.

“Tyramine is found in many foods, including aged cheeses, some wines, beans, yeast products, chicken liver and pickled herring, to name just a few”. –Need to do more research here.

At this point I would like to say that after looking into Ehlrich, it is clear to see where her motivation for these statements and erroneous study lies. I have found that most of her research centers around the efflux of calcium ions in the brain (as seen in degenerative brain disorders). She has even personally funded other scientists to do similar research. This rhetoric is just a sad attempt in trying to gain attention for her main pursuit - by doing terrible, poorly analyzed lab experiments and linking it to something completely non-analogous
- Not what you would expect from a professor at Yale!
Anyway, for those STILL concerned, the use Deprenyl might be prudent.

I have posted some of my research on the drug below. Read it and draw your own conclusions


Deprenyl is a drug that was discovered around 1964-65 by Dr. Joseph Knoll and colleagues. It was originally developed as a “psychic energizer,” designed to integrate some amphetamine-like brain effects with antidepressant effects. Also known as L-deprenyl, (-)-deprenyl, and selegiline, deprenyl has been intensively researched over the past 36 years - many hundreds of research papers on deprenyl have been published. Knoll has stated that deprenyl “...is an exceptionally lucky modification of PEA [phenylethylamine], an endogenous ... member of the family to which also the transmitters noradrenaline and dopamine belong.” Deprenyl has shown a unique and exciting pharmacologic/clinical profile. It is the only potent, selective MAO-B inhibitor in medical use.Deprenyl is a “catecholamine activity enhancer.” Deprenyl has been shown to protect nerve cells against a wide (and growing) number of neurotoxins. Deprenyl has also been shown to be a “neuroprotection/ neurorescue agent” when nerve cells are exposed to damaging or stressful conditions.
Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative of phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. Whereas PEA and its long-lasting variants, the amphetamines, are mixed-acting stimulants of the sympathetic system in the brain, they primarily enhance the impulse propagation generated release of catecholamines (catecholamine activity enhancer, CAE, effect) and displace catecholamines in higher concentration (catecholamine releasing effect). (-)Deprenyl is the first CAE substance in clinical use devoid of catecholamine releasing activity. (-)Deprenyl is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in the literature, has become a universally used research tool for selectively blocking B-type MAO and is still the only selective MAO-B inhibitor in world wide clinical use. In contrast to MAO inhibitors which strongly potentiate the catecholamine releasing effect of tyramine, (-)deprenyl inhibits it and is free of the 'cheese effect', which makes it a safe drug. Because its lack of the catecholamine releasing activity deprenyl is devoid of amphetamine like dependence capacity.
DEPRENYL: MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that deprenyl was a unique kind of MAO inhibitor - a selective MAO-B inhibitor, without the “cheese effect.” To fully appreciate what this means, some technical background is necessary.
Some of the most important neurotransmitters in the brain are the monoamine transmitters: serotonin, dopamine and noradrenalin. After being secreted into the synaptic gap, where one neuron connects to another, many to the transmitter molecules are reabsorbed by the secreting neuron and then disposed of by enzymes called “monoamine oxidases” (MAO). This prevents excessive levels of transmitters from accumulating in the synaptic gap and “over-amping” the brain. However, with aging MAO activity significantly increases in the human brain, often to the point of severely depressing necessary levels of monoamine transmitters. In the 1950s the first antidepressant drugs to be developed were MAO inhibitors.
By 1968, further research had shown that there were two types of MAO-A and B. It is primarily intestinal MAO-A that digests incoming tyramine. Most of the MAO inhibitors that have been used clinically inhibit both MAO-A and MAO-B, however deprenyl has the unique ability to prevent tyramine from getting into noradrenalin-using nerve calls, and it’s only when tyramine enters noradrenalin nerve cells that control arterial blood pressure that it triggers the “cheese effect.” Deprenyl thus has a dual “safety lock” in preventing the “cheese effect,” making it far safer than other MAO inhibitors. At doses over 20-30 mg/day, however, deprenyl does start to significantly inhibit MAO-A

“CHEESE EFFECT”: When most MAO inhibitors are used in people consuming a diet rich in a substance called “tyramine,” a dangerous, even fatal, high blood pressure crisis can be triggered. Tyramine is found in many foods, including aged cheeses, some wines, beans, yeast products, chicken liver and pickled herring, to name just a few.

MAO-B breaks down dopamine and the “traceamine” phenylethylamine (PEA). At doses of 10 mg + per day deprenyl will inhibit MAO-B about 90%. MAO-B inhibition can significantly increase synaptic dopamine levels.

Deprenyl (and its “cousin”, PEA) are “catecholamine activity enhancers”.
Catecholamines refers to the inter-related neurotransmitters dopamine, noradrenalin, and adrenalin. Catecholamines are the transmitters for key activating brain circuits - the mesolimbic-cortical circuit and the locus coeruleus. The neurons of the mesolimbic-cortical circuit and locus coeruleus project from the brain stem, through the mid-brain, to the cerebral cortex. They help to maintain focus, concentration, alertness and effortful attention. Dopamine is also the transmitter for a brainstem circuit - the nigrostriatal tract - which connects the substantia nigra and the striatum, a nerve tract that helps control bodily movement and which partially dies off and malfunctions in Parkinson’s disease.
When an electrical impulse travels down the length of a neuron - from the receiving dendrite, through the cell body, and down the transmitting axon - it triggers the release of packets of neurotransmitters into the synaptic gap. These transmitters hook onto receptors of the next neuron, triggering an electrical impulse which then travels down that neuron, causing yet another transmitter release. What Knoll and colleagues discovered through their highly technical experiments is that deprenyl and PEA act to more efficiently couple the release of neurotransmitters to the electrical impulse that triggers their release.
In other words, deprenyl (and PEA) cause a larger release of transmitters in response to a given electrical impulse. It’s like “turning up the volume” on catecholamine nerve cell activity. And this may be clinically very useful in various contexts - such as Parkinson’s disease and Alzheimer’s disease, where the nigrostriatal tract and mesolimbic-cortical circuits under-function, as well as in depression, where they may be under-activity of both dopamine and noradrenalin neurons.
Knoll’s research also indicates that after sexual maturity the activity of the catecholamine nervous system gradually declines, and that the rate of decline determines the rate at which a person or animal ages.
Knoll therefore believes that deprenyl's catecholamine activity enhancers effect explains its anti-aging benefit. Knoll also believes that deprenyl's catecholamine activity enhancer activity is independent of its MAO-B inhibition effect, because in rats he has shown catecholamine activity enhancer effect at doses considerably lower than that needed to achieve MAO-B inhibition.
Knoll’s work indicates that PEA is also a catecholamine activity enhancer substance. (16) PEA is a trace amine made in the brain that modulates (enhances) the activity of dopamine/noradrenalin neurons. (16,21) Autopsy studies have shown that while deprenyl increases dopamine levels in Parkinson patient brains by only 40-70%, deprenyl increases PEA levels 1300 - 3500%! PEA is the preferred substrate for MAO-B, the MAO that deprenyl inhibits. Paterson and colleagues have shown that PEA has an extremely rapid turnover due to its rapid and continuous breakdown by MAO-B. (21) Thus deprenyl's catecholamine activity enhancer activity has a dual mode of action. At low, non-MAO-B inhibiting doses, deprenyl has a direct catecholamine activity enhancer activity.
At higher, MAO-B inhibiting doses, deprenyl creates an additional catecholamine activity enhancer effect, due to the huge increases in brain PEA levels that deprenyl causes, PEA also being a catecholamine activity enhancer substance. Many authors have pointed out the probable dopamine neuron activity enhancing effect of PEA in Parkinson patients taking deprenyl.
Knoll’s discovery of PEA’s catecholamine activity enhancer effect now explains this PEA dopamine-enhancing effect


Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum and protects the nigrostriatal dopaminergic neurons from selective neurotoxins (6-hydroxydopamine, MPTP, DSP- Maintenance of an animal on deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. Many other protective effects of (-)deprenyl, denoted as 'neuroprotective', 'trophiclike neurorescue', 'apoptosis reducing', etc, have been described. All the protective actions of (-)deprenyl are thought to be primarily related to the CAE effect of the drug. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the age-related loss of their capacity to ejaculate, slows the age-related decline of their learning capacity and prolongs their life. Parkinsonian patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Parkinsonian patients maintained, after diagnosis, on (-)deprenyl, need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improves the performance of patients with Alzheimer's disease. It is concluded that patients developing Parkinson's or Alzheimer's disease need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. Because of the peculiar pharmacological spectrum and safety of the drug it may be advisable to combat the age-related decline of the nigrostriatal dopaminergic neurons in man by taking 10-15 mg (-)deprenyl weekly during the postdevelopmental phase of life. Prophylactic (-)deprenyl medication may improve the quality of life in the latter decades, delaying the time of natural death and decreasing the susceptibility to age-related neurological diseases.



Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo
Itschak Lamensdorf1, Shai Porat2, Rabi Simantov2 and John P.M. Finberg*,1
1 Rappaport Faculty of Medicine, Technion, POB 9649, Haifa, Israel
2 Department of Molecular Genetics, Weizmann Institute of Science, Israel
*Correspondence to: John P.M. Finberg, Rappaport Faculty of Medicine, Technion, POB 9649, Haifa, Israel
1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process.
2. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg-1, i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals.
3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg-1, s.c.).
4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine.
5. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals.
6. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.
Sustained antidepressant effect of PEA replacement
by
Sabelli H, Fink P, Fawcett J, Tom C
Rush University and the
Center for Creative Development,
Chicago, Illinois, USA.
J Neuropsychiatry Clin Neurosci 1996 Spring; 8(2):168-71

ABSTRACT
Phenylethylamine (PEA), an endogenous neuroamine, increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It has been proposed that PEA deficit may be the cause of a common form of depressive illness. Fourteen patients with major depressive episodes that responded to PEA treatment (10-60 mg orally per day, with 10 mg/day selegiline to prevent rapid PEA destruction) were reexamined 20 to 50 weeks later. The antidepressant response had been maintained in 12 patients. Effective dosage did not change with time. There were no apparent side effects. PEA produces sustained relief of depression in a significant number of patients, including some unresponsive to the standard treatments. PEA improves mood as rapidly as amphetamine but does not produce tolerance.







L-deprenyl (Selegiline) used in the treatment of Parkinson's and Alzheimer's disease also enhances longevity. Oxidized low density lipoprotein promotes atherosclerosis and is toxic to both vascular and neural tissue. The reported association between vascular dysfunction and neurodegenerative diseases prompted us to investigate the effect of l-deprenyl, a MAO-B inhibitor, on low density lipoprotein (LDL) oxidation. LDL was isolated from freshly collected blood and the kinetics of copper induced oxidation of LDL was monitored continuously by spectrophotometry. Oral administration (10 mg) or in vitro (2.8 to 84 microM) addition of l-deprenyl inhibited oxidation of LDL isolated from healthy men and post-menopausal women. This is the first report demonstrating that the antioxidant action of l-deprenyl may be antiatherogenic and cardioprotective. Such an action could contribute to reported extension of life span associated with long-term administration of the drug. In conjunction with inhibition of LDL oxidation, l-deprenyl is unique in that it demonstrates protective effects on both vascular and neuronal tissue. Prophylactic use of low doses of l-deprenyl may accord protection against vascular and neurodegenerative diseases associated with aging.