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.
poster:undopaminergic
thread:834421
URL: http://www.dr-bob.org/babble/20080606/msgs/834645.html