From: Rafal Smigrodzki (rms2g@virginia.edu)
Date: Sat Feb 08 2003 - 18:18:44 MST
----- Original Message -----
From: "gts" <gts_2000@yahoo.com>
To: <extropians@extropy.org>
Sent: Saturday, February 08, 2003 5:58 AM
Subject: Re: Performance enhancement with selegiline
> ABSTRACT
> Neuroprotection by deprenyl and related compounds
>
> Maruyama W, Naoi M
>
> Department of Basic Gerontology,
> National Institute for Longevity Sciences Obu, Japan.
> maruyama@nils.go.jp
> Mech Ageing Dev 1999 Nov; 111(2-3):189-200
>
> There is an increasing number of data by in vitro and in vivo experiments,
> indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even
> though detailed mechanism remains to be clarified. In this paper
> neuroprotection by (-)-deprenyl and structurally related compounds was
> examined in concern with the suppression of apoptosis induced by a
reactive
> oxygen species, peroxynitrite generated from SIN-1. The apoptotic DNA
> damage was quantitatively determined using dopaminergic SH-SYSY cells and
by
> a single cell gel electrophoresis (comet) assay. DNA damage induced by
> peroxynitrite was proved to be apoptotic by prevention of the damage by
> cycloheximide or actinomycin-D. (-)-Deprenyl and other propargylamines
> protected the cells from apoptosis in a dose-dependent way. (-)-Deprenyl
> protected the cells even after it was washed out, suggesting that it may
> initiate the intracellular process to repress the apoptotic death program.
> The study on the structure-activity relationship of (-)-deprenyl analogues
> revealed that a N-propargyl residue with adequate size of hydrophobic
> structure is essentially required for the anti-apoptotic activity. These
> results suggest that (-)-deprenyl and related compounds may protect
neurons
> from apoptosis and be applicable to delay the deterioration of neurons
> during advancing ageing and in neurodegenerative disorders.
> =======
>
> I'm reposting this abstract above, Rafal, because you failed to address
it,
> much less refute it, in your reply to the last message to you.
### No need to refute it in the context of my claims - in vitro studies are
not evidence of anything whatsoever in PD, especially if clinical evidence
already excludes a clinical effect.
See below.
-----------------------------
>
> Rafal wrote:
>
> >> Other studies show that selegiline increases lifespan in <snip> human
PD
> >> patients.
>
> > ### Quote them and show they are more reliable and trustworthy than
> DATATOP.
>
> I think I have already posted several that make that claim, and I don't
know
> why I should even bother to report more of them. I have quoted at least
> half a dozen abstracts here, Rafal, and you have failed to address the
data
> and claims in those abstracts in any detail whatsoever! Instead you just
> keep restating the same old argument (that selegiline is only helps with
> symptoms rather than with neuroprotection, as if I didn't hear it the
first
> time), and you base that argument on the *single* study that *you*
> personally prefer to recognize as the *only* valid study, as if I and
> everyone here should consider you to be the world's leading authority on
the
> subject.
### I don't need to address dozens of abstracts irrelevant to PD.
-----------------------
>
> You've given us no reason to believe that you have assessed the evidence
> better than other experts who specialize in this field and who still
> currently believe that the preponderance of the evidence supports the view
> that selegiline is neuroprotective in PD. Maybe they are right or maybe
they
> are wrong, but you Rafal certainly don't have a monopoly on such
knowledge.
> I will however for the moment concede that the evidence for
neuroprotection
> in PD is not unequivocal, and in fact I sincerely do agree that isn't,
just
> so that we can get past this point. Okay? Nevermind PD for now.
### Experts at the American Academy of Neurology, as well as my mentors,
Professor F. Wooten, and other movement disorders specialists I am learning
from, have exactly the views I presented. Experts in the field no longer
believe that selegiline is neuroprotective in PD. I am glad you agree on
this.
-------------------------
>
> Here above is again is the abstract I posted in my last message, which you
> ignored like most others I have posted. Please respond to it in
> detail.Specifically, please explain why this research does not support my
> contention that selegiline is neuroprotective *in general* -- setting
aside
> for the moment any specific contradictions that might be present in the PD
> literature. (Perhaps PD is not a good model for general life-extension
> purposes. After all neither you nor I have clinical PD (I hope) -- and as
> stated in the header this discussion is really about performance
enhancement
> with selegiline for normal transhumanist folks like you and me.)
### Now, as far as I remember, I never claimed that selegiline cannot be in
some regimens neuroprotective - my argument was strictly regarding the
neuroprotection in PD. Whether this drug is neuroprotective in tissue
culture, or in lab animals, or whether some dosing regimen (different from
the one tested in DATATOP) confers a clinical benefit, I do not know.
In general, in vitro evidence can only be treated as a suggestion to start a
clinical trial, never as proof of clinical efficacy. If all that works in
the Petri dish or in a rat worked in humans, our life expectancy would be
two hundred years already. There are huge differences between what is
happening in your brain and in culture - these are different cells, in a
different medium, different oxygen concentration, their gene expression
patterns differ from the originals, there are significant interspecies
differences in anti-oxidant properties, and in susceptibility to
transformation, mostly they are actively dividing cells without the same
pattern of network connections, basically, comparing apples and oranges.
Of course, since we have difficulty with looking at the brain in situ, we
have to use model systems, but always with the understanding that the final
arbiter of usefulness is the clinical trial.
-------------------------
>
> I'd like to think you are not so closed-minded, Rafal. You have often
> criticized me for such, yet on this matter you are speaking from the same
> conservative perspective as do those who criticize the entire subject of
> anti-aging medicine -- your hard-line skepticism about this subject is
> hardly in the spirit of transhumanism or extropianism.
### You don't get much extropy from touting expensive medicines that work
only in rats but fail in clinical trials. I am full of hope and eager to see
progress in neuroprotection, in fact, this is the very subject of my own
research, to try to understand the mechanism of mitochondrial impact on the
death of neurons in PD and AD, but it is a hope tempered by a hard-nosed
skepticism - I see cool ideas that never pan out daily. One of the other
projects my group is working on now might actually lead to replacement of
damaged mitochondrial DNA - if..., if... if..., and I can see a lot of
reasons why it might fail. Maybe it will advance us into and era of
transhuman mitos, maybe not. .
--------------------------
>
> Note that the abstract is dated 1999, far more recent than the study that
> you've stated is "the last word."
>
> Tell us why we should not accept this research as valid.
### It's valid in its own right - as a suggestion for more basic research,
but not for popping pills.
Rafal
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