From: gts (gts_2000@yahoo.com)
Date: Wed Jan 29 2003 - 13:20:47 MST
Rafal Smigrodzki wrote:
> gts wrote:
> >
> > There is a tremendous amount of favorable research into deprenyl for
> > various purposes. It increases lifespan in mice and dogs (and humans,
> > hopefully).
>
> ### Hopefully?
Yes, "hopefully," in the same way that CR works in humans, "hopefully."
Unfortunately there have been no controlled studies on healthy humans in
this area, but the animal studies are reason to have hope.
> It's also an excellent antidepressant, especially when
> > taken with DL-phenylalanine and B-6 (it increases levels of the
> > natural mood enhancer phenylethylamine, and selectively inhibits the
> > MAO-B enzyme that breaks down dopamine)
>
> ### How does it compare to MAOI's?
It *is* a MAOI, but a unique and selective one. See below.
> It's not a coincidence that MAOI's are third-line antidepressants - they
are
> too risky and not sufficiently effective compared to SSRI's, TCA's, and
> atypicals.
Selegiline, is as I wrote, a *selective* inhibitor of MAO-B. There are two
MAO enzymes, MAO-A and MAO-B. Conventional MAOI's inhibit both enzymes, and
it is the inhibition of MAO-A that creates risks (MAO-A is necessary for the
breakdown of tyramine, an amino acid found in certain foods like aged
cheeses. Excessive levels of tyramine can lead to hypertensive crises, so
those who take conventional MAOI's must watch their diet.) Selegiline at
modest dosages inhibits only MAO-B and requires no dietary restrictions.
> . It enhances libido. It is
> > neuroprotective; it almost certainly prevents or delays the onset of
> > parkinson's disease in addition to being a treatment for it.
>
> ### Quote some studies giving us the "almost certain" feeling.
Parkinson's Disease (PD) is characterized by the death of dopaminergic
neurons. Numerous studies show that selegiline protects those neurons. In
animal models of PD, the neurotoxin MPTP is used to cause PD. Selegiline
protects against MPTP and numerous other neurotoxins and excitotoxins. It
may also delay or prevent the onset of Alzheimer's Disease.
Here are a few of many, many studies concerning the neuroprotective effects
of selegiline:
--- Neuroprotective actions of selegiline. Ebadi M, Sharma S, Shavali S, El Refaey H. Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203 . mebadi@medicine.nodak.edu J Neurosci Res 2002 Feb 1;67(3):285-9 Abstract Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B. Selegiline delays the onset of disability in de novo parkinsonian patients.--a novel mechanism of action? Muller T, Kuhn W, Kruger R, Przuntek H Department of Neurology, St. Josef-Hospital, University of Bochum, Federal Republic of Germany. J Neural Transm Suppl 1998;52:321-8 Abstract In clinical studies the MAO-B inhibitor selegiline appears to slow the progression of neurological deficits in Parkinson's disease (PD) and the cognitive decline in Alzheimer's disease (AD). The mechanisms of action remain unclear. Several lines of evidence indicate an immune-mediated pathophysiology of PD and AD. According to animal trials, selegiline increases the survival rate of immune suppressed mice. Stimulation of the immune response to bacterial or viral infection or in chronic inflammatory processes in managed by an increased synthesis of the cytokines interleukin-1 beta (IL-1 beta) and subsequent interleukin-6 (IL-6). Outcome of viral or bacterial infections in the brain highly correlates with levels of the cytotoxic cytokine tumor-necrosis-factor-alpha (TNF). The aim of our study was to characterize the influence of selegiline on the biosynthesis of IL-1 beta, IL-6 and TNF in human peripheral blood mononuclear cells (PBMC) from healthy blood donors. After isolation and washing PBMC were cultured without and with selegiline in three different concentrations (0.01 mumol/l, 0.001 mumol/l, 0.0001 mumol/l) in a humidified atmosphere (7% CO2). Then cultures were centrifuged and supernatants were collected for IL-1 beta, IL-6 and TNF ELISA-assays. Treatment of cultured PBMC with various concentrations induced an increased synthesis of IL-1 beta (ANOVA F = 9.703, p = 0.0007), IL-6 (ANOVA F = 20.648, p = 0.0001) and a reduced production of TNF (ANOVA F = 3.770, p = 0.040). These results indicate, that the influence of selegiline on the cytokine biosynthesis may also contribute to its putative neuroprotective properties. The pharmacology of (-)deprenyl Birkmayer J J Neural Transm Suppl 1986; 22:75-89 ABSTRACT (-)Deprenyl (Selegilinum hydrochloricum, Jumex, Eldepryl) developed in the early sixties as a new spectrum, potent, irreversible MAO blocker (Knoll et al., 1965) was introduced as the first selective inhibitor of B-type MAO (Knoll and Magyar, 1972). In striking contrast to MAO inhibitors which strongly potentiate the pressor effect of tyramine, (-)deprenyl was described to inhibit the tyramine-induced release of noradrenaline in vascular smooth muscle (Knoll et al., 1968). The peculiar pharmacological spectrum of (-)deprenyl allowed its use as an adjuvant to the levodopa therapy of Parkinson's disease (for review see Birkmayer and Riederer, 1985). Levodopa therapy revolutionized the medication of Parkinson's disease, but severe side-effects forced the search for adjuvants with a levodopa-sparing effect. Peripheral decarboxylase inhibitors are now efficiently used for this purpose. It was reasonable to expect further potentiation and prolongation of the effect of levodopa in parkinsonians with concurrent administration of MAO inhibitors. A number of irreversible inhibitors of this type were tested in combination with levodopa, and potentiation of the antiakinetic effect of the latter was demonstrated; however, the supervention of distressing side-effect (greatly increased involuntary movements, hypertensive reactions, toxic delirium) terminated any further work along this line. There was a concensus that to give MAO inhibitors concurrently with levodopa was contra-indicated. This conclusion was called in question, however, by the development of deprenyl. (-)Deprenyl is a safe MAO inhibitor which can be given concurrently with levodopa and a peripheral decarboxylase inhibitor for the long run without the supervention of any distressing side-effects. For details regarding the pharmacology of (-)deprenyl we refer a number of reviews (Knoll 1976, 1978, 1980, 1982, 1983, 1986). The aim of this paper is to give a brief survey of the most important experimental data which demonstrate that (-)deprenyl facilitates dopaminergic tone in the brain in a peculiar manner and gives a satisfactory explanation for the observation that long-term (-)deprenyl treatment prolongs the life span of Parkinsonian patients significantly (Birkmayer et al., 1985). L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro Mytilineou C, Radcliffe P, Leonardi EK, Werner P, Olanow CW Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. J Neurochem 1997 Jan; 68(1):33-9 ABSTRACT L-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that delays the emergence of disability and the progression of signs and symptoms of Parkinson's disease. Experimentally, deprenyl has also been shown to prevent neuronal cell death in various models through a mechanism that is independent of MAO-B inhibition. We examined the effect of deprenyl on cultured mesencephalic dopamine neurons subjected to daily changes of feeding medium, an experimental paradigm that causes neuronal death associated with activation of the NMDA subtype of glutamate receptors. Both deprenyl (0.5-50 microM) and the NMDA receptor blocker MK-801 (10 microM) protected dopamine neurons from damage caused by medium changes. The nonselective MAO inhibitor pargyline (0.5-50 microM) was not protective, indicating that protection by deprenyl was not due to MAO inhibition. Deprenyl (50 microM) also protected dopamine neurons from delayed neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory effect on NMDA receptor binding, it is likely that deprenyl protects from events occurring downstream from activation of glutamate receptors. As excitotoxic injury has been implicated in neurodegeneration, it is possible that deprenyl exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic damage.
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