Deprenyl (Selegiline Hcl)

[The Anonymizer]

Can Deprenyl (Selegiline) Extend Human Lifespan?

by Ben Best

Several years ago L-deprenyl (selegiline) was the darling drug of life-extensionists. Some negative Parkinson's Disease studies then caused Deprenyl to fall into disrepute among both life-extensionists and conventional gerontologists. But recent studies merit a re-evaluation of deprenyl by life extensionists. And there are good reasons why the negative Parkinson's Disease studies which have discouraged gerontologists should be considered irrelevant for lifespan increase.
In 1988 Dr. Joseph Knoll -- Professor and Chairman of the Department of Pharmacology at Semmelweis University of Medicine in Budapest, Hungary -- published a paper [*1] reporting that with L-deprenyl (now often called selegiline) he more than doubled the remaining life expectancy of 24-month old rats from 36 to 50 months. A few years later, a Canadian group reported [*2] that the same dosage of deprenyl (the equivalent of 10 mg/day for a 170-pound person) used by Knoll had extended the remaining life expectancy of 24-month old rats by 16%.
The reasons for this discrepancy may be because the Canadians had used Fischer-344 rats which have a life expectancy of 28 months. Dr. Knoll in demonstrating a doubling of life spans had used Wistar-Logan rats that live 36-months. The Fischer-344 rats used by the Canadians had been within 4 months of the end of their lives.
In 1992 the Japanese researcher K.Kitani doubled the dose of deprenyl used by the previous researchers to 0.5mg/kg in a lifespan study on Fischer-344 rats beginning at 18 months and 24 months. Although average lifespan was increased 15% and 34% respectively, no increase in maximum lifespan was seen [*3]. Knoll attributed these failures to achieve his own dramatic results to the use of the short-lived Fischer rats and to the excessively high dose of deprenyl [*4]. At the 2004 American Aging Association Conference Kitani reported that he had halved the dose to the standard 0.25mg/kg/injection (3 times per week) and increased mean life span 44% for females and 32% for females starting from 24 months. Nonetheless, no significant increase in maximum lifespan was seen.
Deprenyl had been discovered in 1964 by Knoll and his associates. Currently, only the L-form (selegiline) of this drug is in widespread clinical use, primarily for its ability to inhibit the "B" form of MonoAmine Oxidase.
MonoAmine Oxidase (MAO) is an enzyme that functions in the brain to break-down (inactivate) neurotransmitters. The "A" form, MAO-A, is found in most neurons and is most effective for breaking-down the neurotransmitters serotonin, adrenalin & noradrenalin. MAO-B, by contrast, is found in non-neuron brain cells (glia cells called astrocytes) and is more effective in breaking-down the neurotransmitter dopamine.
Drugs that inhibit MAO-A are used as anti-depressants, whereas drugs that inhibit MAO-B are more effective as treatments for Parkinson's Disease. Reducing the breakdown of serotonin, adrenalin & noradrenalin with MAO-A inhibition not only reduces depression, but elevates blood pressure -- often an undesireable "side effect". Deprenyl will inhibit both MAO-A and MAO-B in dosages above 30-40 mg per day, so it was initially used as an anti-depressant at these dosages. But soon, deprenyl's selective inhibition of MAO-B at dosages below 20 mg/day made it a useful therapy for treating the chronic dopamine depletion of Parkinson's Disease -- without the blood-pressure elevation problems.
It is quite an unexpected result that a MAO-B inhibitor could double the remaining life expectancy of normal animals. But recent studies continue to affirm the ability of deprenyl to extend remaining lifespan (although not to the extent of doubling), of both laboratory animals and Alzheimer's Disease patients.
Using deprenyl dosages equivalent to 4 mg/day for a 170-pound person, middle-aged female Syrian hamsters experienced a 16% increase in maximum lifespan, but no effect was seen for males [*5]. One reason for the sexual divergence might be indicated by the fact that male Wistar rats have twice the P450 cytochrome enzyme in the liver as female Wisters.
Although it takes too many years to do lifespan studies on long-lived species, another experiment was conducted on elderly beagle dogs. The dogs were given the equivalent of 77 mg/day for a 170-pound person. 80% of the deprenyl dogs survived to the end of the experiment, whereas only 39% of the placebo dogs survived [*6].
Studies of deprenyl on Syrian hamsters and Fischer-344 rats have also demonstrated improved spatial learning and long-term memory [*7 & *8]. One study on Alzheimer's Disease patients showed a 15% improvement in behavioral symptoms with 10 mg/day deprenyl [*9]. Another study of Alzheimer's patients receiving 10 mg/day deprenyl showed an increase in median survival of 215 days as compared with placebo [*10]. A well-controlled study looking for a 20% difference on the Brief Psychiatric Rating Scale found failed to find that much difference between Alzheimer's patients and controls after 6&nbps;months on 10mg daily deprenyl [*11].
How does deprenyl extend lifespan? More pointedly, why would a substance that prevents dopamine breakdown result in extended youth? In fact, deprenyl not only inhibits MAO-A and MAO-B, but has a number of other independent actions that protect neurons (protecting the brain). It is only possible to guess, but as the ultimate regulator of hormones and the immune system the brain can exert its effect on every cell in the body. A youthful brain may be the key to a youthful body.
Part of deprenyl's protection of brain cells comes through the inhibition of MAO-B. Over 80% of the dopamine in the human brain is in the basal ganglia. MAO-B in the basal ganglia is inhibited more than 90% by 10 mg/day of deprenyl -- resulting in a 40-70% increase in dopamine. MAO-B inhibition reduces degredation of phenylethylamine even more effectively than it inhibits dopamine degredation. Phenylethylamine stimulates release of dopamine and serotonin, besides acting as a direct stimulant on dopamine receptors [*12]
The breakdown products of dopamine resulting from MAO-B degradation are hydrogen peroxide, ammonia and an aldehyde. Aldehydes are highly reactive compounds that can modify proteins. Ammonia is also toxic, particularly to glia (non-neuron brain cells). Hydrogen peroxide in the presence of ferrous iron ion can lead to hydroxyl radicals, the most toxic of all free radicals. Hydrogen peroxide can easily pass into the cell nucleus where it can encounter iron ions to produce hydroxyl radicals that damage and mutate DNA. (Carnosine, which has been shown to reduce cellular senescence, also inhibits MAO-B free radical generation.)
Besides causing MAO-B inhibition, deprenyl can increase the formation of the natural anti-oxidant. enzymes SuperOxide Dismutase (SOD) and catalase in the substantia nigra, striatum and cerebral cortex regions of the brain. Joseph Knoll has contended that it is this effect of deprenyl, rather than MAO-B inhibition, which results in lifespan extension. Most deprenyl lifespan studies have been conducted on rats, whose brains (unlike those of humans) use MAO-A, rather than MAO-B, to metabolize dopamine. So inhibition of MAO-B metabolism of dopamine seems unlikely to be the mechanism by which deprenyl extends a rat's lifespan.
The dose of deprenyl for the induction of antioxidant enzymes is highly dependent upon the strain, age, sex and species of animal. The equivalent of 75 mg/day for a 170-pound person produced optimal superoxide dismutase induction in old C57BL male mice [*13] and female beagle dogs [*14]. Female Fischer-344 rats achieve maximum induction at the equivalent of 15 mg/day for a 170-pound person. SOD & catalase activity is less for larger or smaller doses -- meaning 15 mg/day is optimal. The optimal dose for male Fischer-344 rats is ten times greater -- the equivalent of 150 mg/day for a 170-pound person. Old female Fischer-344 rats, on the other hand, do best with the equivalent of about 75 mg/day. Dosages of the equivalent of 150 mg/day significantly decrease the activity of glutathione peroxidase in both old and young female Fischer-344 rats [*15]. Without glutathione peroxidase (or enough catalase) to eliminate hydrogen peroxide, SOD conversion of superoxide to hydrogen peroxide can lead to the formation of the deadly hydroxyl radical.
The fact that both too much or too little deprenyl can reduce its anti-oxidant effect -- and the fact that optimum dose varies so greatly with strain, age, sex and species -- makes the prediction of optimal dosages for human beings on the basis of animal studies very difficult.
DNA repair capability has been positively correlated with maximum lifespan for many species and many "accelerated aging diseases" are associated with DNA repair defects. DNA damage also correlates with neurodegenerative disease. DNA repair is facilitated by the enzyme Poly(ADP-Ribose) Polymerase-1 (PARP-1) . Deprenyl has been shown to increase PARP-1 expression in hamster cells subjected to gamma-radiation, suggesting an additional possible mechanism for deprenyl in neuroprotection and lifespan extension [*16].
Whether or not deprenyl is a "wonder drug", the multiplicity of its effects are certainly a cause for wonder. In the 1990 Canadian lifespan study [*2] it was noted that the control animals had significantly higher Blood Urea Nitrogen (BUN), indicative of deprenyl's protection of the kidney. Deprenyl protects neurons from hypoxia/ischemia damage [*17]. Deprenyl increases cell levels of the natural anti-oxidant enzyme superoxide dismutase by direct alteration of gene/protein transcription/synthesis. By the same kind of direct action on DNA, deprenyl also increases nerve growth factors, proteins halting "cell suicide" (apoptosis) and other proteins involved in protecting neurons -- 40 or more such genes in all [*18].
At least two studies have shown that deprenyl could be of value in reducing ischemic damage in the brain. A study involving 14 days of deprenyl on rats [*19] and 20 minutes of hypoxia/ischemia showed reduction of area of damage of 75% in the forebrain and about 20% in the cortex. For the hippocampus, 30-38% of the area was damaged in controls, but no damage was seen in the depenyl-treated rats. A similar study on gerbils [*20] showed reduced damage to the CA1 area of the hippocampus for deprenyl given more than a week before, immediately after and more than a week after ischemia due to vessel occlusion. Cell cultures exposed to peroxynitrite have been protected from apoptotic DNA damage by deprenyl [*21].
Understanding the role of deprenyl in the treatment of Parkinson's Disease is important for life-extensionists because of the controversy surrounding the question of whether deprenyl protects neurons in a clinical setting or merely treats symptoms. A great deal of research has gone into attempting to answer this question.
Parkinson's Disease is the second most common neurodegenerative disease (after Alzheimer's Disease). It affects about 2% of the population. The neurodegeneration in this case is very selective -- it is the dopamine-producing neurons in the pars compacta of the substantia nigra ganglion that degenerates. To compensate for the loss, dopamine receptors in the striatum of the brain increase in number -- and dopamine turnover & release accelerates. But when dopamine in the striatum is depleted to 20% the original level, compensation has reached its limit and symptoms of Parkinson's Disease appear. Levodopa can be used by brain cells to synthesize dopamine, which can alleviate Parkinsonian symptoms, but the degeneration continues. Within 5-10 years from the start of treatment the effectiveness of levodopa begins to fail, while side-effects become intolerable.
There is ample evidence that the neuron degeneration in the substantia nigra is due to free-radical oxidation. Most studies indicate a 30-40% increase of iron in the substantia nigra of Parkinson patients. Aluminum -- which can displace iron bound to protein and thereby increase reactivity -- is also increased. Although Parkinson symptoms can be induced in laboratory animals by injecting iron into the substantia nigra, this does not prove that iron-accumulation is what ultimately causes Parkinson's Disease.
Reduced glutathione levels are lower in the substantia nigra in Parkinsonism, and there is evidence that this depletion occurs earlier than the increase in iron. Depletion of reduced glutathione may itself be subsequent to a prior cause. That oxidation contributes significantly to neurodegeneration may still not answer the question of what begins the whole process.
Two large clinical trials, both consisting of about 800 Parkinson patients, have served as a focus for the role of deprenyl as a neuroprotective agent in clinical practice. The first of these trials was DATATOP (Deprenyl And Tocopherol Antioxidant Therapy Of Parkinsonism), a randomized, double-blind study at 28 US and Canadian sites that tested the effectiveness of 2000 IU/day Vitamin E and 10mg/day deprenyl in delaying the need for levodopa therapy in early-stage Parkinson patients.
Vitamin E was never shown to be of any benefit in Parkinsonism. But the first released results announced that deprenyl had delayed the need for levodopa therapy by a factor of 57% [*22]. A subsequent publication of DATATOP results [*23] was less enthusiastic. It acknowledged that at least part (and perhaps all) of the delayed need for levodopa was due to deprenyl relieving symptoms (substituting for levodopa), while the underlying neurodegeneration continued. A claim was made for neuroprotection, but the study design could not prove such protection. After a few more years of patient follow-up, the conclusions ceased to be positive at all: "deprenyl does not provide an advantage in preventing or postponing complications from levodopa therapy" and "by the end of the study, subjects receiving the different treatments had comparable degrees of parkinsonian disability and were taking comparable amounts of levodopa" [*24 & *25].
The second large clinical trial, the PDRG-UK (Parkinson's Disease Research Group of the United Kingdom) contained a more devastating indictment of deprenyl: after 5-6 years follow-up, patients taking a combination of levodopa with deprenyl had a 57% greater chance of dying than patients taking levodopa alone [*26]. A storm of protest arose in the medical community [*27 & *28]. The results were counter to those found in nearly all previous studies. Pooled results from many small studies showed opposite results from those of PDRG-UK, namely slightly reduced mortality with deprenyl. The PDRG-UK trials had not been blinded at all, patients knew their medications and could change groups at will. Nearly 50% of the subjects had dropped-out completely. The most seriously afflicted patients could have been the ones most earnest about receiving both medications. The fact that deprenyl was only used in combination with levodopa opens the possibility of levodopa/deprenyl and levodopa/deprenyl/Parkinson's Disease interactions which might not be relevant to life-extensionists taking deprenyl.
Unlike other studies, PDRG-UK trial participants had not been excluded on grounds of excess age, other diseases or other medications being taken. The PDRG-UK patients receiving levodopa alone had death rates over 3 times as great, and the levodopa/deprenyl patients had death rates over 5 times as great, as the non-deprenyl and deprenyl-treated patients (respectively) in the pooled results of 7 other controlled long-term studies. In defense, A.J.Lees and other representatives of PDRG-UK wrote that these conditions more accurately reflect true clinical practice than trials that screen for participants more carefully [*29]. Lees and associates also stated that their study design was superior to that of DATATOP and several others because mortality rather than advent of levodopa therapy was chosen as the end-point. A better interpretation is probably that the PDRG-UK study was able to command authority by having so many patients, but should be regarded with suspicion because of the poor controls which allowed the study to become so large.
Although causes of death due to deprenyl had not been well identified in the PDRG-UK paper, a subsequent paper co-authored by A.J.Lees concluded that "Therapy with deprenyl and levodopa in combination may be associated with severe orthostatic hypotension not attributable to levodopa alone" [*30]. A more carefully designed study, which studied deprenyl alone, rather than in combination with levodopa, seemed to confirm a side-effect of orthostatic hypotension for Parkinson patients taking deprenyl [*31]. But the DATATOP study had reported "No significant treatment-related changes in blood pressure or pulse recordings" although a 2% incidence of non-life-threatening cardiac arrhythmias were reported for the deprenyl group [*23].
Two subsequent (smaller) clinical trials attempted to address the design flaws of DATATOP and PDRG-UK, both being double-blind, placebo-controlled. One used mortality as the end-point [*32] and the other used measures of physical disability [*33]. Both concluded that deprenyl has neuroprotective action in clinical use. In support of this conclusion is another study which found more neurons and fewer neuron inclusion-bodies in the substantia nigra of autopsied patients who had been taking deprenyl [*34].
Even if 10 mg/day deprenyl does lower blood pressure for some Parkinsonian patients, it is questionable how relevant this result is for people without neurodegenerative disease who are taking deprenyl in smaller doses for life-extension or cognitive-preservation purposes. Transient elevated blood pressure is more often encountered in such cases, which is why morning dosing is common. And it should not be forgotten that Parkinsonian patients have already lost over 80% of their substantia nigra neurons -- with the remaining neurons typically being in a degenerative state. Moreover, Parkinson's Disease also attacks other midbrain nuclei, including the locus coeruleus (which produces most of the brain's norepinephrine). With norepinephrine (and serotonin) at about 50% of normal levels, it is understandable that Parkinsonian patients might suffer from low blood pressure.
Life-extensionists have understandably had a difficult time trying to determine what dose would be optimal for a human seeking the life-extension and neuroprotective benefits of deprenyl. Dosages in excess of 20-30 mg/day could create high blood pressure problems by MAO-A inhibition. Dosages in the 10 mg/day range would reduce the oxidation stress of the breakdown products of dopamine metabolized by MAO-B, but the resulting elevated dopamine levels might not be desirable. Deprenyl binds to MAO-B irreversibly, and it takes 2 weeks for MAO-B levels to return to normal. A single 5 mg dose can cause 86% MAO-B inhibition within 2-4 hours. Inhibition remains at 90% for 5 days, and does not return to baseline for 2 weeks [*35]. Deprenyl induction of enzyme synthesis (including, presumably, anti-oxidant enzymes) can take place at levels below those required for MAO-B inhibition [*21].
Therefore, a dose in the range of 1 mg/day might be optimal for a 40-year-old 170-pound person. Twice-weekly dosing has been based on the fact that deprenyl binds MAO-B irreversibly. But more frequent dosing might be better for steady induction of enzyme synthesis.
Aside from body weight, age is a very important consideration. As a person gets older, neurons decrease in number while glial cells (which synthesize MAO-B) increase -- meaning that MAO-B levels increase with age. This may be the reason that dopamine content of the striatum (caudate nucleus) typically decreases by 13% per decade after age 45. A person over 45 would want to counteract the excessive MAO-B in a dose proportional to his or her age. This could mean up to 5 mg daily for an elderly person with no symptoms of Parkinson's Disease or Alzheimer's Disease. Deprenyl has been shown to produce vasodilation by rapid increase in nitric oxide production and to protect the vascular endothelium from the toxic effects of amyloid-beta peptide. Whether or not deprenyl can extend maximum lifespan, there is reason to believe that it can extend mean lifespan and protect from neurodegenerative disease. There may be considerable individual variation in what dose is optimal. Decisions based on incomplete information are never very satisfying, but such decisions are -- and will always be -- a condition of life.

[The Anonymizer]

Modulation of gene expression rather than monoamine oxidase inhibition: (-)-Deprenyl-related compounds in controlling neurodegeneration
Neurology (USA), 1996, 47/6 SUPPL. 3 (S171-S183)

(-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL- 2 and BCL-x(L), nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial 'signals' that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.



L-Deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro
Journal of Neurochemistry (USA), 1997, 68/1 (33-39)

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.



Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa
Annals of Neurology (USA), 1996, 39/1 (29-36)

In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 plus or minus 4 (mean plus or minus SD) months of observation or need early initiation of deprenyl (selegiline) during a 2-month withdrawal of experimental treatments. While maintaining the blindness of their original deprenyl and tocopherol treatment assignments, these 310 subjects were administered deprenyl 10 mg/day (open label) and were monitored systematically at 1- to 3-month intervals for up to 18 months (12 plus or minus 5 mo). During this extended trial, the 189 subjects who had been assigned originally to active deprenyl tended to reach the end point of disability faster than the 121 subjects who had not been assigned originally to deprenyl (hazard ratio, 1.43; 95% CI, 0.98, 2.09; p = 0.065). However, the differential rates of reaching the end point may have been due in part to the more severe baseline impairment of deprenyl-assigned subjects, who benefited originally from deprenyl but who were more likely to require levodopa during this extended period of observation. Prior treatment with deprenyl did not lead to superior survival with respect to the end point of disability requiring levodopa, suggesting that the initial advantages of deprenyl were not sustained.



Novel sites of action for deprenyl in MPTP-parkinsonism: Metabolite-mediated protection against striatal neurotoxicity and suppression of MPTP-induced increase of dopamine turnover in C57BL mice
Progress in Brain Research (Netherlands), 1995, 106 (155-171)

In the present study we provide further evidence for our recent finding that DEP has neuroprotective effects against dopaminergic toxicity of MPTP and its 2'-substituted analogs in mice, which are associated with the ability of its major metabolites, 1-methamphetamine and 1-amphetamine to block the neuronal uptake of the toxic pyridinium metabolites of MPTP and its analogs. Here we demonstrated that protection by a 30-min DEP posttreatment (10 mg/kg) against MPTP (40 mg/kg)-induced decrease of striatal dopamine level is reduced when mice received SKF 525A (25 mg/kg), an inhibitor of the metabolism of DEP 10 min prior to DEP treatment. For the first time, we demonstrated that a 30-min pre- or post-treatment with DEP (10 mg/kg) provided substantial protection against striatal dopamine depletion induced by 2'Et-MPTP (30 mg/kg), which is primarily bioactivated by MAO-A. A 30-min posttreatment with DEP (but not by pargyline or clorgyline), in addition to protection against dopamine depletion, also prevents the decrease in striatal mazindol binding (an indicator of the integrity of dopaminergic terminals) induced by MPTP (40 mg/kg), 2'Me-MPTP (15 mg/kg) or 2'Et-MPTP (30 mg/kg). A subacute DEP treatment of mice with severe injury in the terminal fields of the nigrostriatal dopaminergic system (80-90% loss of dopamine; 2-4-fold increase in dopamine turnover as reflected by higher metabolite/DA ratios) enhanced the recovery of striatal dopamine level and suppressed the MPTP-induced elevation of dopamine turnover. Deprenyl treatment was applied in a wide range of dose (0.01-20 mg/kg, i.p., eight times over 18 days from the 3rd day after the last MPTP injection) to mice that had received MPTP (30 mg/kg; i.p.) for 5 consecutive days. The effect of subacute DEP treatment on the recovery of striatal dopamine level was most pronounced at a cumulative dose of 0.8 mg/kg, indicating that higher dosage of DEP may be less beneficial.


In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striataI L-DOPA and dopamine metabolism
Journal of Neural Transmission - Parkinson's Disease and Dementia Section (Austria), 1995, 10/2-3 (79-89)

Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the 'cheese effect' such as Ro 41-1049 are comparable to the irreversible NAG-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.


Selegiline: A review of its clinical efficacy in Parkinson's disease and its clinical potential in Alzheimer's disease
CNS Drugs (New Zealand), 1995, 4/3 (230-246)

Selegiline (deprenyl) increases nigrostriatal dopamine levels by several mechanisms, including selective and irreversible inhibition of cerebral monoamine oxidase type-B. Through this mechanism it may also protect neurons against damage by free radicals and possibly exogenous neurotoxins. When used alone in patients with early Parkinson's disease, oral selegiline 5 mg twice daily initially reduces symptoms severity compared with placebo. During prolonged therapy, selegiline slows the rate of symptoms progression and delays the need for levodopa therapy by 6 to 9 months. The benefits of coadministration of selegiline with levodopa as de novo therapy in early Parkinson's disease compared with levodopa monotherapy remain unclear. Studies have shown either similar disease progression in both treatment groups after 3 years or significantly slowed disease progression and reduced levodopa requirement after 14 to 54 months in patients treated with both drugs compared with levodopa monotherapy. In patients with more advanced disease who have mild levodopa response fluctuations, concomitant selegiline allows a reduction in levodopa dosage. Improvements in overall disability and 'end-of-dose' fluctuations are observed, although benefits are rarely maintained for longer than a year. Improvements in cognitive function, behaviour and activities of daily living have been observed in patients with Alzheimer's disease following administration of selegiline 10 mg/day for up to 15 months, and the drug appeared to be more effective in this regard than 1-acetylcarnitine, oxiracetam and phosphatidylserine in single-blind studies. In addition, preliminary findings suggest that selegiline may have an additive effect when coapministered with cholinergic therapy. At the dosage recommended for Parkinson's disease and Alzheimer's disease, selegiline is not associated with the tyramine ('cheese') reaction. Thus, selegiline is a valuable treatment option for de novo therapy of patients with early Parkinson's disease, improving symptoms and postponing the need for levodopa therapy. Whether it also offers clinically significant neuroprotection remains unclear. Selegiline is a useful adjunct to long term levodopa therapy in patients with more advanced disease experiencing response fluctuations, and recent findings suggest that it may offer some clinical benefit to patients with Alzheimer's disease.


Clinical pharmacokinetics of drugs for Alzheimer's disease
Clinical Pharmacokinetics (New Zealand), 1995, 29/2 (110-129)

Pharmacological treatment of patients with Alzheimer's disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a miner route of elimination for this drug. Pharmacokinetic data pertaining to epiastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period. Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum. Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver; and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites in the cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier. Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment. Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion. To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.


Anticonvulsant and antiepileptogenic effect of L-deprenyl (selegiline) in the kindling model of epilepsy
Journal of Pharmacology and Experimental Therapeutics (USA), 1995, 274/1 (307-314)

L-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase type B, but also exerts several effects on dopamine and noradrenaline systems independent of monoamine oxidase type B inhibition. Thanks to these properties, L-deprenyl has gained wide acceptance in the therapy of Parkinson's disease by using L-deprenyl both with levodopa and alone. Furthermore, L-deprenyl improves the performance of patients with Alzheimer's disease. Epilepsy, particularly temporal lobe epilepsy with complex-partial seizures, is often associated with disturbances of cognitive function and behavior, and it has been suggested that a drug combining cognition-enhancing and antiepileptic activity would be of benefit in the treatment of epileptic patients. This prompted us to study if L-deprenyl exerts anticonvulsant efficacy in amygdala-kindled rats, i.e., a useful model of complex-partial seizures in humans. In addition to anticonvulsant activity, i.e., effects on already developed seizures, we determined whether L-deprenyl exhibits antiepileptogenic properties, i.e., suppressive effects on development of kindling. In all experiments, behavioral alterations of the rats in response to L-deprenyl were monitored closely. In order to assess the role of active metabolites in the anticonvulsant and behavioral effects of L-deprenyl in the kindling model, the D-enantiomer of deprenyl, which is metabolized to more potent compounds (D-amphetamine and D-methamphetamine) than the L- enantiomer, was used for comparison. In fully kindled rats, L-deprenyl potently increased the threshold for focal afterdischarges. The most marked increase in afterdischarge threshold (up to 250% above control) was seen after a dose of 10 mg/kg, whereas the D-enantiomer was ineffective at this dosage. In contrast to the lack of anticonvulsant activity, D-deprenyl was more potent than L-deprenyl to induce amphetamine-like behavioral adverse effects such as stereotypies, thus indicating that degradation to active metabolites is involved in the behavioral but not anticonvulsant effects of deprenyl. This was substantiated by the observation that increase of dosage of L-deprenyl to 20 or 40 mg/kg induced marked amphetamine-like adverse effects, whereas the anticonvulsant effect was reduced compared to lower doses. Chronic treatment with L-deprenyl during kindling acquisition did not prevent kindling, but significantly retarded the development of some kindling parameters. The present study is the first to demonstrate potent anticonvulsant effects of L-deprenyl. In view of the neuroprotective and cognition-enhancing effects of this drug, L-deprenyl might be of clinical benefit in patients with epilepsy.


What is it that l-deprenyl (selegiline) might do?
CLIN. PHARMACOL. THER. (USA), 1994, 56/6 II SUPPL. (781-796)

There have been many claims that l-deprenyl may have distinct properties in slowing and perhaps even in reversing the progression of Parkinson's disease and other neurodegenerative conditions. This article will consider the paucity of evidence that such is the case in humans and the more detailed results from studies with experimental animals indicating that deprenyl may indeed express such a property. The conflicting data on its mechanism of action are considered, and the concept that it may function to enhance neuronal fitness is advanced as an alternative to the neuroprotection and neurorescue hypotheses. Possible lines of experimental development that would help resolve some of the many unanswered questions regarding l-deprenyl function are outlined.


Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal
SYNAPSE (USA), 1994, 18/2 (86-93)

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L- Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.


Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons
J. NEUROL. SCI. (Netherlands), 1994, 125/1 (11-13)

Deprenyl, a selective monoamine oxidase B inhibitor, is effective in Parkinson's disease, and can slow the cognitive deterioration in Alzheimer's disease. However, it is not known whether this agent has a trophic effect on spinal motor neurons. We have studied neurotrophic effects of deprenyl on spinal motor neurons, using explanted ventral spinal cord culture from 13-day-old rat embryos. Deprenyl-treated cultures significantly enhanced neurite outgrowth with cultures of ventral spinal cord. Our data suggest that deprenyl is one of the candidate for neurotrophic factors on spinal motor neurons in vitro. A possible role for deprenyl in amyotrophic lateral sclerosis remains to be defined.


Effect of L-Deprenyl, its structural analogues and some monoamine oxidase inhibitors on dopamine uptake
NEUROPHARMACOLOGY (United Kingdom), 1994, 33/6 (763-768)

The effect on dopamine uptake by L-deprenyl, its structural analogues and different types of monoamine oxidase (MAO) inhibitors was investigated. Both direct (3H)dopamine uptake into rat striatal slices and binding of a specific dopamine uptake inhibitor (3H)GBR-12935 were used in the present study. L-Deprenyl exhibits a relatively weak dopamine uptake inhibitory effect in vitro, while D-deprenyl possesses a very potent inhibitory effect. The potent effect of D-deprenyl on dopamine uptake may be responsible, at least in part, for its behavioral effects and abuse liability. L-Methamphetamine, a metabolite of L-deprenyl, does not inhibit (3H)GBR-12935 binding but it reduces the retention of (3H)dopamine in striatal tissues, suggesting that it may enhance dopamine release. The MAO-A inhibitors clorgyline and brofaromine also exhibit dopamine uptake inhibitory effects. Irreversible and reversible MAO-B inhibitors, however, such as pargyline, aliphatic N-methylpropargylamines, Ro 19-6327 and MDL-72974A and MAO-A inhibitor moclobemide do not possess any appreciable inhibitory effects on dopamine uptake. Dopamine uptake is probably unrelated to the pharmacological actions of L-deprenyl.


Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat
NEUROCHEM. RES. (USA), 1993, 18/12 (1299-1304)

The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO- B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.


Monoamine oxidase (MAO): Relationships to foods, poisons and medicines
BIOG. AMINES (Netherlands), 1993, 9/5-6 (355-365)

Monoamine oxidase has an important role in metabolism of biogenic amines and in disposing of exogenous amines. As information about MAO and its inhibitors has unfolded, effects which are deleterious in some patients have proven therapeutically beneficial in other conditions. The central nervous system effects of an antituberculosis drug, iproniazid, led to its use as an antidepressant and to the discovery of MAO inhibitors. Understanding the role of MAO in noradrenergic neurons explained why orthostatic hypotension occurs in some patients treated with a MAO inhibitor and why MAO inhibitors found use as antihypertensive drugs. Reversal of the tranquilizing effects by MAO inhibitors was explained also. Differences among MAO inhibitors in their potency in precipitating hypertensive crises after ingestion of foods with high tyramine content was explained when subtypes MAO-A and MAO-B were defined. MAO-B inhibitors were not associated with these reactions to tyramine ingestion and were deemed 'safe'. MAO-B was found to be important for the bioactivation of MPTP to MPP+ which causes selective destruction of dopaminergic nigrostriatal neurons. In humans and in non-human primates, this results in a motor deficit almost identical to Parkinson's disease. The high levels of MAO-B in the endothelium of brain blood vessels appear to protect the brain of rats from MPTP toxicity. Trials of a 'safe' MAO-B inhibitor, deprenyl, for potentiating the antiparkinsonian effects of DOPA, suggested that this drug slowed the progression of Parkinson's disease. This observation and the demonstrated role of MAO-B in bioactivation MPTP were the bases for a large multicenter placebo-controlled clinical trial of deprenyl for treatment of early Parkinson's disease. The apparent success of this trial has stimulated searches for newer more effective agents to inhibit MAO-B and to retard the progression of degenerative diseases of the central nervous system.


Enhanced hydroxyl radical generation by 2'-methyl analog of MPTP: Suppression by clorgyline and deprenyl
SYNAPSE (USA), 1992, 11/4 (346-348)

Sodium salicylate was infused through a microdialysis probe placed in the striatum of anesthetized rats in order to assay the formation of hydroxyl radical (.OH) in the extracellular fluid in vivo. In addition to causing sustained dopamine release, intrastriatal infusion of the 2'-methyl analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), the nonenzymatic .OH adduct of salicylate in the brain dialysate. Inhibition of monoamine oxidase (MAO) by clorgyline and deprenyl completely blocked the formation of 2,3-DHBA and the sustained dopamine overflow induced by 2'-CH3-MPTP. The results indicate that the enhanced formation of cytotoxic .OH by 2'-CH3-MPTP is suppressed by MAO inhibitors. These data support the hypothesis that the protective effect of MAO inhibitors on the neurotoxicity induced by MPTP analogues may be due not only to the inhibition of MPTP metabolism by MAO but also the blockade of the formation of .OH free radicals. An enhanced generation of cytotoxic .OH free radicals in the striatum which in turn leads to oxidant damage may be relevant to the development of parkinsonism- like changes in animals produced by MPTP analogues.


A review of the pharmacology of selegiline
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1991, 84/136 (44-59)

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity of MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article



Neurochemical insights into monoamine oxidase inhibitors, with special reference to deprenyl (selegiline)
ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (43-55)

Monoamine oxidase (MAO) is distributed in neurons and nonneuronal tissue in the human central nervous system. It occurs there as MAO type A and MAO type B. It is not, however, established where both types are located intra- and/or extra-neuronally. Recently, the use of selective MAO-B blockers has shown beneficial effects in the treatment of Parkinson's disease (PD). Knowledge about the locus of action of MAO inhibitors is therefore of great importance. Our findings indicate that MAO-B inhibitors like deprenyl act by blocking neuronal and extra-neuronal MAO-B. This demonstrates that in the early stages of PD the action of deprenyl improves dopamine neurotransmission and hormonal action, whereas in the advanced stages of the disease, when there is progressive loss of dopaminergic neurons accompanied by gliosis, the drug seems to exert beneficial effects via the hormonal route.

[darwinmcduck]

Do you have to see a doctor in order to obtain this?

[Whitey]

This is a prescription medication in the US. But it can also be obtained as a research chemical. I know that IBE has it, and it has been quite effective on its test subjects.

[The Anonymizer]

Originally Posted by darwinmcduck

Do you have to see a doctor in order to obtain this?

overseas pharmacies are your best bet. check the Overseas Pharmacies forum in the Classifieds section

[neverfail]

Tremendous info! I use 5mg/d and it essentially cured my ADD. I also don't find myself as tempted to use durgs like ritalin or coke, which I was prone to do in the past.

Be Well...............nf

[danschn]

I dont want this to come out as being a dick but all of the research that was posted was atleast 10 years old.. I did also notice that there hasnt really been posts on this thread for a very long time either.

[danschn]

Just did a little research and I am very mistaken.. there is alot of current research about it. I apologize. I am suprised that I have never heard of it.. I am going to be a doctor in less than 6 months... its funny the stuff they really push and the shit that actually might help they leave out.

[UncleXNL]

Originally Posted by darwinmcduck

Do you have to see a doctor in order to obtain this?

Yes, you do, unfortunate.

But you're in luck. I'm a docter!!

And whats more I found that D-Deprenyl can increase human lif-span to a very large extent.

The terminal sickness "aging" can be prolonged, a huge amount.
I am currently finding a total cure for aging I thik it will cost me a few more months.

For now this is the best science has to offer.

Since we all suffer from aging, there is no risk in prescribing you some D-Deprenyl.

You will feel about 10 year younger 20 minutes after you take some. Of course as docter I wil send it to you with guid on how and when to use it, for best effectiveness.

Just send a mail to UncleXNL at hotmail dot com if you need some, I can send it over! From Europe, of course you pay a few expenses USD $15 + postage. It come in a 10ml. flask with pipette for easy dossage.

Mail me for info, if you want. Best quality you will find! The only you will find....

Uncle X PhD, MSc, MBA

[tilltheend]

great read ANON!