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Registered: 02/03/03
Posts: 89
Last seen: 11 years, 7 months
Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4
    #3587865 - 01/06/05 08:32 AM (13 years, 5 months ago)

http://scholar.google.com is a useful tool for a global search in scientific publication

databases. The interesting thing is that you can find things that are not available at the

standard search tools (like Pubmed). I searched for publications on the chemistry of Sceletium

Tortuosum (KANNA) and found something that is highly interesting for the potential users of

this plant (at least that subset that has some interest in neurochemistry).

M Napoletano, C Fraire, F Santangelo, E Moriggi - View as HTML
... PDE4 is a cAMP-specific phosphodiesterase highly expressed in inflammatory cells ...
struck by the chemical similarities between the sceletium alkaloid mesembrine ...

This is a preprint of a publication and it seems like this text never got published

officially. The main information that is of interest to us: Mesembrine, one of the active

compounds in Sceletium has a strutural similarity to pharmaceuticals that inhibit the enzyme

PDE4 (phosphodiesterase 4). PDE inhibitors are a very interesting class of pharmaceuticals.

Besides other uses, they might be of interest as novel antidepressants. It also seems

that this publication confirmed the activity of mesembrine as an inhibitor of PDE4, but this

is not really clear (at least for me).

The current consensus ist that Sceletium acts as a short term selective serotonin reuptake

inhibitor (SSRI). This is based on some obscure sources and unpublished data and is in my

opinion quite doubtful. The hypothesis of PDE4 inhibition as a mechanism of action is at least

as plausible, if not more so.

Some info about the psychological effects of the PDE4 inhibitor rolipram:

Link to the Google cache of the publication:

Edited by heidegger (01/06/05 08:42 AM)

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Registered: 08/16/02
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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: heidegger]
    #3587887 - 01/06/05 09:06 AM (13 years, 5 months ago)

Very interesting  :thumbup:

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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: heidegger]
    #3588290 - 01/06/05 11:27 AM (13 years, 5 months ago)

What is PDE4?

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Ethno Apprentice
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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: Gumby]
    #3588315 - 01/06/05 11:33 AM (13 years, 5 months ago)


Gumby said:
What is PDE4?

ya lol iv never fuckin heard of it.


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[_381_] gnemo

Registered: 12/11/02
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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: Gumby]
    #3609791 - 01/10/05 10:15 PM (13 years, 5 months ago)

...it's probably a receptor sight in a certain part of the brain.

Eco friendly extraction is the only way to go for Dmt, mescaline, and iboga

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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: heidegger]
    #3611637 - 01/11/05 09:13 AM (13 years, 5 months ago)


heidegger said:
the enzyme PDE4 (phosphodiesterase 4).

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Registered: 02/03/03
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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: YidakiMan]
    #3741282 - 02/06/05 05:36 PM (13 years, 4 months ago)

After downloading the .pdf - version of the article and re-reading it I have become 99% sure that the Sceletium alkaloiods act as phosphodiesterase inhibitors (and propbably not as SSRI) in a way comparable to rolipram. The significance of this can hardly be overestimated! If this holds true than sceletium is much more than a short-lived mood brightener. It could be used as a real antidepressant, as a medication in multiple sclerosis, Alzheimer's, asthma, inflammation, as a nootropic and much more.
All of these uses have been documented for PDE inhibitors, but pharmaceutical preparations seem to be hardly available. The advent of a natural PDE inhibitor that has a historical use is really surprising.

This information does not deserve to linger around in a pre-print chemistry archive. If I find the time I will write a short review about the pharmacology and phenomenology of psychological effects induced by sceletium and how the hypothesis of phosphodiesterase inhibition fits in.

If this is really true, we will soon see a dramatic increase in the scientific and public interest in this plant.


May I add some scientific abstracts to inform or at least impress:

Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory.

Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E.

Center for Neurobiology and Behavior, Columbia University, 722 West 168th Street, New York, NY 10032, USA.

In an attempt to improve behavioral memory, we devised a strategy to amplify the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple high-frequency trains of electrical stimulation induce long-lasting long-term potentiation, a form of synaptic strengthening in hippocampus that is greater in both magnitude and persistence than the short-lasting long-term potentiation generated by a single tetanic train. Studies using pharmacological inhibitors and genetic manipulations have shown that this difference in response depends on the activity of cAMP-dependent protein kinase A. Genetic studies have also indicated that protein kinase A and one of its target transcription factors, cAMP response element binding protein, are important in memory in vivo. These findings suggested that amplification of signals through the cAMP pathway might lower the threshold for generating long-lasting long-term potentiation and increase behavioral memory. We therefore examined the biochemical, physiological, and behavioral effects in mice of partial inhibition of a hippocampal cAMP phosphodiesterase. Concentrations of a type IV-specific phosphodiesterase inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocampal slices to stimulation with forskolin and induced persistent long-term potentiation in CA1 after a single tetanic train. In both young and aged mice, rolipram treatment before training increased long- but not short-term retention in freezing to context, a hippocampus-dependent memory task.

Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment.

Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O.

The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.

Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.

Maxwell CR, Kanes SJ, Abel T, Siegel SJ.

Stanley Center for Experimental Therapeutics in Psychiatry, Division of Neuropsychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.

OVERVIEW: All current antipsychotic medications work by binding to Gi-coupled dopamine (DA) D2 receptors. Such medications are thought to affect cellular function primarily by decreasing DA-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP).However, several studies indicate that cAMP signal transduction abnormalities in schizophrenia may not be limited to D2-containing cells. The current study examines the potential of using non-receptor-based agents that modify intracellular signal transduction as potential antipsychotic medications. METHODS: The indirect DA agonist amphetamine has been used to model the auditory sensory processing deficits in schizophrenia. Such pharmacologically induced abnormalities are reversed by current antipsychotic treatments. This study examines the ability of the phosphodiesterase-4 inhibitor, rolipram, to reverse amphetamine-induced abnormalities in auditory-evoked potentials that are characteristic of schizophrenia. RESULTS: Rolipram reverses amphetamine-induced reductions in auditory-evoked potentials. CONCLUSION: This finding could lead to novel approaches to receptor-independent treatments for schizophrenia.

Phosphodiesterase type IV inhibitors prevent ischemia-reperfusion-induced gastric injury in rats.

Kyoi T, Kitazawa S, Tajima K, Zhang X, Ukai Y.

Research Laboratories, Nippon Shinyaku Co., Ltd., Kisshoin, Minami, Kyoto 601-8550, Japan. t.kyoi@po.nippon-shinyaku.co.jp

The effects of selective inhibitors of phosphodiesterase type IV (PDE4) on ischemia-reperfusion-induced gastric injuries were investigated in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery, and reoxygenation was performed by removal of the clamp. Ischemia-reperfusion produced gastric hemorrhagic injuries and increased the content of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) activity in gastric mucosa. Rolipram (0.03-0.3 mg/kg, s.c.) and Ro-20-1724 (0.3-3 mg/kg, s.c.) prevented the development of gastric injury in a dose-dependent manner, and it also inhibited the increase in mucosal TNF-alpha content and MPO activity induced by ischemia-reperfusion. The anti-ulcer drug irsogladine (1-10 mg/kg, p.o.), which is known to possess a PDE4 inhibitory action, also inhibited the gastric injury produced by ischemia-reperfusion, as well as the increase in TNF-alpha levels and MPO activity. It is concluded that the ability of PDE4 inhibitors to inhibit cytokine TNF-alpha synthesis and the infiltration of polymorphonuclear leukocytes underlies their gastroprotective effects in ischemia-reperfusion-induced gastric injury. Our experiments suggest that drugs that inhibit PDE4 isoenzyme, such as the anti-ulcer drug irsogladine, may be a useful adjunct therapy for the treatment of the gastric damage that follows ischemia-reperfusion.

Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats.

Itoh T, Tokumura M, Abe K.

Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan. tetsuji.itoh@shinonogi.co.jp

The brain cAMP regulating system and its downstream elements play a pivotal role in the therapeutic effects of antidepressants. We previously reported the increase in activities of phosphodiesterase 4, a major phosphodiesterase isozyme hydrolyzing cAMP, in the frontal cortex and hippocampus of learned helplessness rats, an animal model for depression. The present study was undertaken to examine the combination of effects of rolipram, a phosphodiesterase 4 inhibitor, with imipramine, a typical tricyclic antidepressant, on depressive behavior in learned helplessness rats. Concurrently, cAMP-response element (CRE)-binding activity and brain-derived neurotrophic factor (BDNF) levels related to the therapeutic effects of antidepressants were determined. Repeated administration of imipramine (1.25-10 mg/kg, i.p.) or rolipram (1.25 mg/kg, i.p.) reduced the number of escape failures in learned helplessness rats. Imipramine could not completely ameliorate the escape behavior to a level similar to that of non-stressed rats even at 10 mg/kg. However, repeated coadministration of rolipram with imipramine (1.25 and 2.5 mg/kg, respectively) almost completely eliminated the escape failures in learned helplessness rats. The reduction of CRE-binding activities and BDNF levels in the frontal cortex or hippocampus in learned helplessness rats were ameliorated by treatment with imipramine or rolipram alone. CRE-binding activities and/or BDNF levels of the frontal cortex and hippocampus were significantly increased by treatment with a combination of rolipram and imipramine compared to those in imipramine-treated rats. These results indicated that coadministration of phosphodiesterase type 4 inhibitors with antidepressants may be more effective for depression therapy and suggest that elevation of the cAMP signal transduction pathway is involved in the antidepressive effects.

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery.

Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT.

Biology Department, Hunter College, City University of New York, New York, NY 10024, USA.

Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.

PDE4 inhibitors in COPD--a more selective approach to treatment.

Vignola AM.

Instituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Ospedale V. Cervello, IT-90146, Palermo, Italy. vignola.m@iol.it

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.

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Registered: 02/03/03
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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: heidegger]
    #3741364 - 02/06/05 05:59 PM (13 years, 4 months ago)

To make things a little clearer for people that do not know what a phosphodiesterase does in the context of neuronal tissue:

Nerve cells communicate via synapses. One nerve cells emits neurotransmitters on the presynaptic side, and the other nerve cell binds these transmitters on the postsynaptic side. Thereby, signals are transmitted from the first nerve cell to the second nerve cell. Most psychotropic pharmaceuticals alter this conduction from the presynaptic to the postsynaptic side by mimicking the transmitter.

However, it does not stop with the binding of the transmitter at the postsynaptic side. Now the secondary messengers come into play. While the transmitters travel OUTSIDE of the cell, the secondary messengers float around INSIDE of the postsynaptic cell.

The binding of the transmitter at the postsynaptic side triggers some enzymatic cascades that hand the transduced information over to the secondary messengers, which in turn trigger some cellular mechanisms in the nerve cell.

One prominent secondary mesenger is cAMP (cylcic AMP). Intracellular cAMP levels at the synapse rise in response to the binding of neurotransmitters and stay elevated until cAMP is degraded by enzymes, the PHOSPHODIESTERASES.

When phosophodiesterases are inhibited, levels of cAMP remain higher and the cellular response to neurotransmitters is increased.

That's it. Was that comprehensible?

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Re: Pre-Print Publication: Sceletium (Mesembrine) is an inhibitor of PDE4 [Re: heidegger]
    #3742453 - 02/06/05 10:24 PM (13 years, 4 months ago)

Great article. Thanks for the read.

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