2626 replies to this topic

[gizmobrain]

I picked up a bottle of L-Carnosine from the local vitamin store, but I'm still waiting on my Catuaba (I actually had to cancel the order with the previous seller, Vitaglo, because they kept telling me they were going to ship, and never did for a week and a half).

It was pricey for an amino acid... so I'm hoping to get some pointers how to stack it. 500mg on an empty stomach with forskolin and quercetin? That's what I did this morning. I felt pretty clear headed, but not motivated to do much. I even laid back down and dozed off for 20 minutes. After about an hour of this, I drank a Monster Rehab. It helped nix the strong desire to lay around, but I still haven't gotten much done since then.

I am aware that increasing LTP is not directly correlated to motivation. Obviously, I'm not counting on the l-carnosine to mimic a powerful stimulant, but since I have the bottle, I want to make the most of it.

Edited by zrbarnes, 30 May 2012 - 08:50 PM.

[X_Danny_X]

How the hell is Quercetin a stronger PDE4 inhibitor than to Luotin (spelling)?


I am taking Depreny(Selegiline), ALCAR, Luotin, CRAZE Performance Fuel, Ashwanghanda, Melatonin, Fish Oil, Spirulina and Eggs.

[csrpj]

i'm following the hype on the CILTEP stack and looking to start one soon.

- my first question, would i feel the benefits after the first day and know if it works for me? if not, how long is that process?

- can i take both artichoke extract and quercetin as the PDE4I component, or do i need to choose one or the other?

- what about adding trans-resveratrol to the mix?

- additionally,it's being said that one should add a dopamine component? should i indeed, even if i eat good food regularly?

lastly, would any of the following supplements interfere (or synergize) with the stack? i'm considering also having (some of) these in my overall stack:
- Epimedium
- pycnogerol
- maca
- DIM
- reishi
- tongkat ali
- xiao yao wan

[middpanther88]

I've been on the CILTEP stack for 2 days. I'm not sure of the effects, but I know I definitely feel different, a good different. As everyone else said, it feels as if your brain feels more open, although I'm not sure if my overall cognition is necessarily better.

Edited by middpanther88, 01 June 2012 - 01:59 AM.

[summertimex]

i just took 2 artichoke and 1 10% forskolin. within an hour there were kind of like waves of "energizing heat" in my brain with like readjusting of energy levels, some aphrodisiasm, a slight darkening of skin tone that looks "natural" yet kind of "homogenizes" the complexion, a shifted sense of visual perception, overall pretty stable wave of "incandesant energy". mostly the effects are probably a buildup 2-3 weeks i assume. overall non-bothersome effects, and probably of overall good nutritional value. it is true that it is not an executive function type thing so far, not really a get up and go energy without dopamine, but it does feel "smooth". there is definetly an "inflation" type feeling, but not in the sense of CNS stimulants or MAOIs more like possible clear digits in the conscious-stream-of-thought area. Its definetly a bit more clear. well the more i think about it, the more i feel its effects, it seems to move with the state of awareness. i am noticing more details in sound, light reflection and it has a mild spatiotemporal "vastening" effect. i would describe it as a kind of "salvidor dali" effect.

Edited by gen6k, 01 June 2012 - 02:44 AM.

[X_Danny_X]

I am thinking of adding Cat's Claw since it is COMT Inhibitor. So I am thinking of adding Cat's Claw, Quercetin, Luteolin, and Forskolin.


Though if Quercetin is more powerful Luteolin, doesn't it make it better than Resevtrol as well?

Also someone posted about Luteolin reducing IGF 2, which is responsible for better memory. Is this correct?

[summertimex]

apparently it does. omega 3s actually reduce igf-1 temporarily, so its better not to take them before bed when most of the igf-1 happens. reservatrol is actually a phytoestrogen which downregulates androgens which then downregulate igf-1 in some fashion. luteolin was used in cancer studies though, so it should be of significant effect. though sometimes signalling is non-linear depending on body location/receptor type, so i dont know if its confirmed globally in the brain.

i would say this is a "nootropic" so far. i was able to close my eyes, quickly recall several historical scenes and assimilate that information in a slightly new way.

Edited by gen6k, 01 June 2012 - 03:34 AM.

[abelard lindsay]

Another interesting recent PDE4 Inhibiton study. Apparently PDE4 inhibition fixes GABA problems in the depressed and CILTEP, being an enhancement to PDE4 inhibtion, probably does that as well.

http://www.ncbi.nlm....pubmed/22629087

J Pharmacol Pharmacother. 2012 Apr;3(2):132-7.
Effect of rolipram, a phosphodiesterase enzyme type-4 inhibitor, on γ-amino butyric acid content of the frontal cortex in mice exposed to chronic mild stress.
Shalaby AM, Kamal SM.
Source
Clinical Pharmacology, Department Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Abstract
OBJECTIVES:

To investigate the alterations in GABA levels by rolipram in the model of depression.

MATERIALS AND METHODS:
The alteration of GABA content by rolipram as a phosphodiesterase enzyme type-4 inhibitor in the frontal cortex (FCx; as a brain region crucial for the control of emotion and cognition) obtained from male mice exposed to chronic mild stress (CMS)-induced anhedonia (the loss of pleasure or lack of sensitivity to pleasure stimuli) was recorded.

RESULTS:
The results demonstrated the reversal of CMS-induced anhedonia after 3 weeks per os of rolipram in a dose of 0.1 mg/kg/day dissolved in distilled water. Furthermore, rolipram showed a significant reduction in duration of immobility in long-term behavioral changes recorded by the FST. Additionally, there was a significant increase in the GABA content of the FCx of rolipram-treated mice exposed to CMS-induced anhedonia.

CONCLUSIONS:
The present study suggested that GABA levels may be decreased in an animal model of depression and its reversal together with the behaviour improvement by rolipram could support the hypothesis that modification in GABAergic activity has a role in mood disorders. These effects may complement the antidepressant effect of rolipram that is originally mediated via inhibition of phosphodiesterase enzyme type-4 [PDE4] that increases cyclic adenosine monophosphate signalling the pharmacotherapy of depression.

This is a full-text study and has lots of great references to other papers on the neuro-chemical effects of PDE4 inhibition.

Edited by abelard lindsay, 01 June 2012 - 03:37 AM.

[abelard lindsay]

Another interesting study. This time PDE4 inhibitors increase BDNF expression when combined with a norepinephrine reuptake inhibitor type anti-depressant.

http://www.ncbi.nlm....ubmed/10633490/

Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus.

[Hebbeh]

reservatrol is actually a phytoestrogen which downregulates androgens which then downregulate igf-1 in some fashion

Do you have a reference? My experience has been quite the opposite. It has a similiar effect as clomid for me. And has been included in a number of body building supps for this reason.

[summertimex]

Do you have a reference? My experience has been quite the opposite. It has a similiar effect as clomid for me. And has been included in a number of body building supps for this reason.

https://www.google.c...iw=1441&bih=597

well im not sure about the exact chain, but usually potent plant-antioxidants function as phytoestrogens. i know there is some other kind of activity with that particular one though.


okay so to describe the memory recall enhancement, it seems to kind of shorten the connection between processing and historical memory with short-term memory. its basically like an L3 cache, if i concentrate on particular scenes, im using mostly a visual reconstruction and can basically dive in and out in to a next historical scene within less than a second. i didnt know how to correctly channel the memory energy, so i ended up bringing up every occasion of a particular type of event. i can also recall the dream versions of those particular types of events that i thought were significant in the past. there is more head-space to travel in, but it has to be concentrated upon to get there, kind of like a "push" which is seemingly a type of low latent inhibition. so far i have only messed around with scenic reconstruction, and mind-space representational painting. overall the memory system is tight, natural and not feeling like its physiologically overpushed. i dont know how much of this is placebo, but i haven't been in to these kind of memory excerises for a while.

[Hebbeh]

Too late to edit but resveratrol actually acts as an anti-aromatase which lowers estrogen and raises testosterone in the process...hardly an anti-androgen.

http://www.ergo-log....ioestrogen.html

I can come up with many more refs if needed.

Any effects on IGF-1 is due to reduction of estrogen....not androgens....but the net effect is more beneficial than determental.

[Hebbeh]

https://www.google.c...iw=1441&bih=597

well im not sure about the exact chain, but usually potent plant-antioxidants function as phytoestrogens. i know there is some other kind of activity with that particular one though.


okay so to describe the memory recall enhancement, it seems to kind of shorten the connection between processing and historical memory with short-term memory. its basically like an L3 cache, if i concentrate on particular scenes, im using mostly a visual reconstruction and can basically dive in and out in to a next historical scene within less than a second. i didnt know how to correctly channel the memory energy, so i ended up bringing up every occasion of a particular type of event. i can also recall the dream versions of those particular types of events that i thought were significant in the past. there is more head-space to travel in, but it has to be concentrated upon to get there, kind of like a "push" which is seemingly a type of low latent inhibition. so far i have only messed around with scenic reconstruction, and mind-space representational painting. overall the memory system is tight, natural and not feeling like its physiologically overpushed. i dont know how much of this is placebo, but i haven't been in to these kind of memory excerises for a while.

And I have no idea what you are talking about.

[X_Danny_X]

apparently it does. omega 3s actually reduce igf-1 temporarily, so its better not to take them before bed when most of the igf-1 happens. reservatrol is actually a phytoestrogen which downregulates androgens which then downregulate igf-1 in some fashion. luteolin was used in cancer studies though, so it should be of significant effect. though sometimes signalling is non-linear depending on body location/receptor type, so i dont know if its confirmed globally in the brain.

i would say this is a "nootropic" so far. i was able to close my eyes, quickly recall several historical scenes and assimilate that information in a slightly new way.

i was actually talking about IGF 2. which one poster mentioned before here that it helps in improving memory. not IGF 1. like Hebbeh mentioned, i actually had more engery, power, etc. when working and taking resevertrol.

I will switch to Quercetin if it is true that it reduction of IGF2 is done by Luteolin and that IGF 2 is responsible for improving memory.

[medievil]

I've been on the CILTEP stack for 2 days. I'm not sure of the effects, but I know I definitely feel different, a good different. As everyone else said, it feels as if your brain feels more open, although I'm not sure if my overall cognition is necessarily better.

I had that feeling with high doses of resveratrol and amphetamine; currently im trying high dose quercetin (3 gram a day till i receive forskolin) aniracetam and a stimulant ill see wheter i can replicate that res with stim feeling again; res is a bit too pricey atm.

My last experiment of adding a bit nefi without a stim failed but i didnt have enough nefi left anyway.

Update: I definatly get that feeling of openness and cognitive enhancement again; i havent tried just quercetin with a stim yet tough to compare.

Damn alot of MPA (amp analogue) potentiation going on; feel a bit overstimulated and a bit of anxiety will be carefull with the dose.

Also since this stack appears to dramatically potentiate stimulants i wonder wheter something like catuaba can completely replicate the benefits of stims in this stack; perhaps togheter with l tyrosine or something else.

Edited by medievil, 01 June 2012 - 05:57 PM.

[medievil]

Does anyone have information on how psychedelics modulate cyclic amp and LTP? They seem to have nootropic potential in treshold doses and long term remission of psychiatric disorders after a psychedelic trip is associated with changes in synaptic plasticity.
Also the psychedelic 2CD is known to have nootropic effects in non psychedelic doses; i took it for several weeks on a daily basis.

Speaking of psychedelics hydergine is a definate substance of intrest for this stack from the limited research i did on it; in 2 weeks i go back for a week to belguim where ive got loads left; will have my forskolin then too.

Anyone here that has hydergine here willing to give it a go?

Edited by medievil, 01 June 2012 - 05:23 PM.

[medievil]

As an aside are there any other compounds like forskolin that induce cAMP? Aside from nefiracetam.

Also we have been looking at quercetin as a PDE4 inhibitor but lets not forget it does far more in the brain as an example it modulates no; it appears to inhibit Inos and increase enos (good) atleast i get that impression it also seems to reduce enos in some conditions.

Im sure it does alot more wich effects LTP.
Curcumin wich also inhibits PDE4 never gave me this openness effect with stims; so im pretty positive its multiple factors going on.


"Nitric Oxide Facilitates Long-Term Potentiation, But Not Long-Term Depression
Peter L. Malen1 and Paul F. Chapman1,2,3
+ Author Affiliations

1 Graduate Program in Neuroscience and
2 Department of Psychology, University of Minnesota, Minneapolis, Minnesota, and
3 Physiology Unit, School of Molecular and Medical Biosciences, University of Wales, Cardiff, United Kingdom
Abstract

Reports that nitric oxide synthase (NOS) inhibition prevents the induction of long-term potentiation (LTP) have been controversial. Recent evidence suggests that NO may help to regulate the threshold for LTP induction. We have tested this hypothesis by examining the effects of stimulus frequency and train duration on synaptic plasticity in the presence of either NO donors or NOS inhibitors. Two different NO donors facilitated LTP induction by stimuli that normally produced only short-term potentiation, whereas NOS inhibitors blocked LTP to stimuli that normally produce small LTP. NO donors facilitated LTP induction even when NMDA receptors were blocked, indicating that NO need not act via NMDA receptors. NO donors and NOS inhibitors were without effect on long-term depression (LTD), suggesting that they act on a distinct potentiating mechanism. Thus, NO could contribute to the establishment of plasticity under physiologically relevant conditions by selectively increasing the probability of LTP induction."

I just took some diazepam for the overstimulation; ill be more cautious with this stack.

EDIT:
"D-Aspartic acid is a novel endogenous neurotransmitter.
D'Aniello S, Somorjai I, Garcia-Fernàndez J, Topo E, D'Aniello A.
Source
Departament de Genètica, Institut de Biomedicina, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Abstract
D-aspartic acid (D-Asp) is present in invertebrate and vertebrate neuroendocrine tissues, where it carries out important physiological functions and is implicated in nervous system development. We show here that D-Asp is a novel endogenous neurotransmitter in two distantly related animals, a mammal (Rattus norvegicus) and a mollusk (Loligo vulgaris). Our main findings demonstrate that D-Asp is present in high concentrations in the synaptic vesicles of axon terminals; synthesis for this amino acid occurs in neurons by conversion of L-Asp to D-Asp via D-aspartate racemase; depolarization of nerve endings with K(+) ions evokes an immediate release of D-Asp in a Ca(2+) dependent manner; specific receptors for D-Asp occur at the postsynaptic membrane, as demonstrated by binding assays and by the expansion of squid skin chromatophores; D-aspartate oxidase, the specific enzyme that oxidizes D-Asp, is present in the postsynaptic membranes; and stimulation of nerve endings with D-Asp triggers signal transduction by increasing the second messenger cAMP. Taken together, these data demonstrate that D-Asp fulfills all criteria necessary to be considered a novel endogenous neurotransmitter. Given its known role in neurogenesis, learning, and neuropathologies, our results have important implications for biomedical and clinical research."

D aspartic acid has been reported to reverse stim tolerance; this can explains it increase in cAMP upregulates D2.

DAA should also be very interesting in this stack.

So to summarize my proposed compounds wich will show high synergy with this stack:
- nefiracetam
- noopept
- Pramiracetam
- Resveratrol
- D aspartic acid
- Hydergine
- Perhaps a low dose of a psychedelic; controversial suggestion but i happen to be MeDieViL.
- That craze preworkout thing
- Viagra (since cGMP potentiates camp but i dunno wheter it would be a good synergy)
- Sex (Learn sexpositions of the kamasutra learning is allways a good idea; difficould positions improve coordination and it feels good so a must in every stack).

Edited by medievil, 01 June 2012 - 06:09 PM.

[medievil]

Lets review PDE5 a bit more.

PDE5 inhibitors and neurogenesis

Neurogenesis is the production of new neurons, and it is a process that is active mostly during prenatal development, though new neurons are also produced during adult life in some areas of the brain such as the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus of mammals, including humans, and other species (Altman and Das 1965; Eriksson et al 1998; Gould et al 1999; Zhao et al 2003; Taupin 2006; Kim and Szele 2007). The functional significance of adult neurogenesis is just beginning to be understood and there is considerable disagreement in literature. There is evidence showing that adult neurogenesis in the hippocampus plays a role in synaptic plasticity (Sandeman and Sandeman 2000; Bruel-Jungerman et al 2006, 2007; Schmidt-Hieber et al 2004) and memory (Shors et al 2001, 2002; Snyder et al 2005; Bischofberger 2007; Bruel-Jungerman et al 2007;Dupret et al 2007; Epp et al 2007; Van der Borght et al 2007). Higher levels of neurogenesis resulting from an enriched environment are reported to correspond to better acquisition of the Morris Water Maze task in mice (Kempermann et al 2002) and new neurons have been shown to be necessary for consolidation of memory after water maze training (Snyder et al 2005). It seems that new neurons can increase mnemonic capacity (Becker 2005), reducing the interference between newly formed memories (Wiskott et al 2006), and adding spatial-temporal details to the new memory (Aimone et al 2006).
It also appears that neurogenesis plays a key role in the regulation of stress and that this is in turn linked to the integrity of the hippocampus. Some studies have, in fact, demonstrated that the positive activity of some anti-depressants is linked to the stimulation of hippocampal neurogenesis (Malberg et al 2000;Manev et al 2001) and that inhibition of hippocampal neurogenesis induced by radiation blocks the effects of anti-depressants (Santarelli et al 2003). Other studies have shown that memory is correlated with mood disorders, particularly with depression, and that mood is regulated by the phenomena of neurogenesis and synaptic plasticity (Castren et al 2005; Paizanis et al 2007).
Hippocampal neurogenesis is controlled by various factors such as physical exercise, stress, sleep, environmental conditions, hormones (testosterone), neurotransmitters (serotonin) and intrinsic growth factors (Cameron and Gould 1994; Lledo et al 2006), which can affect different stages of the neurogenetic process. Neurogenesis is also stimulated by hippocampal or cortical damage (Covolan et al 2000; Blumcke et al 2001; Jiang et al 2001; Jin et al 2001) and could be modified by pathologies such as Alzheimer’s disease (Kuhn et al 2007).
It is interesting to note that some studies have shown that sildenafil plays a role in potentiating neurogenesis through the increase of cGMP levels. NO influenced sensory-induced neurogenesis (Cayre et al 2005) and prenatal development of the brain through cGMP (Chen et al 2004). Furthermore, neuronal growth decreases with age in parallel with the reduction of cGMP levels (Taddei et al 2001). Several studies have demonstrated that sildenafil can be used to stimulate neurogenesis after stroke. In rats, Sildenafil induces neurogenesis, reduces neurological deficit and promotes the functional recovery after stroke and focal cerebral ischemia (Zhang et al 2002; 2006b). Tadalafil has also been used to improve neurogenesis in an embolic model of stroke in rats (Zhang et al 2006a). Thus, it is possible that in the future PDE5 inhibitors might be used to stimulate neuronal function and improve neurogenesis in older subjects or in patients affected by AD and other disorders characterized by hippocampal memory impairment.

PDE5 inhibitors and memory


Role of NO/cGMP in synaptic plasticity and memory

Synaptic plasticity is an active phenomenon consisting of all the structural and/or neuronal functional modifications that allow adaptation to new situations (Hebb 1949). It is thought to be at the bases of learning and memory and occurs in various cerebral structures such as the hippocampus, the cerebral cortex and the cerebellum.
The most studied form of synaptic plasticity is long-term potentiation (LTP) occurring at the excitatory synapses of the hippocampus and consisting of an increase in the amplitude of the post-synaptic excitatory potentials (EPSPs) after high frequency stimulation (tetanus) of the afferent fibers. LTP can be detected in various areas of the hippocampus but it is mostly observed in the CA1 pyramidal cells and pre-synaptic fibers forming the Schaffer collateral, which is implicated in learning and memory. Many studies support the hypothesis that LTP underlies memory (Larson et al 1986; Morris et al 1986; Rose and Dunwiddie 1986; Diamond et al 1988; Greenstein et al 1988; Buchs and Muller 1996; Lynch 2004), although the complex mechanisms involved in memory have not yet been fully clarified. Various studies have shown that LTP and memory depend on a cellular cascade stimulated by an increase of the intracellular concentrations of cAMP with the subsequent activation of PKA and the phosphorylation of the cAMP responsive element binding protein (CREB) (Bourtchuladze et al 1994; Huang and Kandel 1994; Yin et al 1994; Robertson and Sweatt 1996; Abel et al 1997; Montminy 1997; Murphy and Segal 1997; Shieh et al 1998; Tao et al 1998; Otmakhova et al 2002; Stanciu et al 2001; Gooney et al 2002). Besides cAMP, a fundamental role is played by the cGMP/PKG/CREB pathway that seems to act in parallel with the cAMP/PKA/CREB pathway.
Studying the role of the cGMP pathway in memory stems from the crucial need to identify pre- and post-synaptic mechanisms in LTP. In the early 1990s it was suggested that the induction of LTP involves a retrograde message released at the post-synaptic level and acting at the pre-synaptic level (Bohme et al 1991; O’Dell et al 1991; Schuman and Madison 1991). Various studies have shown that NO is necessary for LTP: i) inhibitors of NOS block LTP and this inhibition is corrected administering precursors of NO (Schuman and Madison 1991; Gribkoff and Lum-Ragan 1992; Haley et al 1992; Bohme et al 1991, 1993;Bon et al 1992); ii) knock-out mice for nNOS and eNOS show LTP impairment (Son et al 1996); iii) exogenous application of NO induces plasticity (Zhuo et al 1993; Arancio et al 1996; Bon and Garthwaite 2001); and iv) NO is able to stimulate the release of spontaneous pre-synaptic neurotransmitter release in cell cultures (O’Dell et al 1991).
Given that cGMP is a downstream effector of NO, the involvement of the cGMP/PKG/CREB pathway has also been investigated. These studies showed that: i) inhibitors of GC block the induction of LTP (Haley et al 1992; Zhuo et al 1994; Andreasen et al 2003); ii) analogs of cGMP produce potentiation despite the block of upstream NMDA receptors and NO release (Haley et al 1992; Arancio et al 1995); and iii) inhibitors of GC and of PKG block LTP (Arancio et al 1995, 2001).
Behavioral studies have also shown that NO is involved in the phenomenon of learning and memory (Hawkins 1996; Susswein et al 2004). Bohme and colleagues (1991) demonstrated that the inhibition of endogenous NO impaired spatial learning tested with a radial arm maze and olfactive memory, but had no effect on shock-avoidance learning. Studies on nNOS knockout mice or by using inhibitors of NOS have shown an impairment of spatial performance with the Morris water maze (MWM) and object recognition memory in rats (Chapman et al 1992; Prickaerts et al 1997; Zou et al 1998; Kirchner et al 2004; Koylu et al 2005). Moreover, the block of spatial memory obtained by blocking the NMDA receptors could be restored using NO donors or cGMP analogs (Yamada et al 1996). The effect of NO on behavior is mediated by the cGMP/PKG pathway. In fact, passive avoidance learning in rats increased cGMP levels in the hippocampus and the administration of 8-Br-cGMP, a cGMP analog (Bernabeu et al 1996), or zaprinast, a selective cGMP PDE inhibitor (Prickaerts et al 1997), improved memory. On the other hand, the post-training inhibition of GC or PKG activity blocked memory formation (Bernabeu et al 1996).

Role of NO/cGMP in Alzheimer’s disease

One of the most widespread and invalidating pathologies that causes a deficit of cognitive functions is Alzheimer’s disease (AD). AD is a progressive neurodegenerative disorder characterized by loss of memory and behavioral problems leading to dementia. The advanced stages of the pathology are characterized by the presence of senile plaques at the cerebral level, principally made up of beta-amyloid peptide (Aβ) and neurofibrillary tangles (Selkoe 1994). However, the early symptoms, which consist in the loss of memory, also occur without signs of cerebral alterations and are probably due to a synaptic dysfunction caused by Aβ (Cullen et al 1997; Lambert et al 1998; Itoh et al 1999; Chen et al 2000; Vitolo et al 2002; Walsh et al 2002). It appears, in fact, that Aβ causes a deficit at the excitatory neurotransmission level causing a synaptic dysfunction that precedes the structural alteration with a loss of neurons (Selkoe 2002).
Aβ has various targets that have been well studied and that could identify new therapeutic approaches (Mattson 1997). Various studies suggest that the NO/cGMP pathway can be involved in the pathogenesis of AD. These studies have indicated a dual role for NO: neuroprotective and neurotoxic. Some authors have shown that by acting on the NO/cGMP pathway with NO donors, cGMP analogs, or PDE inhibitors, it is possible to obtain an improvement of the Aβ-induced damage both at the level of the CNS and the vascular system (McCarty 1998; Mattson et al 1999; Paris et al 1999; Troy et al 2000;Wirtz-Brugger and Giovanni 2000). In particular, inhibition of PDEs appears to block the vasoconstriction and inflammation of the microglia induced by Aβ (Paris et al 2000). Given that the NO/cGMP/PKG pathway is involved in LTP, a phenomenon that is altered in the early phases of the pathology in transgenic mouse models (Trinchese et al 2004), it has been demonstrated that this pathway has a protective role with regards to Aβ-induced LTP impairment (Puzzo et al 2005). Moreover, an enhancement of this pathway has been associated with a restoration of the phosphorylation of CREB (Puzzo et al 2005), a transcription factor linked to memory (Bourtchuladze et al 1994; Yin et al 1994; Lonze and Ginty 2002). The potential neurotoxic role of NO has been focused on in many studies showing that activation of iNOS in microglia in response to Aβ is involved in AD pathogenesis (Parks et al 2001; Tran et al 2001; Haas et al 2002; Xie et al 2002). A unifying hypothesis that combines studies on protective and toxic roles of NO is that the two constitutive NOS, n-NOS and e-NOS, have a potential neuroprotective role while i-NOS mediates the oxidative stress induced by NO.

Use of PDE5 inhibitors as a memory enhancer

It has been shown that the PDE5 inhibitor sildenafil influences long-term memory retention in mice by modulating mechanisms involved in memory storage (Baratti and Boccia 1999). Moreover, the inhibition of PDE5 improves object memory (Prickaerts et al 2002, 2004; Rutten et al 2005) and counteracts spatial learning impairment induced by NOS inhibition (Devan et al 2005, 2006) and by blockade of cholinergic muscarinic receptors in rats (Devan et al 2005). Other studies have shown that sildenafil produces a dose-dependent improvement of memory in mice tested with elevated plus maze (Singh and Parle 2003). Sildenafil effects have also been tested on selective auditory attention and verbal recognition memory in humans (Schultheiss et al 2001). Despite the fact that no differences in behavioural patterns were found, sildenafil enhanced the ability to focus attention on streams of auditory stimuli, as revealed by an improvement of the typical ERP components.
As mentioned above, Aβ has been implicated as a key molecule in AD pathogenesis. Several studies have tried to clarify the second messenger pathway(s) by which Aβ affects synaptic plasticity and memory. The cAMP/PKA/CREB pathway has been found to be involved in Aβ-induced LTP impairment (Vitolo et al 2002; Gong et al 2004). Rolipram, a PDE4 inhibitor increasing cAMP levels, reversed the inhibition of PKA activity and CREB phosphorylation most probably by favoring the dissociation of regulatory and catalytic subunits of PKA and the restoration of PKA activity (Vitolo et al 2002). Moreover, treatment with Rolipram re-estabilished LTP and contextual learning in animal models of AD (APP/PS1 mice) and, most importantly, this beneficial effect could be extended beyond the duration of the administration (Gong et al 2004). Aβ has also been found to downregulate the NO pathway leading to a reduction in CREB phosphorylation through reduced activation of PKG (Puzzo et al 2005). Recent studies have shown that nitrates might counteract microglia activation and Aβ deposits (Troy et al 2000; Jantzen et al 2002) and NO-mimetic molecules may reverse cognitive impairment in AD (Thatcher et al 2002, 2005). Thus, enhancers of the cAMP/PKA/CREB or NO/cGMP/PKG/CREB pathways might represent novel classes of compounds that could effectively counteract disease progression by acting at the downstream level of Aβ production. PDE inhibitors have been proposed to be employed as memory enhancers (Blokland et al 2006; Rose et al 2005; Rutten et al 2007). With regard to the use of these inhibitors, it is noteworthy that the development of PDE4 inhibitors as CNS drugs has been a very difficult endeavour because of undesirable side effects, or lack of efficacy at the doses used to avoid side effects. For instance, the PDE4 inhibitor Rolipram, used for its anti-depressant and anti-inflammatory effects, causes a number of side-effects (especially nausea and headache), which have limited its therapeutic use (Souness et al 2000). Thus, it is possible that inhibiting PDE5s might be an alternative and perhaps more suitable strategy than inhibiting PDE4s to develop a drug targeted to CNS and memory.
Based on these findings, and considering that the current therapy for AD (acetylcholinesterase inhibitors, NMDA antagonists, drugs that reduce Aβ levels or its oligomerization, formation of neurofibrils, oxidative stress, and inflammation of the microglia; Schenk et al 1999; Nakagami et al 2002; Walsh et al 2005) has a limited efficacy, our group is currently studying the possibility of using PDE5 inhibitors in AD. Acting on a specific Aβ target such as the NO/cGMP/PKG pathway through PDE5 inhibitors could represent a useful therapeutic approach to block the disease at an early stage, before structural damage occurs. Moreover, it appears that Aβ, other than accumulating in the brain, is also present in the blood stream where it can cause phenomena of vasoconstriction that lead to arterial hypertension (Basun et al 2002; Andreasen et al 2003; Kalaria 2003; Suhara et al 2003; Price et al 2004; Smith et al 2004), often associated with AD (Pasquier and Leys 1998; Gentile et al 2004; Price et al 2004). It would thus be interesting to use PDE5 inhibitors to contrast both the neurological and vascular symptoms associated with this pathology.

[medievil]

It looks like added PDE1 inhibition may be of advantage as PDE4 doesnt operate in the PFC.
Srry for all my spam here but i think with this stack we are onto something and we have to build further on it.

In vivo effects of phosphodiesterase inhibition on basal cyclic guanosine monophosphate levels in the prefrontal cortex, hippocampus and cerebellum of freely moving rats.

Marte A, Pepicelli O, Cavallero A, Raiteri M, Fedele E.

Source

Pharmacology and Toxicology Section, Department of Experimental Medicine, University of Genoa, Genoa, Italy.

Abstract

We have characterized the various phosphodiesterases (PDE) that degrade cyclic GMP in the prefrontal cortex, hippocampus, and cerebellum using the microdialysis technique to measure in vivo extracellular cyclic GMP in awake rats. The following PDE blockers were used (100 and 1,000 microM): 8-methoxymethyl-IBMX (8-MM-IBMX), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), milrinone, rolipram, and zaprinast. For solubility reasons, sildenafil was tested only at 100 microM. All drugs were administered locally in the brain regions through the dialysis probe. At 100 microM, 8-MM-IBMX enhanced the cyclic nucleotide extracellular levels in the prefrontal cortex and hippocampus but not in the cerebellum; EHNA and milrinone were active only in the hippocampus; rolipram was devoid of any effect; zaprinast and sildenafil were effective in all three brain areas. At 1 mM, 8-MM-IBMX, milrinone, and zaprinast increased extracellular cyclic GMP in all the brain regions examined, EHNA became active also in the prefrontal cortex and rolipram showed a significant effect only in the cerebellum. This is the first in vivo functional study showing that, in cortex, PDE1, -2, and -5/9 degrade cGMP, with PDE9 probably playing a major role; in hippocampus, PDE5/9 and PDE1 are mainly involved and seem almost equally active, but PDE2 and -3 also contribute; in cerebellum, PDE5/9 are the main cGMP hydrolyzing enzymes, but also PDE1 and -4 significantly operate.

[vali]

This isn't spam. Thank you for taking the time to contribute.

I've noticed a mental effect as well, but since I've added modafinil to my stack I can't say for sure which drugs are doing what, only that I like the final result. The only thing I can blame fully on forskolin is the change in my bowel movements, which are now softer and more frequent, and the constant farting. Hopefully it doesn't last.

Has anyone had trouble focusing their eyes while on this stack? Like you had to stare at the words and force your eyes to focus correctly?

I have some hydergine, so I'll give it a try later this month and report back.

[medievil]

Why not try it now? Haha my impatience acting up:)

Got forskolin and d aspartic acid coming; is viagra insured in the nhs? im out of money and need some cognitive and penile enhancement.

[medievil]

Do ketones affect LTP btw? Got some coconut oil here might as well eat some now.

[medievil]

Gotu Kola (Centella Asiatica) extract enhances phosphorylation of cyclic AMP response element binding protein in neuroblastoma cells expressing amyloid beta peptide.
Yanan Xu, Zhiming Cao, Ikhlas Khan, Yuan Luo

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.

Journal Article: Journal of Alzheimer's disease: JAD (impact factor: 3.83). 05/2008; 13(3):341-9.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated. In this study, we report that phosphorylation of cyclic AMP response element binding protein (CREB) is enhanced in both a neuroblastoma cell line expressing amyloid beta 1-42 (Abeta) and in rat embryonic cortical primary cell culture. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealing that ERK/RSK signaling pathway might mediate this effect of Gotu Kola extract. Taken together, we provide a possible molecular mechanism for memory enhancing property of Gotu Kola extract for the first time.

ERK signalling is highly involved in LTP if im correct.

[trip96]

Okee medieval! Thanks for this research. I am somewhat new to the medical journal world, but from these articles it would seem that PDE-5 and PDE-1 are of importance to us because of neurogenisis (PDE-5) and where the researchers found action of PDE-1 (prefrontal cortex and cerbelum). Would that mean we could use vinpocetine as a PDE-1 inhibitor, and my earlier Horny goat weed as a PDE-5 inhibitor to achieve these desired effects? I chose these compounds because I already have them on hand.

With a PDE-1 inhibitor, in my case Vinpocetine, you would expect higher functions and working memory to be increased (due to action in prefrontal cortex) and perhaps better motor skills (usefull for say learning an instrument or sports) due to the effect on the cerebellum?

With a PDE-5 inhibitor you would hope for increased neurogenisis and better object memory. The researchers are looking into whether PDE-5 is a better method than PDE-4 due to side effect reasons with PDE-4 and the vasodilation you can achieve with PDE-5. It was also noted that certain antidepressents that are PDE-5 inhibitors work well with memory?

This is really basic but I am learning fast (CILTEP) hahahaha!

I am very interested in furthering this research, I will have a report soon but so far the forskolin quercetin combo with a little caffiene has been very nice. Like you medieval I can get irritated so I also supplement theanine it helps.

Sorry medievil for spelling your name wrong a couple times, too lazy to go back, and auto correct on iPad can be a pain lol.

Stay tuned soon for a report, maybe Monday or Tuesday.n

I would like to discuss a plan and dosages for PDE-1 and 5 inhibitors. Who's got ideas?

[medievil]

Take your vitamine C guys:)

Ascorbic acid augments the adenylyl cyclase-cAMP system mediated POMC mRNA expression and beta-endorphin secretion from hypothalamic neurons in culture.

Yang Z, Copolov DL, Lim AT.

Source

Mental Health Research Institute of Victoria, Royal Park Hospital, Parkville, Australia.

Abstract

Besides acting as an important cofactor in the biosynthesis of catecholamine, ascorbic acid (AA) also modulates the activity of peptidylglycine-alpha-amidating monooxygenase for the post-translational modification of neuropeptides such as alpha-MSH and TRH. We report here a novel action of AA in modulating the secretion of immunoreactive beta-endorphin (ir-beta EP) and mRNA expression of proopiomelanocortin (POMC) following the activation of cAMP-dependent protein kinase A pathway in rat hypothalamic neurons. Primary cultures of hypothalamic neurons from neonatal rats as previously described were employed in the present studies. Six days after plating, cultures were replenished with serum-free media and incubated with vehicle or various doses of AA in the presence or absence of forskolin, 3-isobutyl-1-methylxanthine (IBMX), N6,2'-O-dibutyryladenosine 3'5'-(cyclic)monophosphate [(Bu)2cAMP]. Whereas the basal ir-beta EP release was 22.0 +/- 0.4 pg/well (mean +/- S.E.; n = 3), 10 microM of forskolin treatment increased ir-beta EP release approximately 4.2-fold. Co-incubation with AA enhanced forskolin induced ir-beta EP release and that this enhancing effect of AA was both time related and dose-dependent, with an ED50 of approximately 10 microM and an Emax of 100 microM. At the concentration of 10 microM, AA augmented ir-beta EP release approximately 6.1-fold that of cultures treated with forskolin alone. A similar potentiating effect of AA was also seen in cultures co-treated with IBMX or with (Bu)2cAMP. These enhancing effects of AA were similarly found in the abundance of total cAMP and of POMC mRNA of cultures which received identical treatments. However, it is important to point out that AA alone did not modulate ir-beta EP release or the abundance of POMC mRNA or total cAMP levels of the hypothalamic cultures when protein kinase A pathway was not activated. We thus conclude that AA augments cAMP-dependent protein kinase A pathway-induced production and release of beta EP from rat hypothalamic neurons in culture. Furthermore, this biological effect of AA is, at least in part, mediated through enhancing the responsiveness of the adenylyl cyclase-cAMP system.

Ascorbic acid enhances forskolin-induced cyclic AMP production and pro-ANF mRNA expression of hypothalamic neurons in culture.

Huang W, Yang Z, Lee D, Copolov DL, Lim AT.

Source

Neuroendocrine Laboratory, Mental Health Research Institute of Victoria, Royal Park Hospital, Parkville, Australia.

Abstract

Besides acting as an important cofactor in the biosynthesis of catecholamine, ascorbic acid (AA) also modulates the activity of peptidyl-glycine alpha-amidating monooxygenase for the post-translational modification of neuropeptides such as alpha-MSH and TRH. We report here a novel action of AA in modulating the secretion and mRNA expression of atrial natriuretic factor (ANF) in rat hypothalamic neurons. Primary cultures of hypothalamic neurons from neonatal rats as previously described were employed in the present studies. Six days after plating, cultures were replenished with serum free media and incubated with vehicle or various doses of AA, alone or in the presence of forskolin. Treatment with AA alone significantly increased irANF secretion from the cultures in a time-related and a dose-dependent manner with an ED50 of approximately 3 microM and an Emax of 100 microM. At the concentration of 10 microM, AA augmented irANF release approximately 3 fold that of the controls (55 +/- 7 pg/well; mean +/- SE, n = 3; P < 0.01), but it failed to affect the abundance of pro-ANF mRNA in the cultures. However, 10 microM of AA markedly enhanced forskolin-induced irANF secretion and pro-ANF mRNA abundance of the cultured cells. This potentiating effect of AA on forskolin stimulation showed a good parallelism to the levels of cAMP produced in the hypothalamic cultures. We thus conclude that AA acts alone or in synergism with forskolin to stimulate the secretion and production of ANF in rat hypothalamic neurons; this latter effect may operate at the genomic level and is mediated, at least in part, through the protein kinase A dependent pathway.

[medievil]

next up galantamine or other cholinergics (i hope im not making the thread cluttered i want to list all compounds that affect LTP).

Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation.
Moriguchi S, Shioda N, Han F, Yeh JZ, Narahashi T, Fukunaga K.
Source
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan. shigeki@mail.pharm.tohoku.ac.jp
Abstract
Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01-10 microM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase Calpha (PKCalpha) activities with a bell-shaped dose-response curve peaked at 1 microM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine-rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCalpha. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell-shaped CaMKII and PKCalpha activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell-shaped dose-response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 microM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with alpha7-type nAChR activation. These results suggest that galantamine potentiates NMDA receptor-dependent LTP through alpha7-type nAChR activation, by which the postsynaptic CaMKII and PKC are activated.

Modulation of long-term potentiation by individual subtypes of muscarinic acetylcholine receptor in the rat dentate gyrus.

Luo L, Chen WH, Wang M, Zhu DM, She JQ, Ruan DY.

Source

School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China 230027.

Abstract

The roles of the muscarinic acetylcholine (ACh) receptors (mAChRs) in long-term potentiation (LTP) at many areas of the central nervous system including the hippocampus, have been extensively studied. However, not much is known about the modulation of LTP through individual subtypes of mAChR (M(1)-M(5) subtype). In this study, we investigated the involvement of each individual subtypes of mAChR in LTP induction by intrahippocampal administration of cholinergic ligands at the dentate gyrus (DG) of anesthetized rats. We found atropine, an antagonist of mAChRs, suppressed the induction of LTP. This observation confirmed that the muscarinic system is involved in LTP. We then examined the effects of M(1)AChR antagonists (pirenzepine and telenzepine), M(2/4)AChR antagonists (Methoctramine and {11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one}(AFDX-116)), and M(3/5)AChR antagonist (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP)) on LTP. Our results showed that both M(1)AChR and M(2/4)AChR antagonists but not M(3/5)AChR antagonist suppressed the amplitude of LTP. We also examined the effects of these cholinergic ligands on basal synaptic transmission and found that only pirenzepine augmented the amplitude of population spike. This study suggests that individual mAChR subtypes play different modulation roles in LTP induction in the DG of rats.

Edited by medievil, 02 June 2012 - 01:00 AM.

[X_Danny_X]

What are some PDE-5 inhibitors?

[medievil]

What are some PDE-5 inhibitors?

Viagra and co

[Lufega]

Also we have been looking at quercetin as a PDE4 inhibitor but lets not forget it does far more in the brain as an example it modulates no; it appears to inhibit Inos and increase enos (good) atleast i get that impression it also seems to reduce enos in some conditions.

Im sure it does alot more wich effects LTP.

Here are some of the other things quercetin does:

• Prolyl endopeptidase inhibitor - increases memory
• PDE4 inhibitor - Bronchodilator effect among the other effects discussed here.
• MAO and COMT inhibitor PMID: 12711835
• Reduces COMT protein expression
• Adenosine receptor antagonist. 2000 mg quercetin = 200 mg caffeine
• AChE inhibitor, and memory enhancer.
• Increases absorption of green tea and decreases its methylation. This combo further reduces comt.
• Quercetin acts as a protective agent in mouse corpus cavernosum, increasing the bioavailability of exogenous nitric oxide by protecting it from superoxide anion (O(2)(-)).

That said, I've been using this combo for a couple days now and I've noticed a sick increase in focus. However, it doesn't improve my ADD problems. It did create something I've never experienced before though; Focused ADD !
Sounds contradictory but my ADD has become much more productive. Whenever I go off on a tangent, it takes me 20-30 min. to realize I was doing something else previously. The effects on focus are very intense. I am using phentermine at the moment and it pontentiates the effect of this medication.

[medievil]

What exactly do you take? I assume quercetin; forskolin and phentermine? Doesnt phentermine help your ADHD?