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CNTF based peptide P21

cntf p21 cerebrolysin

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#1 AuralAnomaly

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Posted 09 August 2013 - 01:25 PM


I'm not sure if the person who originally dug up this study wants the credit and therefore blame if things somehow go wrong .. So I'll keep that anonymous for now and just remove their editing. My hope is that after further digging and discussion as to the safety and efficacy of the P21 peptide, members here could open a new thread for a custom synthesis group buy. Here we go:

Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice, Bin Li, FEBS Letters Volume 584, Issue 15, 4 August 2010, Pages 3359-3365

Abstract

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

1. Introduction

As life expectancy in industrialized countries has been increasing by two years per decade in the last 20 years and is predicted to further surge, age-associated dementias like Alzheimer disease (AD) are becoming more and more heavy medical, economic, and social burden in modern society. AD affects over five million in the US and over twenty million worldwide. AD is the most prevalent dementia, followed by vascular dementia and dementia with Lewy bodies. AD has an average progression of 7–10 years, and is both multifactorial and heterogeneous. Despite AD being a severe public health problem, no neuroprotective and specific treatment is yet available. Numerous targets for pharmacological therapies of AD are currently under investigation [1].


To maintain or even restore cognitive health and memory is the ultimate goal in the treatment of dementia. Cerebrolysin (EBEWE Pharma, Unterach, Austria), a preparation of peptides and amino acids produced by standardized enzymatic digestion of porcine brain protein, has been shown to improve memory in patients with mild to moderate cognitive impairment [2] and [3]. This drug has also been shown to display neurotrophic activity in vitro [4] and [5] and in animal models of neurodegeneration [6] and [7]. Cerebrolysin enhances dentate gyrus (DG) neurogenesis in normal adult rats [8] and an APP transgenic model of AD [9].

The neurogenic effect of Cerebrolysin might be based upon the action of peptides in the preparation that are proteolytic products of neurotrophic factors. In a previous study, we found that Cerebrolysin contains peptides which react with neutralizing antibodies to human CNTF, GDNF, IGF-1 and IGF-2. More specifically, the CNTF neutralizing antibody can inhibit the neurogenic effects of Cerebrolysin [5]. Based on epitope mapping of neutralizing antibodies to human CNTF, we found that an 11-mer peptide; Peptide 6 (Ac-VGDGGLFEKKL-NH2) and a subsequence of it, Peptide 6c (Ac-DGGL-NH2), enhanced hippocampus-dependent learning and memory, increased neurogenesis and neuronal plasticity in normal adult mice [10] and [11].

Although peptides in general are readily bioavailable, systemic degradation through proteases and relatively poor blood–brain-barrier (BBB) permeability pose challenges in rendering peptides “druggable”. To address these design goals, we added adamantane building blocks to the C-terminus or both C- and N-termini of Peptide 6c. These bulky, highly lipophilic tricyclic alkane building blocks can increase the BBB permeability of peptides and block enzymatic degradation through exopeptidases. In the present study, we show that when administered peripherally to normal adult mice, the pentamer Ac-DGGLAG-NH2, called P21, significantly enhanced cognition, increased proliferation and neuronal differentiation of adult hippocampal progenitors and promoted the expression of synaptic vesicle proteins, synaptophysin and synapsin I.

2. Materials and methods

Fig. 1 shows the design and structures of peptidergic compounds employed in this study. For synthesis of peptidergic compounds incorporating adamantane building blocks, compounds P21(Ac-DGGLAG-NH2) and P22 (1-Ad-CO-DGGLAG-NH2), animals and housing, one trial object recognition test, spatial reference memory task in the water maze, immunohistochemistry, cell counts by stereology, analysis of the mechanism of action of P21 through LIF receptor in HepG2 cells, and statistical analysis, see Supplementary data.
attachment_005.jpg

Fig. 1.

Design and structures of neurogenic peptidergic compounds incorporating adamantane building blocks. From the neurogenic undecamer Ac-VGDGGLFEKKL-NH2 (Peptide 6) a truncated, still neurogenic tetramer Ac-DGGL-NH2 (Peptide 6c) was designed. Addition of an unnatural amino acid based upon adamantane to the C-terminus of this subsequence via solid phase peptide synthesis methods produced Ac-DGGLAG-NH2 (P21); capping of the N-terminus of P21 with adamantane-1-carboxylic acid yielded 1-AdCO-DGGLAG-NH2 (P22).

3. Results

3.1. Effect of peptides incorporating adamantane on cognitive function in normal adult mice

3.1.1. General behavioral observations


Administration of the full-length CNTF protein in human clinical trials is known to cause anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain [12] and [13]. However, in the present study, we did not observe any alteration in either general physical state, body weight (Fig. 2A), exploratory behavior (Fig. 2C) or swim speed (Fig. 2D) during the period of the study, suggesting that treatment with compound P21 or P22 did not induce any apparent side-effects. In the water maze task, we did not observe any floating behavior suggesting that animals treated with P21 or P22 did not present any sign of depression or locomotor impairment. The only general behavioral characteristic P21 and P22 altered was the level of anxiety of the mice. As shown in Fig. 2B, mice treated with P21 or P22 spent more time in the center of the open field than control animals (P < 0.010, Student t-test) suggesting lower levels of anxiety.
attachment_004.jpg

Fig. 2.

Peptides incorporating AGly improve cognition. P21 and P22 did not induce any effect on body weight (A), exploratory activity © or swim speed (D) but reduced anxiety level of mice (B). (E–F) P21 significantly improved the ability to discriminate a new object versus a familiar object. *P < 0.05; Student t-test. (G) P21 and P22 increased performance in the learning of spatial memory task in water maze. **P < 0.001; two-way ANOVA with post hoc Fisher LSD test. (H) P21 improved performance in the first probe trial (PT1), but treatment with P21 showed no effect 15 days (PT2) or 30 days (PT3) after the end of the treatment. *P < 0.05; Student t-test.

3.1.2. One-trial object recognition task

To examine short-term memory, we conducted a one-trial object recognition task. Mice treated with P21 clearly spent more time exploring the new object than the familiar object whereas other groups did not (Fig. 2E). The percentage of discrimination for animals treated with P21 was significantly increased compared to other groups (P < 0.05, Student t-test; Fig. 2F).


3.1.3. Spatial reference memory task

To investigate potential effects of P21 and P22 on hippocampal dependent memory, we conducted a spatial reference memory task in the water maze. Animals from all groups learned well, as evident by significantly declining escape latencies across training sessions (P < 0.05, two-way ANOVAs; Fig. 2G). However, performance of mice treated with P21 or P22 improved significantly faster than placebo-treated animals. Escape latencies to reach the submerged platform were significantly reduced for groups treated with P21 or P22 compared to control group from training day 2–4 (P < 0.01, two-way ANOVA and post hoc Fisher LSD test).

To evaluate the accuracy and the strength of the platform coordinates encoding, we performed probe trials and measured the time animals spent looking for the platform in the target quadrant. We first carried out a probe trial 24 h after the last day of training. Then, to evaluate remote memory, we performed probe trials 15 and 30 days after the training and the end of the chronic treatment. Analysis of retention of memory in the three probe trials confirmed that all animals had correctly encoded the platform location during training since they spent more than 25% of the trial period looking for it in the target quadrant (Fig. 2H). During the first probe trial, animals treated with P21 focused significantly more on the target quadrant compared to control animals (P < 0.05, Student t-test). However, this beneficial effect disappeared on day 15 and day 30 washout periods after the end of the treatment with the peptide. No statistically significant effect of P22 was observed in the probe trials.

Overall, results from the object recognition task and the spatial reference memory task show that P21 induced positive effects on cognition.


3.1.4. Enhancement of neurogenesis in the DG

Because neurogenesis is thought to have an important role in memory and associated learning [14], [15] and [16], we investigated potential changes induced by chronic treatment with P21 and P22.

Quantitative evaluation of neurogenesis in the DG revealed a significant increase of BrdU positive cells in the granule cell layer (GCL) and subgranular zone (SGZ) of animals treated with P21 (P < 0.05, two-way ANOVA and post hoc Fisher LSD test; Fig. 3A and B). No significant alteration in neurogenesis was observed in the group treated with P22 (Fig. 3A and B).
attachment.jpg

Fig. 3.

Compound P21 promotes neurogenesis in the DG. (A) Representative picture of double labeled BrdU (red) and NeuN (green) positive cells. Scale bar represents 20 μm. (B) Numbers of BrdU positive cells were significantly increased in P21 treated animals in the total DG, GCL and in the SGZ © P21 treatment significantly increased the number of BrdU/NeuN positive cells in the GCL and in the total DG. *P < 0.05, two- way ANOVA and post hoc Fisher LSD test.

To estimate net neurogenesis, we next examined the expression of the marker for mature neurons, NeuN, in the BrdU positive cells in the DG. A significant increase of the number of BrdU/NeuN positive cells was observed in the DG of mice treated with P21 due to a significant increase in BrdU/NeuN positive cells in the GCL (P < 0.05, two-way ANOVA and post hoc Fisher LSD test; Fig. 3A and C). No significant changes were observed in the group of animals treated with P22.


3.1.5. Enhancement of synaptic plasticity

Synapses are critical components of the neural mechanisms underlying learning and memory. In order to investigate whether P21 and P22 have neurotrophic effects, we measured the expression of two synaptic vesicle proteins; synaptophysin and synapsin I.

Significant increases of synaptophysin and synapsin I immunoreactivities were observed in the GCL and molecular cell layer (MCL) of animals treated with P21 (P < 0.001, two-way ANOVA and post hoc Fisher LSD test; Fig. 4A and B). Animals treated with P22 expressed similar levels of immunoreactivity of synaptophysin and synapsin I as did untreated control animals.
attachment_003.jpg

Fig. 4.

Compound P21 promotes synaptic plasticity in the DG. P21 significantly promoted expression of synaptophysin (A) and synapsin I (B) in the GCL and the MCL of the DG. ***P < 0.001, two-way ANOVA and post hoc Fisher LSD test. Scale bars represent 100 μm.

3.1.6. Antagonistic effect of P21 on LIF signaling

To investigate whether P21 affects LIF signaling pathway, we treated HepG2 cells with different concentrations of P21 from 0.01 to 1000 nM along with 0.25 nM LIF for 15 min, and then measured STAT3 phosphorylation by Western blots. We observed that LIF-induced STAT3 phosphorylation was inhibited slightly in a dose-dependent manner. In HepG2 cells, 10 nM of P21 inhibited 30% of LIF-induced phosphorylation of STAT3 (P < 0.005, Student t-test; Fig. 5).
attachment_002.jpg

Fig. 5.

Inhibition of LIF-induced STAT3 phosphorylation by P21 in a dose-dependent manner in HepG2 cells. HepG2 cells were treated with different concentrations of P21 together with 0.25 nM LIF for 15 min, and then the STAT3 phosphorylation at Tyr705 (pY-STAT3) was determined by Western blots. The pY-STAT3 value was normalized to total STAT3 expression. Data are presented as percentages of the value from cells treated with 0.25 nM LIF alone (100%). *P < 0.05; **P < 0.01.

4. Discussion

Neurotrophic factors are critical for neuronal differentiation, maturation, and survival, but in the AD brain, the balance of neurotrophic factors is disturbed. Level of basic fibroblast growth factor is upregulated, whereas the levels of brain-derived neurotrophic factor and neurotrophin 4 are reduced in the hippocampus, the frontal cortex and the parietal cortex (for review, see [17]. Because they are crucial to maintain a healthy neuronal microenvironment, neurotrophins generated excitement over the past decades as therapeutic targets for AD and other dementias. However, inconvenient pharmacokinetics and adverse side-effect profiles have limited clinical utilization of neurotrophic factors [18]. Therefore, chemically modified short peptides able to mimic positive characteristics of neurotrophic factors represent an opportunity to circumvent these obstacles.

Derivatives of the diamondoid C10H16 hydrocarbon adamantane have already been commercialized as antivirals (amantadine, rimantadine) and as central nervous system active drugs. Nowadays, the aminoadamantane Memantine® is the only drug prescribed for moderate to severe cases of AD. Based on the physicochemical and pharmacological properties of drugs incorporating the adamantane motif, an adamantane-based moiety has been used as a drug carrier for poorly absorbed compounds, including peptides, active towards the central nervous system [19] and [20]. In a previous study, we demonstrated the beneficial effect of a CNTF-based tetrapeptide, Peptide 6c, on hippocampus-dependent memory in normal adult mice [11]. We hypothesized that adding lipophilic groups to Peptide 6c could increase its biostability and BBB permeability and consequently enhance its neurotrophic, neuroplastic, and cognitive enhancement activities. We attached the rigid, bulky, and highly lipophilic, unnatural 3-aminoadamantane-1-carboxylic acid (“AGly”) C-terminally to the Peptide 6c to produce compound P21. The rigidity of the -amino acid AGly should block the carboxypeptidase activity, thereby stabilizing Peptide 6c in vivo [21]. Enhancing the overall lipophilicity of Peptide 6c should boost its ability to cross the BBB. By capping the N-terminus of the sequence of Peptide 6c with adamantane-1-carboxylic acid in P22, we speculated that it would further increase lipophilicity and BBB penetration as well as resistance against aminopeptidase activity.

In AD, the hippocampus is the most vulnerable brain region to neurodegeneration [22]. Moreover, hippocampus-dependent cognitive impairments are associated with synaptic loss [23] which occurs early in the development of AD [24]. Reduction of synaptophysin in the hippocampus correlates with cognitive decline in AD patients [25] and with decreased synaptic activity in several mouse models of AD [26] and [27]. Therefore, in the present study we investigated effects of compounds P21 and P22 on hippocampus-dependent cognitive functions and on hippocampal synaptic plasticity.

In the present study, P21 significantly enhanced two different cognitive mechanisms;
-> an object recognition task and

-> a spatial reference memory task.

The one-trial object recognition task is thought to critically depend on the entorhinal cortex, hippocampus and frontal cortex [28], [29], [30] and [31]. In the present study we observed that control animals as well as animals treated with P22 did not preferentially explore the novel object. This null preference did not reflect a lack of interest for novelty but rather enhanced attraction for familiarity [32]. This reveals that, for control and P22-treated animals, familiar object representation is yet to be built and finalized, therefore requiring as much attention as the novel object to complete the encoding. On the contrary, animals treated with P21 displayed a marked preference for the novel object. This suggests that the representation of the familiar object has been fully encoded, and then was not anymore a subject of attention at the expense of the novel stimulus. These results showed that P21 treatment accelerated the encoding of object representation, thus, in the present experimental condition, improved short-term memory performance.

In the spatial reference memory task, the hippocampal system processes information about the relationships among distal environmental cues into a spatial map where spatial coordinates of the submerged platform are encoded [33]. The hippocampus is also crucial for memory storage, consolidation and restitution of the spatial information [34]. In the present study, we observed that both P21 and P22 increased the learning of the task suggesting that both peptides strengthened processing of the spatial environment. However, only P21 positively enhanced performances in the probe trial. This shows that the beneficial effect of P21 on encoding, storage, and consolidation of the spatial information during the treatment period is stronger than of P22.

Examining hippocampal synaptic activity, we next found that P21 induced significant increase in synaptophysin and synapsin I immunoreactivity in the DG. Synaptophysin is a glycoprotein of the presynaptic vesicles [35] involved in the vesicle trafficking machinery [36] by regulating synaptic vesicle exocytosis [37]. Besides, Synapsin I is a neuro-specific phosphoprotein highly concentrated in presynaptic nerve terminals, where, associated with the cytoplasmic surface of the synaptic vesicle, it plays a key role in neurotransmitter release [38]. We observed that P21 positively enhanced synaptophysin and synapsin I levels. This suggests that P21 had a beneficial effect on synaptic plasticity by increasing the presynaptic release of neurotransmitters. We speculate that this augmentation of neurotransmitters in the synaptic cleft potentiates post-synaptic excitability, subsequently enhancing the efficacy of the neuronal network taking charge of stimulus processing to encode, store or recall information.

The contribution of adult hippocampal neurogenesis to memory has been studied at experimental and theoretical levels. Current literature supports the idea that both neural stem cells and immature neurons play distinct roles in hippocampus-dependent memory tasks [39]. Newly born mature cells may have an inherent advantage of being recruited into patterns of new memory networks [40]. In the present work, we observed that P21 increased progenitor cell proliferation as well as neuronal differentiation. Thus, through this neurogenic activity, P21 enhanced the stock of functional neurons to be potentially recruited into neuronal networks of information processing. This characteristic of P21 might be crucial as a potential treatment for neurodegeneration since in AD, although proliferation of immature neurons is increased, newly generated neurons in the DG do not mature [41] and [42].

The present study shows that P21 induces neuronal plasticity and neurogenic properties which consequently enhance cognition. In particular, we have investigated the effects of P21 in the hippocampus, but, considering positive enhancement of the object recognition task which involves other brain structures as well as the hippocampus, we speculate that the beneficial effect of P21 we have shown to be connected with neuronal plasticity in the DG may occur in other brain areas as well.

In previous work we showed that Peptide 6 contains a putative leukemia inhibitory factor receptor-binding sequence of CNTF and interferes with the signal transduction of LIF more than with that of CNTF [10]. Because LIF inhibits neurogenesis in the DG [43], [44] and [45], we hypothesized that Peptide 6 enhances neurogenesis through the CNTF pathway, inducing a partial inhibition of LIF. The present study shows that P21 acts as its parent molecule, the 11-mer peptide, partially inhibiting LIF activity through the STAT3 pathway. Because we did not observe conclusive effects of the closely related derivative P22, which differs in the N-terminal acylation, on cognition, neuronal plasticity and neurogenesis, we assume that incorporating an additional adamantane moeity instead of the smaller N-acetyl group at the N-terminus of P21 to furnish P22, probably prevented a proper interaction of the active –DGGL– subsequence with its receptors.

Overall, in the present study we have shown that the CNTF-derived peptidergic compound, P21, incorporating a γ-aminoadamantane-1-carboxylic acid at its C-terminus, is neurogenic and neuroplastic and enhances cognition in normal adult mice. It is important to note that demonstrating positive effects of the studied peptides is a challenging task because it is difficult to observe enhancement of cognition due to ceiling effects in normal adult mice we have used previously. Although we previously observed beneficial effects of the CNTF tetra peptide, Peptide 6c, on memory [11], the improvements in object recognition and spatial reference memory we report here for the pentamer P21 are more pronounced. We thus conclude that the lipophillically modified, CNTF-derived pentamer P21 is an attractive candidate for the development of pro-cognitive drugs to prevent and treat learning and memory disorders and neurodegenerative diseases such as AD.
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[38] P. Greengard, F. Valtorta, A.J. Czernik and F. Benfenati, Synaptic vesicle phosphoproteins and regulation of synaptic function, Science 259 (1993), pp. 780–785. View Record in Scopus | Cited By in Scopus (706)

[39] J.B. Aimone, J. Wiles and F.H. Gage, Potential role for adult neurogenesis in the encoding of time in new memories, Nat. Neurosci. 9 (2006), pp. 723–727. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (235)

[40] N. Kee, C.M. Teixeira, A.H. Wang and P.W. Frankland, Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus, Nat. Neurosci. 10 (2007), pp. 355–362. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (193)

[41] B. Li, H. Yamamori, Y. Tatebayashi, B. Shafit-Zagardo, H. Tanimukai, S. Chen, K. Iqbal and I. Grundke-Iqbal, Failure of neuronal maturation in Alzheimer disease dentate gyrus, J. Neuropathol. Exp. Neurol. 67 (2008), pp. 78–84. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (37)

[42] K. Jin, A.L. Peel, X.O. Mao, L. Xie, B.A. Cottrell, D.C. Henshall and D.A. Greenberg, Increased hippocampal neurogenesis in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA 101 (2004), pp. 343–347. View Record in Scopus | Cited By in Scopus (341)

[43] T. Shimazaki, T. Shingo and S. Weiss, The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells, J. Neurosci. 21 (2001), pp. 7642–7653. View Record in Scopus | Cited By in Scopus (159)

[44] M.A. Bonaguidi, T. McGuire, M. Hu, L. Kan, J. Samanta and J.A. Kessler, LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells, Development 132 (2005), pp. 5503–5514. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (75)

[45] S. Bauer and P.H. Patterson, Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain, J. Neurosci. 26 (2006), pp. 12089–12099. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (68)

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#2 aarfai

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Posted 16 December 2013 - 07:10 AM

Why isn't this community researching further into this compound? It seems very promising...
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#3 barbelith42

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Posted 19 August 2014 - 04:54 AM

Anyone else tried P21 from Ceretropic? As mentioned in the article, this is supposedly an active ingredient of the famed Cerebrolysin (which I have yet to try). I'd love to hear anecdotal comparisons.



#4 StevesPetRat

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Posted 19 August 2014 - 07:39 PM

CNTF doesn't get enough love around here

#5 barbelith42

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Posted 20 August 2014 - 04:30 AM

I've been noticing a subtle effect from P21. It's nice and "light", and stacks well on top of 10mg Noopept 3-5 days/week. There is an ever-so-slight increase of psychological presence for me, at least 4 days in. 250-1,000 mcg goes very well with 125-250mcg of Selank without much sedation. I'll continue taking it before classes and see how effective it is long-term. Oh, and I had an incredibly vivid multi-sensory dream just before I woke up from a nap after having some in the afternoon that I was able to turn lucid and wake up from consciously. However, I have been taking the above Noopept dosage for 2 weeks and it seems to have a similar effect. I had one similar experience without the conscious awakening in the last 2 weeks since starting the above regimen, but upon adding P21 for 2 days I had this even more vivid experience. I hadn't had a lucid dream in months, even years, before this. I'm starting to like these nootropics.



#6 matter_of_time

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Posted 29 December 2014 - 07:57 PM

I am using P21 now for four days. I can say this could be the next big thing after Cerebrolysin (the only nootropic which I really love).

I really do not understand not many other ppl are talking about this or is everybody keeping the information for himself.

 

I am stopped taking al my other supplement even fish olie and uridine.


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#7 aarfai

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Posted 29 December 2014 - 09:23 PM

Interesting. What are you experiencing that you love so dearly?



#8 matter_of_time

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Posted 30 December 2014 - 06:32 AM

until now I cant say much about an increase in mental performance but I can say I was a little stressed out and my stress levels disappeared within one week.

 

P21 also makes me sleep like a baby, I have not slept so good since ages. 



#9 di36

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Posted 30 January 2015 - 11:21 AM

why p21 is not talked about?It seems very vey promising.

 

Is it only selled by ceretropic?



#10 dz93

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Posted 30 January 2015 - 03:20 PM

Looks like p21 doesn't help much in the grammar department.
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#11 Rior

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Posted 31 January 2015 - 05:22 PM

Any subjective comparisons to Cerebrolysin?  I'm currently in a Cerebrolysin regimen right now, and have been fully reminded how much of a miracle worker this drug is.   Cerebrolysin, to me, has been the greatest nootropic and cognitive aid I have ever used.


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#12 oppenheimer82

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Posted 24 February 2015 - 12:41 PM

Any subjective comparisons to Cerebrolysin?  I'm currently in a Cerebrolysin regimen right now, and have been fully reminded how much of a miracle worker this drug is.   Cerebrolysin, to me, has been the greatest nootropic and cognitive aid I have ever used.

what effects are you seeing?



#13 Reformed-Redan

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Posted 25 February 2015 - 03:00 AM

Hate to sound like a party pooper; but, the Nootropics gains presented in the study seem modest to say the least. If you have unlimited funds by no means let anything stop you from taking it.

#14 sunshinefrost

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Posted 27 February 2015 - 11:29 PM

I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.

#15 lourdaud

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Posted 06 March 2015 - 09:05 PM

Any subjective comparisons to Cerebrolysin?  I'm currently in a Cerebrolysin regimen right now, and have been fully reminded how much of a miracle worker this drug is.   Cerebrolysin, to me, has been the greatest nootropic and cognitive aid I have ever used.

 

Agreed, cerebrolysin is absolutely amazing. It's incredible how much easier learning is but to just say that you learn at a faster rate would be to put it midly - it really helps you to learn something new, the only way to describe it is that it expands your mind. Psychedelics taken aside, this is something you won't get from any other nootropic.

 

The sad part for me is that I can't take it without getting my sleep messed up. I normally wake up in the middle of the night but usually I won't have any problems going back to sleep. On cerebrolysin however, I'll wake up wide awake and know that I'll stay that way for several hours and even downers in big doses won't put me back to sleep.



#16 resveratrol_guy

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Posted 11 March 2015 - 08:30 PM

I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.

 

What's a dose, in this case? Did you mix it with bacteriostatic water, as suggested by Ceretropic (assuming that's where you bought it)? Was it intramuscular, intravenous, or subcutaneous?

 

Apart from mood stabilization and better sleep, has anyone seen actual memory improvements?

 

I can't help but think that the adamantane bonding was the wrong strategy in this case; intuitively, a lipid shell would permit better cerebral delivery without requiring much if any modification of the P6 or P6c peptides. Longvida works this way, with great success vs. pure oral curcumin. By contrast, resveratrol is delivered as a pure compound, which is rapidly neutralized by the liver and has hardly any time to do its magic; indeed, its human effects fall far short of its murine ones at the same dose per kg.


Edited by resveratrol_guy, 11 March 2015 - 08:33 PM.


#17 resveratrol_guy

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Posted 13 March 2015 - 03:18 AM

For the record, Synzael provided other informative sources of P21 user experience data which I've linked in this post.

 



#18 sunshinefrost

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Posted 27 March 2015 - 12:47 PM

 

I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.

 

What's a dose, in this case? Did you mix it with bacteriostatic water, as suggested by Ceretropic (assuming that's where you bought it)? Was it intramuscular, intravenous, or subcutaneous?

 

Apart from mood stabilization and better sleep, has anyone seen actual memory improvements?

 

I can't help but think that the adamantane bonding was the wrong strategy in this case; intuitively, a lipid shell would permit better cerebral delivery without requiring much if any modification of the P6 or P6c peptides. Longvida works this way, with great success vs. pure oral curcumin. By contrast, resveratrol is delivered as a pure compound, which is rapidly neutralized by the liver and has hardly any time to do its magic; indeed, its human effects fall far short of its murine ones at the same dose per kg.

 

 

the dose was minimal i don't remember, it's been more than a month but i did mix it with bacteriostatic water and i DID buy it from ceretropic. I tried subcutaneous and as soon as i puncture 1 millimeter of skin it burned like hell, i don't think anybody could have gone through with this. i'm worried i might have used a dangerous substance. 

 

Did anyone else get this sensation of injecting burning acid into their bodies ?even ifthe batch i received wasn't good this can't be a good sign of quality. 

 

i wrote to the administrator and they didn't offer any kind of replacement products nor did they manifest really big concerns. if i were them i would have offered to analyse the batch they had sent me. 

 

don't buy this


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#19 dz93

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Posted 27 March 2015 - 01:18 PM



I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.


What's a dose, in this case? Did you mix it with bacteriostatic water, as suggested by Ceretropic (assuming that's where you bought it)? Was it intramuscular, intravenous, or subcutaneous?

Apart from mood stabilization and better sleep, has anyone seen actual memory improvements?

I can't help but think that the adamantane bonding was the wrong strategy in this case; intuitively, a lipid shell would permit better cerebral delivery without requiring much if any modification of the P6 or P6c peptides. Longvida works this way, with great success vs. pure oral curcumin. By contrast, resveratrol is delivered as a pure compound, which is rapidly neutralized by the liver and has hardly any time to do its magic; indeed, its human effects fall far short of its murine ones at the same dose per kg.

the dose was minimal i don't remember, it's been more than a month but i did mix it with bacteriostatic water and i DID buy it from ceretropic. I tried subcutaneous and as soon as i puncture 1 millimeter of skin it burned like hell, i don't think anybody could have gone through with this. i'm worried i might have used a dangerous substance.

Did anyone else get this sensation of injecting burning acid into their bodies ?even ifthe batch i received wasn't good this can't be a good sign of quality.

i wrote to the administrator and they didn't offer any kind of replacement products nor did they manifest really big concerns. if i were them i would have offered to analyse the batch they had sent me.

don't buy this

There probably wasn't any reason to be concerned. First off, you're taking a research chemical, its your responsiblility and fault if something goes wrong. Second, you're the first I've heard about having this reaction. There could be numerous reason why you had this. You could be allergic to the substance, your body just simply rejected it, you injected it wrong, etc. I've injected Semax wrong before and have had a burning sensation. There will always be a risk when choosing to experiment with research chemicals.

Why should ceretropic give you a new sample of a product you had a bad reaction with? For you to place blame on them even more? In my experience, ceretropic has been great with customer service and quality products and he does actively test his products. Regardless of your opinion on ceretropic, you do need to understand that this is a research chemical not meant for human consumption.
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#20 sunshinefrost

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Posted 07 May 2015 - 09:11 PM

what are the chances of this peptide causing prions ? 



#21 megatron

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Posted 08 May 2015 - 05:22 PM

what are the chances of this peptide causing prions ? 

 

Well it's synthesized and contains no extracts from pig brain like cerebrolysin does.


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#22 barbelith42

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Posted 23 May 2015 - 06:24 AM

 

 

I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.

 

What's a dose, in this case? Did you mix it with bacteriostatic water, as suggested by Ceretropic (assuming that's where you bought it)? Was it intramuscular, intravenous, or subcutaneous?

 

Apart from mood stabilization and better sleep, has anyone seen actual memory improvements?

 

I can't help but think that the adamantane bonding was the wrong strategy in this case; intuitively, a lipid shell would permit better cerebral delivery without requiring much if any modification of the P6 or P6c peptides. Longvida works this way, with great success vs. pure oral curcumin. By contrast, resveratrol is delivered as a pure compound, which is rapidly neutralized by the liver and has hardly any time to do its magic; indeed, its human effects fall far short of its murine ones at the same dose per kg.

 

 

the dose was minimal i don't remember, it's been more than a month but i did mix it with bacteriostatic water and i DID buy it from ceretropic. I tried subcutaneous and as soon as i puncture 1 millimeter of skin it burned like hell, i don't think anybody could have gone through with this. i'm worried i might have used a dangerous substance. 

 

Did anyone else get this sensation of injecting burning acid into their bodies ?even ifthe batch i received wasn't good this can't be a good sign of quality. 

 

i wrote to the administrator and they didn't offer any kind of replacement products nor did they manifest really big concerns. if i were them i would have offered to analyse the batch they had sent me. 

 

don't buy this

 

 

 
you could have a paraben or benzyl alcohol allergy (http://www.ncbi.nlm....v/pubmed/139248
 
if not, it sounds like you hit a nerve and or had a histamine response. insulin injection sites: https://www.bd.com/r....aspx?IDX=10629 . That will likely solve the pain issue. as for the second, google "site reaction" -- some people have really sensitive skin, but for me that went away. always rotate sites ~1" away in a grid if you see any inflammation in the same site so you don't build scar tissue and exacerbate the issue. check out a video of a medical professional giving a subcutaneous injection.
 
yes, it increased my ability to learn, use, and remember new procedural information -- especially in math and physics. this supports my (anecdotal) findings here:
 

 

 

"Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice"
Bin Li, Lukas Wanka, Julie Blanchard, Fei Liu, Muhammad Omar Chohan, Khalid Iqbal, Inge Grundke-Iqbal
http://www.sciencedi...01457931000520X

Abstract

"Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus."

 

 

We'll see if that all works out exactly the same in humans, but more and more recent evidence seems to suggest that there is the potential for this kind of effect in adult humans, e.g.: http://www.ncbi.nlm.nih.gov/pubmed/25689626

 

It could be completely a placebo effect, but I subjectively experienced an increased ability to learn and use information at a faster rate. If that is placebo, maybe I was just having more fun. If not, this is a pretty amazing step forward in the ability to harness our naturally-occurring biological processes, and hopefully use them at their highest capacity for as long as possible. I have found that cycling use on during times when I am able to exercise, study, and -- most importantly -- eat right and sleep well produces the kind of effects that are noticeable during and after use.

 

Edited by barbelith42, 23 May 2015 - 06:25 AM.


#23 Blake Thacker

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Posted 15 December 2016 - 04:53 AM

P21 is back in stock at Ceretropic. 

 

 Here is the Reddit thread started a few days ago.      https://goo.gl/zU7h5H


Edited by Blake Thacker, 15 December 2016 - 04:54 AM.

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#24 Christian Hunter

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Posted 14 March 2017 - 12:10 AM

 

 

I just tried 1 tenth of a dose and i had to stop. It felt like i was injecting fire. Anybody had reactions like this ? What the hell is this ?

In constrast Cerebrolysin was super smooth.

 

What's a dose, in this case? Did you mix it with bacteriostatic water, as suggested by Ceretropic (assuming that's where you bought it)? Was it intramuscular, intravenous, or subcutaneous?

 

Apart from mood stabilization and better sleep, has anyone seen actual memory improvements?

 

I can't help but think that the adamantane bonding was the wrong strategy in this case; intuitively, a lipid shell would permit better cerebral delivery without requiring much if any modification of the P6 or P6c peptides. Longvida works this way, with great success vs. pure oral curcumin. By contrast, resveratrol is delivered as a pure compound, which is rapidly neutralized by the liver and has hardly any time to do its magic; indeed, its human effects fall far short of its murine ones at the same dose per kg.

 

 

the dose was minimal i don't remember, it's been more than a month but i did mix it with bacteriostatic water and i DID buy it from ceretropic. I tried subcutaneous and as soon as i puncture 1 millimeter of skin it burned like hell, i don't think anybody could have gone through with this. i'm worried i might have used a dangerous substance. 

 

Did anyone else get this sensation of injecting burning acid into their bodies ?even ifthe batch i received wasn't good this can't be a good sign of quality. 

 

i wrote to the administrator and they didn't offer any kind of replacement products nor did they manifest really big concerns. if i were them i would have offered to analyse the batch they had sent me. 

 

don't buy this

 

 

I've had this exact thing happen to me, and I think I figured it out (at least in my case).

 

For me, it came down to my not being careful enough with the alcohol wipes.  

 

I use those small alcohol wipes (to clean the top of the rubber stoppers as well the injection area) and at least twice I believe I contaminated the solution by transferring some of the alcohol into the solution (perhaps at the dilution stage, when adding bacteriostatic water to the lyophilized powder, or even in withdrawing a dose for injection).  

 

I figured out what I did with Epitalon Amidate (the one that requires a lot of BST water to properly dilute all the solids).

 

I took a first dose/subq shot, totally fine, but next morning noticed that the solution hadn't fully dissolved the powder (tiniest bit of material on bottom), so added BST water too hastily and, though it didn't register at the time, I must have inadvertently pushed some of the alcohol into the solution because it felt like I'd injected acid!  I was furious with myself, but it did solve a mystery that occasionally spoiled a peptide.

 

Now that I'm more careful, it hasn't happened since.

 

Best, 

Christian Hunter

Austin, TX


Edited by Christian Hunter, 14 March 2017 - 12:23 AM.

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#25 Hyperflux

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Posted 14 March 2017 - 02:57 AM

I used P21 @1mg daily for 8 weeks (ceretropic spray), I don't think it was even close to all the hype. I'm not sure it did anything for me long-term. That's just me though, lots of people are raving about it.

#26 Junk Master

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Posted 14 March 2017 - 04:15 AM

I just finished a bottle of P21 nasal spray and found it very interesting.  In fact, if the cost weren't so prohibitive I'd really like to compare it to I.M. cerebrolysin.

 

One of the most fascinating aspects of P21 was how sometimes it almost felt stimulating, while others it definitely made me sleepy.

 

All in all, I really do think there were moments of enhanced clarity, calm, and focus I could attribute directly to the nasal spray.  

 

For someone with sleep apnea and idiopathic narcolepsy it almost felt like sleep in a spray...again, at times.

 

Others, I definitely felt an almost overstimulated fatigue to the point of sleepiness.



#27 monowav

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Posted 26 March 2017 - 12:35 AM

would p21 exacerbate an autoimmune disease, like MS? Anyone worried about producing CNTF antibodies? 



#28 normalizing

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Posted 26 March 2017 - 06:08 PM

so not many interested in this it seems. is it the high price? 87.99 for a small spray bottle? wow it either works great or its just costly to synthesize it



#29 beefnewton

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Posted 26 March 2017 - 06:48 PM

I used it (Ceretropic's) subcutaneously at 500mcg up to 2mg per day with no real effect, injected into very lean areas.  More hype than result for me, though others seem to be quite fond of it.



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#30 normalizing

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Posted 26 March 2017 - 07:53 PM

well, if injecting it doesnt bring much, how would nasal spray help at all






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