Peptides > P21 (P021)

P21 (P021)

P21 is a nootropic peptide known for its potential to enhance neurogenesis. In animal research, P21 has demonstrated the ability to elevate BDNF (brain-derived neurotrophic factor) levels, which plays a vital role in stimulating nerve growth while also reducing the formation of Amyloid plaques and Tau proteins associated with Alzheimer’s disease. BDNF is not only associated with boosting neurogenesis but also with the regulation of specific enzymes responsible for the development of tau and amyloid plaques in Alzheimer’s brains. Studies in animals have indicated that P21 can lead to improved cognitive function.

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1. What is P21?


2. P21 Peptide Structure


3. P21 Research

What is P21?

P21 is a synthetic modification designed to mimic CNTF (ciliary neurotrophic factor), a naturally occurring protein that plays a crucial role in promoting neuron growth in humans. While CNTF’s effects have primarily been explored within the nervous system, receptors for this peptide can also be found in other parts of the body, such as bone. CNTF has been demonstrated to support the synthesis of neurotransmitters and the growth of neurites. Moreover, it provides protection to neurons and their supporting cells against inflammatory attacks. Beyond its neurotrophic properties, CNTF is known to increase feelings of satiety, leading to reduced food intake.

It’s important to note that CNTF and cerebrolysin are distinct molecules, just as P21 differs from cerebrolysin. The discussion below highlights the differences between P21 and cerebrolysin.

A recombinant version of CNTF was developed and marketed as Axokine, primarily tested as a potential treatment for amyotrophic lateral sclerosis (ALS). However, Axokine is currently unavailable for sale. An intriguing observation is that the body tends to produce antibodies against Axokine relatively quickly. This suggests the possibility of co-administering P21 and exogenous CNTF in certain situations, potentially enhancing CNTF levels while minimizing the interference of antibodies.

P21 Peptide Structure

Sequence: DGGL-adamantane-G
Molecular Formula: C30H54N6O5
Molecular Weight: 578.3 g/mol
Synonyms: P021, Peptide 021

P21 Research

Development of P21 P21 is a small peptide derivative of CNTF (Ciliary Neurotrophic Factor). The development of P21 involved a process called epitope mapping. This process utilized antibodies to identify specific binding sites on the target molecule, in this case, CNTF. Antibodies against active sites of the CNTF receptor were used to initially pinpoint the CNTF binding site. These antibodies were then employed to confirm which small synthetic peptides could mimic CNTF binding, effectively interfering with antibody binding. This effort resulted in the creation of P21. P21 not only binds to the CNTF receptor but also has the ability to traverse the blood-brain barrier and placental/lactational barriers. P21 is a tetra-peptide derived from the most active region of CNTF, specifically amino acid residues 148–151. An adamantylated glycine was added to the C-terminal end of P21 to enhance its permeability through the blood-brain barrier and reduce degradation by exopeptidases.

Natural CNTF, due to its size and other limitations, cannot readily cross the blood-brain barrier, has poor plasma stability, and can even promote the development of anti-CNTF antibodies when administered systemically. While direct administration to the cerebrospinal fluid is an option, it is generally avoided due to potential pain, infection risk, and adverse effects. In contrast, P21 demonstrates exceptional stability in artificial gastric juice for over 30 minutes, allowing it to pass through the stomach in most cases. It is nearly 100% stable in the intestine over a period of two hours, facilitating absorption. Moreover, P21 remains stable in blood plasma for more than three hours.

Mechanism of Action of P21 P21 exerts several effects within the central nervous system, with its primary impact occurring in the dentate gyrus. Here, it enhances neurogenesis and neuron maturation in the granular cell layer and sub-granular zone. The dentate gyrus, part of the hippocampal formation located in the temporal lobe of the brain, contributes to the formation of new episodic memories, spontaneous exploration/learning in new environments, and information pre-processing, particularly in pattern separation. Pattern separation enables mammals to distinguish one memory from another and is of significant interest to neuroscientists because the dentate gyrus is one of the few brain regions known for substantial neurogenesis in adults.

Research in mouse models suggests that P21 does not directly bind to the CNTF receptor. Instead, it appears to inhibit antibodies or other molecules that neutralize CNTF. Consequently, P21 increases the concentration of CNTF, which is one of the most potent promoters of neurogenesis, effectively mimicking its effects.

Experiments in mice demonstrate that P21 boosts the levels of BrdU positive cells in the dentate gyrus. BrdU is a synthetic nucleoside used to detect proliferating cells in living tissues. Its concentration in the dentate gyrus of mice administered P21 is significantly higher compared to control mice, indicating that P21 promotes cell proliferation in this region. To determine whether these proliferating cells are neurons, the expression of NeuN, a marker for mature neurons, can be measured. NeuN levels are also notably increased in mice administered P21, particularly in the region of increased BrdU, supporting the notion that P21 enhances neurogenesis.


Another component of P21’s activity appears to arise through its inhibition of LIF-STAT signaling. LIF, short for leukemia inhibitory factor, is a cytokine, similar to interleukin 6, that plays an important role in embryogenesis. It is responsible for inhibiting differentiation and thus acts to bring an end to cell proliferation in a controlled way, a process that can be important for enhancing tissue maturation even if it comes at the expense of decrease proliferation. By inhibiting LIF, P21 removes one of the roadblocks to neurogenesis and thus sets the brain to a more embryologic state in which neuron growth is favored.

In Alzheimer’s Disease (AD), the brain’s natural response to damage, including the loss of neurons and synapses, is to increase activity in the dentate gyrus. Unfortunately, in many aging brains, the capacity to support neurogenesis is compromised, leading to unsuccessful attempts at replacement. P21 comes into play by enhancing the activity of the dentate gyrus enough to overcome this limitation, effectively shifting the balance of neurotrophic factors in favor of neurogenesis. This suggests that addressing the effects of AD may not be solely reliant on limiting amyloid deposition in the brain. Interestingly, despite the early onset of plaque deposition in AD, the visible effects of this deposition tend to manifest later in life when the balance of neurotrophic factors shifts away from promoting neurogenesis. Research has demonstrated that P21’s neurotrophic support leads to elevated levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-4, while also reducing the mitogenic effect of fibroblast growth factor 2 (FGF2). Intriguingly, when administered before the onset of AD in mouse models, P21 prevents the cognitive decline typically associated with the condition. This suggests that P21 may have even greater significance as a preventive measure than as a potential treatment.

It’s important to note that BDNF is not only associated with promoting neurogenesis but also with downregulating specific enzymes responsible for tau and amyloid plaque formation in AD brains. Specifically, BDNF decreases the activity of the GSK3-beta protein, which plays a critical role in catalyzing both the formation of amyloid beta from amyloid precursor protein and the phosphorylation of tau protein. These processes are key steps in the development of AD, ultimately leading to inflammation and neurodegeneration.


It’s noteworthy that the overproduction of GSK-3beta has been implicated in various disease processes, including type 2 diabetes, several forms of cancer, and bipolar disorder. There’s optimism that GSK-3beta inhibitors like P21 could prove valuable in the treatment of conditions such as stroke, cancer, and especially bipolar disorder.

Specifically, P21 appears to counteract the downward trend in MAP2 (microtubule-associated protein 2) expression in brains affected by AD. MAP2 serves as a marker for synaptic growth between neurons, and a decline in its levels suggests reduced synaptogenesis/neurogenesis, indicating disease progression in AD. Similarly, P21 has been observed to reverse decreases in:

  • Synapsin I, a crucial protein for synaptic communication between neurons.
  • GluR1 (AMPA receptor), a receptor responsible for fast synaptic transmission.
  • NR1, a glutamate receptor associated with synaptic plasticity and learning.

What’s particularly intriguing about the effects of P21 on synapsin I, GluR1, and NR1 is that it can elevate them to levels beyond what is naturally seen in both diseased and healthy brains. This has led researchers to speculate that P21 may not only be beneficial for restoring function in diseased brains but also for enhancing function in normal brains. Consequently, it holds the potential as a nootropic and cognitive performance enhancer for tasks requiring cognitive abilities. It’s important to note that research in this regard has not yet been conducted in animal models, let alone human trials. In fact, P21’s efficacy in promoting neurogenesis is so pronounced that it surpasses the levels of neurogenesis observed in healthy, untreated brains.

Dr. Khalid Iqbal, a professor of neurochemistry at the New York State Institute for Basic Research, suggests that P21 administration is likely to be most beneficial in AD and other neurodegenerative diseases when administered during the period of synaptic compensation. In simpler terms, the optimal timing for P21 administration in the context of disease is when it can enhance and support the body’s natural response to neuron loss. Given P21’s remarkable benefits and lack of serious side effects in animal studies, it appears to be an ideal candidate for use in this context. When combined with early detection using clinical biomarkers, P21 may offer a significant opportunity for neuroscience to slow or even halt the progression of neurodegeneration. Dr. Iqbal explains that in AD, particularly in the early stages, the problem lies in the imbalance between neuron death and neurogenesis. P21 helps to tilt this balance toward neurogenesis and, at least in limited animal studies, improves diseased brains even beyond the levels of neurogenesis observed in healthy brains. In essence, P21 promotes neuroplasticity by addressing deficits in neurogenesis, not only on a histological level but also in clinical measures of cognition, memory, and reasoning.

What Does P21 Do? In simple terms, P21 enhances cognitive function and provides protection to the central nervous system. It achieves these effects by promoting the maturation of precursor cells into fully developed neurons and by facilitating synaptogenesis, the formation of connections between neurons, which is crucial for learning and memory.

Specifically, P21 offers a range of benefits related to learning, memory, and cognitive function. In mouse models, it improves object discrimination and spatial reasoning. P21 increases levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-4, both of which are essential for neurogenesis and synapse formation. Notably, P21 raises the levels of these proteins beyond normal levels in healthy brains, suggesting that it may enhance learning and memory even in individuals with normal brain function.

Food Intake While there have been no direct studies on the impact of P21 on food intake, there is reason to believe it may suppress appetite. This effect is associated with the stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) synthesis, triggered by increased CNTF levels. By elevating CNTF levels through the reduction of neutralizing antibodies, P21 activates the JAK/STAT pathway, leading to increased levels of alpha-MSH. Both alpha-MSH and neurogenesis have been linked to reduced food intake, suggesting that P21 might influence satiety in future research.

Adverse Effects In mouse models of Alzheimer’s disease, P21 and its close relative P22 have not exhibited apparent side effects. While this does not guarantee a lack of side effects in humans (which remains uncertain), the absence of obvious adverse effects in mouse models provides hope that P21 may have limited side effects if it progresses to clinical trials. The only noted side effect thus far is that mice treated with P21 have lower anxiety levels compared to control animals. It’s important to note that this effect is not necessarily undesirable.

Many neurogenic compounds can induce fatigue, but there is no evidence to suggest that P21 causes fatigue at this time.

What is Cerebrolysin? Cerebrolysin and P21 are distinct substances, often confused in discussions about nootropics. Cerebrolysin is a mixture of peptides with various effects, including promoting neurogenesis. P21 has shown greater efficacy than cerebrolysin in animal studies.

How Does Cerebrolysin Work? Cerebrolysin also appears to have significant effects in the dentate gyrus. In mouse models of Alzheimer’s disease, cerebrolysin enhances synaptic plasticity and cognitive performance. While the exact mechanisms behind these benefits are not entirely clear, cerebrolysin is thought to protect neural progenitor cells (NPCs) from factors like amyloid plaques, ensuring their survival and differentiation into mature neurons. This protection contributes to increased neurogenesis.

There is reason to believe that one component of cerebrolysin may neutralize antibodies against CNTF, similar to P21. While cerebrolysin contains CNTF, this antibody-neutralizing component is likely the primary contributor to its overall effects. Researchers have identified an 11-amino-acid peptide within cerebrolysin that may be responsible for antibody neutralization. This peptide, DGGL, enhances hippocampus-dependent learning and memory in mice via neurogenesis. Importantly, DGGL is a sub-component of P21, lacking the adamantane moiety. The adamantane moiety in P21 is not the active component but helps prevent DGGL degradation and facilitates its passage across the blood-brain barrier. Consequently, while cerebrolysin is not P21, it contains a precursor to P21 and can be considered a precursor to P21 isolation and development.

Clarifying Cerebrolysin vs. P21 Cerebrolysin and P21 are distinct compounds. P21 is a synthetic analogue of CNTF, while cerebrolysin is a peptide mixture containing various brain chemicals, including CNTF. P21 comprises four amino acids from CNTF, along with an added adamantane moiety. P21 is best described as a synthetic analogue of one component of cerebrolysin, not as a derivative of cerebrolysin. P21 has demonstrated greater efficacy in animal studies than cerebrolysin, which has been largely abandoned as a treatment due to its potential to raise autoantibodies against CNTF.

Summary P21 is a nootropic peptide known for its ability to promote neurogenesis in both healthy and diseased states, although it has only been tested in mouse and rat models. It contains adamantane, a common additive in neurogenic peptides, which facilitates its passage through the blood-brain barrier. In animal studies, P21 has been shown to increase BDNF levels, promoting neurogenesis and inhibiting the formation of plaques and tangles seen in Alzheimer’s disease (AD). P21 may also affect satiety and weight gain, although further research is needed in this area. P21 and cerebrolysin, while sometimes confused, are not the same substance.

P21 exhibits minimal side effects and has good bioavailability when administered subcutaneously in mice. However, the dosage in mice does not directly scale to humans. P21 is available for purchase at Peptide Sciences, but it is intended solely for educational and scientific research purposes and should not be used for human consumption. Only licensed researchers should consider acquiring P21 for their studies.

Article Author

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.


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