In a world that is getting increasingly challenging to navigate, we need to be as cognitively enhanced as possible. Pinealon is a cytogen, also known as a tripeptide (EDR), composed of the amino acid sequence Glu-Asp-Arg. Contrary to its name and certain claims, Pinealon does not originate in the pineal gland, but in cortexin, indicating that it is naturally present in bovine or porcine cortex, and specifically those less than 1 year old. Current available date reveals that Pinealon is the most powerful Khavinson peptide for enhancing cognition and improving physical performance in healthy individuals. It also demonstrates potent Geroprotective and neuro-regenerative effects, which are capable of completely reversing damage caused by Alzheimer’s and Huntington’s diseases in vitro. Like all of Khavinson’s peptides, its mechanisms of action within the body involve ligand binding to various DNA promoter regions, influencing the expression of various genes.
Mechanisms of action:
With Pinealon’s remarkable capacity to directly enhance gene expression in mind, below are some of the genes it regulates, offering us a clearer understanding of how it exerts its effects.
GDF11
Pinealon possesses a binding site within GDF11 and has been observed to provide similar benefits to GDF11, including an increase in its expression.
The “GDF11 Protein as a Geroprotector” study discusses Khavinson and how GDF11 is responsible for some cognitive improvement, age reversal, and health improvement effects, particularly in blood transfusions from young to older individuals.
As mentioned, GDF11 is considered a rejuvenation factor in old age. Without supplementation, natural GDF11 levels tend to decline to near-zero at an average age of 73.71 years old. With supplementation, it reverses the aging process in male mice and reduces the depression phenotype in old mice by promoting neural autophagy. Additionally, it plays a crucial role in stem cell production and DNA repair. GDF11 has been shown to increase vasculature in the hippocampus and cortex of old mice when administered systemically. While it does not cross the blood-brain barrier (BBB) in appreciable quantities, it does show benefits in spinal cord injury. Higher GDF11 levels are associated with reduced incidence of cardiovascular events and death, as well as regenerating myocardial tissue after ischemic injury. GDF11 is also a positive regulator of muscle growth by reversing age-related dysfunction in muscle. It increases wound healing in diabetic mice and shows anti-aging benefits to the skin.
When examining “bioregulator” peptides like Pinealon, it’s essential to consider the broader context rather than focusing solely on a specific gene in isolation. Given its natural origin in young and healthy animals, it is unlikely to be detrimental to health. This is one of the reasons why Khavinson’s peptides are known for their absence of side effects.
FKBP1B
Pinealon binds to the histone H1.3 protein and increases the expression of the FKBP1b gene. FKBP1b has been shown to reverse age-related intracellular Ca2+ dysregulation as well as cognitive and memory impairments in aging rats. It also restores the expression of 872 out of 876 genes in the direction opposite of aging in the hippocampus of mice, which are associated with structure categories including cytoskeleton, membrane channels, and extracellular region. Early AD also shows downregulated FKBP1B.
PPAR’s
Pinealon significantly upregulates PPARA/G genes in humans, which have strong associations with athletic performance. PPARG upregulation is also a potential target to benefit spinal cord injury. PPAR gene polymorphisms associated with the “g” allele result in decreased function and have a high correlation to reduced hand grip strength, as well as increased risk of breast cancer and Alzheimer’s Disease. PPARA also has an important role in regulating autophagy and clearing AB plaques by increasing the microglia and astrocytes around the AB plaques and enhancing the formation of autophagosomes.
HSPA1A
Pinealon upregulates HSPA1A by about 3x in humans, though the dosage used was not specified. It codes for heat shock protein 70 and is associated with the learning process in mice put through the Morris water maze. It improves insulin sensitivity and decreases lipid counts, including within the brain. It improves wound healing in vivo, promotes proper AR function, prevents muscular dystrophy, and enhances muscle hypertrophy, as well as spermatogenesis. It prevents aggregation of misfolded proteins such those present in Alzheimer’s Disease, Huntington’s disease, and Parkinson’s Disease, possibly partially through decreased cdk5, leading to improved resistance to oxidative stress and an increase in SIRT1. Lower levels of heat shock protein 70 are also associated with ADHD in children, hinting that its upregulation may play a role in benefiting ADHD ⁹⁷.
FNDC5/Irisin
Pinealon increases FNDC5 gene expression, by binding to the gene in 5 regions, which codes for Irisin. Irisin is a positive regulator of muscle growth, and aids in restoration of the nucleus pulposus cells in mice as well as stopping disc degeneration, and protecting against motor dysfunction in rats with spinal cord injury. It has been shown to increase telomerase and therefore the Hayflick limit, as well as SIRT1, a longevity and anti-cancer pathway that activates caspases in cancer cells specifically but not healthy cells. Irisin stimulates mitochondrial biogenesis and mitophagy, prevents mitochondrial damage in PD, and provides potent antioxidant effects and reduces ferroptosis in hypoxia.
Caspase 3
Pinealon is able to bind directly to CASP3 ³⁰ and reduce caspase 3 expression, which is a regulator of apoptosis under hypoxia, and it was found to be the best peptide tested for hypoxia. Inhibition of caspase 3 results in the upregulation of mitochondrial complex 1 of the electron transport chain, leading to increased ATP. In spinal cord injury, caspase 3 is upregulated and leads to cell death, suggesting that lowering it can assist in spinal cord injury. In Alzheimer’s Disease, caspase 3 activation has been shown to occur in dendritic spines in the hippocampus, leading to activation of calcineurin and phosphorylation of glur1, and resulting in spine degeneration and memory deficits. Caspase 3 inhibition rescues these deficits. Caspase 3 inhibition is also associated with Pinealon’s purported ability to regenerate the skin.
TPH1/Serotonin
Pinealon forms a hydrogen bond in the CCTGCC promoter region of the TPH1 gene, which increases its expression. This leads to increased serotonin synthesis within cultured cerebrocortical neurons of mice origin. In humans, the TPH1 gene has been found to have low expression in the cortex but high expression in the midbrain, such as the raphe nuclei. Therefore, it can be assumed that increased serotonin synthesis primarily occurs in the midbrain in humans.
Pinealon enhances cognition, mood, TBI recovery, protects from hypoxia, reverses neurodegeneration, and improves physical performance.
- Improved intellectual markers in male wrestlers and older men
⦁ Improved spatial orientation and attention in aging rhesus monkeys while increasing the speed of learning by 1.5x - Improved mice performance in the Morris water maze and was associated with increased Nr2a/Nr2b ratio. The enhanced memory was retained even after streptozotocin-induced diabetes
- Conferred neuroprotection to NMDA receptors by inhibiting the deleterious effects of high homocysteine, through preventing homocysteine’s activation of ERK1/2 in NMDAR’s. It was noted more effective than carnosine for this purpose and at much lower concentrations.
- Improved asthenic symptoms and psych emotional state in workers under stressful conditions
- In TBI, Pinealon improved memory, lowered intensity and duration of headaches, increased emotional stability, and improved sense of well-being and being rested after a night’s sleep, accounting for Pinealon’s regenerative properties
- Pinealon is shown to completely reverse the damage to mushroom spines in hippocampal cultures treated with Aβ42 in the amyloid synaptotoxicity AD model, completely restores the damage to dendritic spines in Medium Spiny Neurons in an in vitro model of Huntington’s disease, and improves locomotion and accuracy of movements in a flying insect model of Parkinson’s disease
- Increases athletes’ performance, breath-holding time, and decreases markers of biological aging
More on the significant physical performance enhancement
Furthermore, in rats that were running on treadmill until exhaustion, it increased the time ran by up to 254%. However, it should be noted that it was injected in this study at an unknown dosage.
Pinealon also increased heart rate power curves in athletes. The heart rate was 10-12 beats per minute lower while exerting the same power output.
Pinealon vs SSRIs:
Pinealon only enhances the synthesis of serotonin through TPH1, rather than inhibiting SERT. It may have a low incidence of sexual side effects because TPH1 is expressed in the hypothalamus, where it’s shown to be a potential target to decrease neuroendocrine disruption. SSRIs are generally associated with memory impairments in humans, though not always
Pinealon vs Cortexin:
Pinealon has been shown to stimulate proliferative activity of neurons more than cortexin, as indicated by increased ki-67 and vimentin. Pinealon has also shown to reduce apoptosis more than cortexin as indicated by reduced p53 expression.
As mentioned earlier, Pinealon is also shown to improve cognition in healthy humans and improves mice performance in the water maze test more than cortexin.
ERK1/2 activation:
Serotonin signals through GPCRs to increase cAMP levels, which activates PKA, which phosphorylates CREB. CREB plays a role in LTP, which is believed to be a cellular basis for learning and memory. PKA can activate the ERK1/2 pathway directly, or it can be activated in some 5-HT receptors through GPCRs, β-arrestins, and small GTPases. ERK1/2 is not associated with an increase in inflammatory cytokines, unlike other MAPKs such as p38 and JNK ¹⁶. Irisin and ERK1/2, which Pinealon also activates directly, can each reinforce the other.
Activation of ERK1/2 influences cellular redox balance by activating NRF2, which in turn activates heme oxygenase 1, glutathione, catalase, and superoxide dismutase, all of which are antioxidants. Pinealon has been shown in a study of cerebellar neurons to activate ERK1/2, possibly through the mechanisms explained above, though it could be multifaceted, and this activation is at least partially responsible for protecting those cells in a dose-dependent manner from hydrogen peroxide. However, Pinealon’s speculated ability to bind to three regions in the GPX1 gene, which code for glutathione, and regions in the SOD1 gene which code for superoxide dismutase, may also contribute to its demonstrated antioxidant effect.
Pinealon in Alzheimer’s Disease (AD):
The above study showing protection from H2O2 is relevant to AD, as oxidative stress is one of the theories implicated in AD, and H2O2 is generated during the early stages of aggregation of amyloid plaques associated with AD. According to the A1 astrocyte theory, damage caused by amyloid plaques can trigger microglia to release pro-inflammatory cytokines, chemokines, and ROS, thereby leading to A1 type astrocytes, which ultimately cause neurons and oligodendrocytes to self-destruct. This phenomenon is also seen in Parkinson’s disease and Huntington’s disease.
The hippocampus is the main brain region where neurogenesis can still occur throughout adulthood. It has been found that reductions in hippocampal neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in neurons, and compromised hippocampal circuitry in Alzheimer’s disease. When Aβ42 peptide is added to a culture of neurons, inhibition of ERK1/2, PI3K/Akt, and consequently BDNF occurs, which leads to mitochondrial dysfunction, secretion of pro-inflammatory cytokines, and cell death ⁴⁵. GDF11 improves neurogenesis and vascularization, heatshock protein 70 prevents aggregation of misfolded proteins, PPARA improves the correct functioning of microglia and astrocytes, non-amyloidogenic ERK1/2 stimulates neurogenesis in the hippocampus, and Irisin additionally activates STAT-3 and BDNF in the hippocampus. STAT-3 activation has also been shown to reverse cognitive deficits in AD by increasing NMDAR expression and synaptogenesis, which is inhibited in AD by increased oligomeric amyloid beta peptide that causes internalization of the receptor and weakens synapses. The ERK1/2 pathway also stimulates oligodendrocytes to myelinate axons, protecting neurons. Myelination is reduced in Alzheimer’s disease and ERK1/2 restores myelination. It is through these mechanisms and all of the above targets, such as GDF11, FKBP1B, HSPA1A, and PPARA/G, that may contribute to the complete regeneration seen in Ab42 toxicity model.
Pinealon in Parkinson’s Disease (PD):
Pinealon has shown to improve symptoms in Parkinson’s disease by increasing DOPA and Dopamine. Pinealon was shown to have a binding site within the CALM1 gene, which codes for calmodulin. The binding analysis did not state whether it increased or decreased its activity. Since calmodulin can bind to Gi proteins in the D2 receptor and reduce its signaling through a cAMP mechanism, it is possible that Pinealon decreased CALM1 and hence led to an increase in D2 signaling. This would explain the enhanced locomotion and accuracy of movements witnessed in flying insects. PPARA regulates cholinergic-driven activity of midbrain dopamine through a mechanism involving α7 nicotinic receptors. This would also make sense as α7 agonists showed benefits in PD.
How to learn more about Pinealon
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