By Cocer Peptides 
23 days ago
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Aging, as an inevitable natural process in living organisms, has long been a focal point of scientific research. As organisms age, cells gradually enter a senescent state, and the accumulation of these senescent cells can negatively impact the normal functioning of tissues and organs, leading to various age-related diseases. FOX04 – DRI is beneficial for clearing senescent cells.
Overview
DSIP peptide, Delta-Sleep-Inducing Peptide, is a neuro-regulatory peptide bio-regulator. It promotes sleep regulation. Additionally, it influences body temperature regulation, heart rate, blood pressure, pain threshold, and the lymphatic factor system, with these effects exhibiting circadian rhythm dependency.
Mechanism of Action of DSIP Peptide on Sleep
Neurotransmitter Regulation
5-Hydroxytryptamine (5-HT): 5-HT is an important neurotransmitter closely associated with sleep regulation. In insomnia states, such as the PCPA-induced insomnia model, 5-HT levels are significantly reduced. Research indicates that DSIP peptides can increase 5-HT levels in hippocampal tissue, thereby improving sleep. 5-HT can regulate neuronal excitability by acting on different receptor subtypes, thereby influencing the sleep-wake cycle. 5-HT1A receptor agonists can promote non-rapid eye movement (NREM) sleep, while 5-HT2A receptor antagonists may reduce wakefulness time, and increase total sleep time. DSIP peptides may exert their regulatory effects on sleep by modulating the release, reuptake, or interaction with receptors of 5-HT.
Dopamine (DA): Dopamine also plays a crucial role in sleep regulation. Under normal conditions, the activity of dopaminergic neurons contributes to maintaining wakefulness. Imbalances in dopamine levels may lead to sleep disorders. In some insomnia models, dopamine levels decrease, and DSIP peptides can partially restore dopamine levels. Dopamine regulates neural signaling by binding to different dopamine receptors. DSIP peptides may improve sleep by influencing the activity of dopaminergic neurons, regulating dopamine synthesis, release, or metabolism. It can act on key enzymes involved in dopamine synthesis, such as tyrosine hydroxylase, affecting the rate of dopamine synthesis and thereby influencing the sleep-wake balance.
Glutamate (Glu): Glutamate is the primary excitatory neurotransmitter in the central nervous system. During insomnia, glutamate levels may be altered. Scientific studies have found that DSIP peptides can regulate glutamate levels in hippocampal tissue, increasing reduced glutamate levels in some models. Glutamate regulates neuronal excitability by binding to ionotropic and metabotropic glutamate receptors. DSIP peptides can maintain neuronal excitability balance by regulating glutamate receptor function or influencing glutamate release and uptake mechanisms, thereby exerting a positive effect on sleep. They can modulate the activity of glutamate transporters to control extracellular glutamate concentrations, preventing excessive or insufficient levels from adversely affecting sleep.
Melatonin (MT): Melatonin is an amine hormone secreted by the pineal gland that plays a crucial role in regulating the sleep-wake cycle. In a rat model of insomnia, melatonin levels in the hippocampus were significantly reduced, and DSIP peptide was able to increase melatonin levels. Melatonin regulates the circadian rhythm and sleep by binding to MT1 and MT2 receptors. DSIP may exert its regulatory effects on sleep by influencing melatonin synthesis and secretion in the pineal gland, or by modulating the expression and function of melatonin receptors. It may regulate the activity of key enzymes involved in melatonin synthesis, such as aromatase N-acetyltransferase (AANAT), thereby influencing melatonin synthesis levels.
Figure 2 Expression of FOXO4 in human testes detected by immunofluorescent staining.
Effects on neuronal cells
In a PCPA-induced insomnia rat model, HE staining revealed that the model group rats exhibited significantly increased intercellular spaces, smaller cell size, irregular morphology, and loose matrix in the hippocampal tissue. In contrast, the DSIP peptide-treated group (such as the sleep peptide combined with cell-penetrating peptide group P-DSIP) showed reduced intercellular spaces, more ordered cell arrangement, and more uniform distribution in the hippocampal tissue. This suggests that DSIP peptide can improve sleep-induced damage to hippocampal neurons, maintain their normal morphology and structure, thereby ensuring their normal physiological functions, and facilitate sleep regulation. The normal structure of neurons is the foundation for neural signal transmission and integration. The protective effect of DSIP peptide on neuronal cells may help restore the normal function of neural pathways related to sleep regulation.
DSIP peptides may influence neuronal electrophysiological activity. Neurons transmit information by generating action potentials, and the electrical activity patterns of neurons change during sleep. DSIP peptides may regulate ion channels on neuronal cell membranes, altering neuronal excitability and firing frequency, thereby influencing sleep states. They may enhance the activity of certain potassium ion channels, making neurons more prone to entering a resting state and promoting the onset of sleep.
Blood-brain barrier-related mechanisms
The blood-brain barrier (BBB) is an important barrier between blood and brain tissue, restricting the entry of many substances from blood into brain tissue. The metabolism of DSIP peptides at the blood-brain barrier is catalyzed by aminopeptidases. In cultured bovine brain microvascular endothelial cells (BBMEC, a blood-brain barrier model), peptidyl dipeptidase A can also metabolize DSIP by sequentially hydrolyzing dipeptides or tripeptides from the carboxy terminal of this nonapeptide. By adding peptidyl dipeptidase A inhibitors (such as captopril) and aminopeptidase inhibitors (such as besartan), DSIP metabolism in BBMECs can be completely stabilized, indicating that by regulating the activity of these enzymes, more DSIP peptides can cross the blood-brain barrier and reach brain tissue to exert their sleep-regulating effects. A study attempted to fuse DSIP peptides with peptides capable of crossing the blood-brain barrier (such as CBBBP) to form DSIP-CBBBP fusion peptides. These fusion peptides can better regulate neurotransmitter levels, such as 5-HT, glutamate, dopamine, and melatonin, resulting in better effects on improving sleep. By optimizing the ability of DSIP peptides to cross the blood-brain barrier, their regulatory effects on sleep can be enhanced.
The role of DSIP peptides in improving sleep
1. Increasing total sleep time
In animal experiments, DSIP peptides demonstrated the ability to increase total sleep time in animals, regardless of whether administered via intravenous or nasal routes. In experiments with New Zealand white rabbits, intravenous injection of DSIP peptides resulted in a significant increase in total sleep time compared to the saline control group. Intranasal administration was equally effective, with the intranasal group of New Zealand white rabbits exhibiting significantly longer total sleep time than the saline group. This indicates that DSIP peptide can effectively promote the onset of sleep in animals and maintain prolonged sleep duration. Increased total sleep time is crucial for bodily recovery and the maintenance of normal physiological functions, as it allows all organs and systems to rest adequately, aiding in tissue repair, endocrine system regulation, and other processes.
In a rat model exposed to chronic low-pressure hypoxia (HH), intervention with phosphorylated DSIP peptide (p-DSIP) was administered. According to the results, p-DSIP enhanced non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) in rats, increasing total sleep time. This demonstrates that DSIP peptide promotes sleep across different sleep states, improving sleep structure and enhancing sleep quality.
2. Extending slow-wave sleep duration
Slow-wave sleep (SWS), also known as deep sleep, is crucial for bodily recovery and repair. DSIP peptide significantly extends slow-wave sleep duration in animals. In experiments with New Zealand white rabbits, both intravenous and intranasal administration of DSIP resulted in significantly longer slow-wave sleep duration in the treated group compared to the saline control group. During the slow-wave sleep stage, metabolic rate decreases, and physiological activities such as heart rate and breathing slow down, allowing the body to engage in self-repair and energy storage. DSIP peptides can extend slow-wave sleep duration, thereby enhancing the body's recovery capacity, alleviating fatigue, and strengthening immunity.
From a neurobiological perspective, DSIP peptides may regulate neurotransmitter levels, increase 5-HT and melatonin levels, and inhibit excessive neuronal excitation in the brain, thereby promoting the onset and maintenance of slow-wave sleep. Its protective effects on neuronal cells, maintaining their normal structure and function, also contribute to creating a neural environment conducive to slow-wave sleep.
3. Improving sleep-related behaviors
In behavioral experiments, such as the open field test, elevated plus maze test, and tail suspension test, DSIP peptides demonstrated significant improvements in the behavioral performance of insomniac animals. In the open field test, the model group rats showed significantly reduced movement distance and activity time, while rats treated with DSIP peptide (e.g., the P-DSIP group) exhibited significantly increased movement distance and activity time, indicating that DSIP peptide can improve the activity capacity of insomniac rats and alleviate activity inhibition caused by insomnia. In the elevated plus maze test, the number of times the model group rats entered the open arm and the time spent in the open arm were significantly reduced. However, after administration of DSIP peptide, such as in the P-DSIP group, the number of times the rats entered the open arm and the time spent in the open arm significantly increased, indicating that DSIP peptide can improve anxiety-like behavior in insomniac rats. In the tail suspension test, the model group rats showed a significant increase in immobility time and a significant decrease in struggle time. However, after administration of DSIP peptide (such as the GABA group, P-DSIP group, and DSIP group), the rats showed a significant decrease in immobility time and a significant increase in struggle time, indicating that DSIP peptide can improve depressive-like behavior in insomniac rats. DSIP peptide can improve emotional and behavioral issues caused by insomnia.
Applications of DSIP Peptide in Sleep Regulation
In clinical research, in some small-scale clinical observations, after administering DSIP peptide-related formulations to insomnia patients, the sleep quality of some patients improved to varying degrees, such as shorter sleep onset time, increased sleep depth, and reduced nighttime awakenings. Additionally, DSIP peptide can be used alone for insomnia treatment or in combination with other traditional sleep medications. Research indicates that when combined with certain anxiolytic or antidepressant medications, DSIP peptides exhibit synergistic effects, effectively improving patients' sleep quality and emotional state. When used in combination with benzodiazepines, DSIP peptides can reduce the dosage of benzodiazepines, lower the risk of adverse reactions, and enhance therapeutic efficacy.
Conclusion
As a natural sleep regulator, DSIP peptide demonstrates efficacy in sleep regulation mechanisms, sleep improvement effects, and application aspects.
Sources
[1] Mu X, Qu L, Yin L, et al. Pichia pastoris secreted peptides crossing the blood-brain barrier and DSIP fusion peptide efficacy in PCPA-induced insomnia mouse models[J]. Frontiers in Pharmacology, 2024,15. https://api.semanticscholar.org/CorpusID:273205621
[2] Roy K, Chauhan G, Kumari P, et al. Phosphorylated delta sleep inducing peptide restores spatial memory and p-CREB expression by improving sleep architecture at high altitude[J]. Life Sciences, 2018,209:282-290.DOI:10.1016/j.lfs.2018.08.026.
[3] Augustijns P F, Ng K Y, Williams T M, et al. Peptidyl dipeptidase A-catalyzed metabolism of delta sleep-inducing peptide in bovine brain microvessel endothelial cells: a cell culture model of the blood brain barrier[J]. Biochemical and Biophysical Research Communications, 1995,210(3):987-994.DOI:10.1006/bbrc.1995.1754.
[4] Yehuda S, Carasso R L. DSIP--a tool for investigating the sleep onset mechanism: a review[J]. International Journal of Neuroscience, 1988,38(3-4):345-353.DOI:10.3109/00207458808990695.
[5] Obál F J, Kovalzon V M, Kalikhevich V N, et al. Structure-activity relationship in the effects of delta-sleep-inducing peptide (DSIP) on rat sleep[J]. Pharmacology Biochemistry and Behavior, 1986,24(4):889-894.DOI:10.1016/0091-3057(86)90432-6.
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