Semax

Semax Research

What is Semax?

Semax is a synthetic peptide compound and belongs to a type of nootropic. Its main component is an analog of thyrotropin-releasing hormone (TRH), combined with other amino acids (such as valine and leucine). Semax can improve cognitive functions by regulating neurotransmitters (such as dopamine and norepinephrine) in the central nervous system, including enhancing memory, improving attention, and learning ability.

What is the research background of Semax?

Development based on ACTH fragments: 

Semax is composed of the ACTH (4 - 7) fragment and the tripeptide Pro - Gly - Pro (PGP). ACTH, namely adrenocorticotropic hormone, is a hormone secreted by the anterior pituitary gland and plays an important role in regulating the function of the adrenal cortex. Researchers analyzed the structure of ACTH, extracted a specific fragment (4 - 7) from it, and combined it with the tripeptide PGP to synthesize Semax. This synthesis method enables Semax to retain part of the activity of ACTH and also have unique biological characteristics ^[1].

Exploration of epilepsy treatment: 

Epilepsy is a disorder of brain function characterized by abnormal depolarization of neurons. Seizures are a major symptom of epilepsy, usually caused by brain injury. Although current drugs for treating epilepsy have certain effects, they also have some negative health impacts. In this situation, researchers began to look for new treatment methods. As a neuropeptide, Semax peptide acts directly on the central nervous system and has no hormonal activity, so it will not cause negative health impacts. This provides new possibilities for the treatment of epilepsy ^[2].

Treatment of ischemic stroke: 

Ischemic stroke is a serious disease, and due to its high incidence and high disability rate, it has always been a focus of medical research. Semax peptide, due to its neuroprotective and immunomodulatory effects, is applied to the treatment of ischemic stroke. Studies have shown that Semax can inhibit the expression of inflammatory genes and activate the expression of neurotransmitter genes, thus exerting neuroprotective effects at the transcriptional and protein levels ^{[3, 4]}.

A new direction for the treatment of depression: 

Selective serotonin reuptake inhibitors (SSRI) are commonly used drugs for the treatment of depression during pregnancy, but SSRIs can cross the placenta and may affect the maturation of the fetal brain. As a synthetic analog of ACTH (4-10), Semax has obvious nootropic and neuroprotective activities. Research has found that Semax can reduce the behavioral and neurochemical changes in rats caused by early exposure to fluvoxamine, providing a new idea for the treatment of depression^[5].

Advantages of peptide substances: 

Semax is a synthetic peptide substance with a unique mechanism of action. It can act directly on the central nervous system, synthesize some proteins in the brain, and exert antioxidant effects. For example, in a rat model of epilepsy, Semax peptide can reduce the MDA level and synthesize three proteins that are not synthesized in epileptic rats^[2].

As a regulatory peptide, the research history of Semax can be traced back a long time ago. Studies have shown that Semax has application prospects in memory disorders, decreased efficiency of mental work, and post-COVID syndrome, in addition to somatoform and psychosomatic diseases^[6].

Analysis of changes in the level of the pJNK and pCREB proteins during ischemia and Semax treatment in the subcortical structures and frontoparietal cortex of rats at 24 h after tMCAO.

Source:PubMed^[4]

How does the mechanism of action of Semax in treating epilepsy specifically affect brain function?

Antioxidant effect

Semax has antioxidant properties. Epilepsy usually leads to an increase in oxidative stress in the brain, and Semax can reduce the damage to the brain caused by oxidative stress. Oxidative stress will produce excessive reactive oxygen species, such as malondialdehyde (MDA). Studies have shown that Semax can reduce the MDA level in the brains of epileptic rats by up to 40.46%^[2]. By reducing the MDA level, Semax can alleviate the damage of oxidative stress to neurons, thus protecting brain function.

Synthesis of brain proteins

Semax can synthesize some proteins in the brain. In the study of epileptic rats, after treatment with Semax, three proteins that were not synthesized in epileptic rats were synthesized. The molecular weights of these proteins are 93.54kDa, 66.76kDa, and 59.66kDa^[2]. They can play important roles in maintaining the normal function of the brain and repairing damaged neurons.

Influence on the brain neuron network

Through resting-state functional magnetic resonance imaging (resting-state FMRI) studies, it has been found that Semax has an impact on the brain neuron network. In the study of healthy volunteers, compared with the control group, a larger volume of the rostral (intermediate anterior cortex) sub-component of the default mode network was detected in the Semax group^[7]. This indicates that Semax may improve brain function by regulating the connections and activities of the brain neuron network.

When Semax was injected daily into audiogenic seizure-prone rats from the 7th to the 11th day of life, it was found that the audiogenic seizure pattern of the rats changed when they were 1 month old, and both drugs could enhance neurogenesis in the hippocampal dentate gyrus. Neurogenesis may be related to the learning, memory, and repair functions of the brain, and Semax may improve brain function by promoting neurogenesis.

When Semax was injected into five inbred mouse strains of newborns (from the 2nd to the 7th day of life), it significantly reduced the susceptibility to convulsions only in 1-month-old DBA / 2J mice^[8]. This also indicates that Semax may affect brain function through some mechanism and reduce the susceptibility to epilepsy.

Lack of hormonal activity

Semax is a neuropeptide that acts directly on the central nervous system and has no hormonal activity, so it will not cause negative health effects (Puspita R, 2018). This gives Semax certain advantages in the treatment of epilepsy, avoiding the possible side effects of traditional antiepileptic drugs.

What is the specific mechanism by which Semax regulates immune function?

Enhancing immune response-related signaling pathways: 

Semax can enhance the antigen presentation signaling pathway. Antigen presentation is a key process for the immune system to recognize and process foreign antigens. By enhancing this signaling pathway, Semax can promote the recognition and response of the immune system to foreign substances such as pathogens^[1]. In addition, Semax can also strengthen the impact of ischemia on the interferon signaling pathway. Interferon plays an important regulatory role in the immune response, including antiviral, antitumor, and regulating the activity of immune cells. The strengthening of the interferon signaling pathway by Semax helps to improve the overall activity of the immune system^[1].

Influencing the immunoglobulin synthesis process: 

Semax significantly increases the expression of genes encoding the heavy chains of immunoglobulins. Immunoglobulins play a key role in humoral immunity and can specifically bind to antigens, thus eliminating foreign substances such as pathogens. Semax promotes the synthesis of immunoglobulins, which helps to enhance the humoral immune function of the body ^[1].

Regulating the activity of immune cells: 

Semax has a great influence on genes encoding cytokines, stress responses, and ribosomal proteins. Cytokines play an important role in immunomodulation and can regulate the proliferation, differentiation, and activity of immune cells. Semax regulates the activity of immune cells by influencing the expression of these genes, thereby regulating immune function^[1].

What are the applications of Semax?

Treatment of epilepsy

Influence on neurons: 

Epilepsy is a disorder of brain function characterized by abnormal depolarization of neurons. Semax peptide is a neuropeptide that acts directly on the central nervous system and does not contain hormonal activity, so it will not have a negative impact on health. Semax can reduce the MDA level in the brains of epileptic rats. MDA is an indicator of lipid peroxidation, and high levels of MDA are associated with oxidative stress and cell damage. Semax can reduce the MDA level in the brains of epileptic rats by up to 40.46% ^[9].

Synthesis of proteins: 

Semax can also synthesize some proteins in the brains of epileptic rats. Studies have found that Semax can synthesize three proteins that were not originally synthesized in the brains of epileptic rats, and the molecular weights of these proteins are 93.54 kDa, 66.76 kDa, and 59.66 kDa respectively^[9].

Treatment of ischemic stroke

Enhancing neurotrophin transcription: 

Semax (MET-GLU - amino acid - phenylalanine - proline - glycine - proline) peptide is a synthetic melanocortin derivative used for the treatment of ischemic stroke. Studies have shown that Semax can enhance the transcription of neurotrophins and their receptors and modulate the expression of genes involved in the immune response. Whole-genome RNA sequencing analysis shows that in the transient middle cerebral artery occlusion (tMCAO) model in rats, Semax inhibits the expression of inflammatory genes and activates the expression of neurotransmitter genes^[4].

Regulating the expression of key proteins: 

24 hours after tMCAO, an upregulation of active CREB was observed in subcortical structures, including the focus of ischemic injury; MMP - 9 and c - fos were downregulated in the adjacent frontoparietal cortex; under the action of Semax, active JNK was also downregulated in these two tissues. The inhibition and recovery of activation in the processes of inflammation and cell death may contribute to the neuroprotective effect of Semax at the transcriptional and protein levels ^[4].

Relieving acute stress

Reducing pain: 

In an acute stress model, Semax has a certain impact on the behavior and pain sensitivity of rats. In the inescapable intermittent foot shock stress and forced cold water swimming stress models, both Semax and the opioid receptor antagonist naloxone can attenuate the stress-induced analgesia (SIA) in the inescapable foot shock stress model, but do not affect the pain threshold in the forced cold water swimming stress model^[10].

No impact on behavioral changes: 

Both Semax and naloxone do not affect the behavior of rats in the above acute stress models^[10].

Improving memory and attention: 

Semax can stimulate the working memory and attention of experimental animals and humans, increase resistance to hypoxia, and improve cerebral blood circulation. Semax significantly improves the memory and attention of healthy people under extreme activity conditions. In addition, Semax has currently been successfully used to treat patients with different diseases of the central nervous system. In most cases, this peptide shows positive effects without producing negative side effects or complications related to administration^[11].

In conclusion, as a synthetic peptide compound, Semax shows significant curative effects in the fields of epilepsy, ischemic stroke, acute stress, and cognitive impairment through multiple mechanisms such as regulating the expression of neurotrophins (such as BDNF) and their receptors (TrkB), inhibiting the inflammatory response, resisting oxidative stress, and immunomodulation. It can also improve the recovery of nerve function, reduce brain damage, and enhance memory and attention.

Relevant Citations

[1] Medvedeva E V, Dmitrieva V G, Limborska S A, et al. Semax, an analog of ACTH(4-7), regulates expression of immune response genes during ischemic brain injury in rats[J]. Molecular Genetics and Genomics, 2017,292(3):635-653.DOI:10.1007/s00438-017-1297-1.

[2] Puspita R, Pratamastuti D, Safitri A, et al. The Potency of Semax Peptide Therapy toward MDA Level and Protein Profile in Epilepsy Rats (Rattus norvegicus), 2018[C]. https://api.semaxnticscholar.org/CorpusID:90160574

[3] Dergunova L V, Dmitrieva V G, Filippenkov I B, et al. The Peptide Drug ACTH(4-7)PGP (Semax) Suppresses mRNA Transcripts Encoding Proinflammatory Mediators Induced by Reversible Ischemia of the Rat Brain[J]. Molecular Biology, 2021,55(3):346-353.DOI:10.1134/S0026893321010040.

[4] Sudarkina O Y, Filippenkov I B, Stavchansky V V, et al. Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion[J]. International Journal of Molecular Sciences, 2021,22(12).DOI:10.3390/ijms22126179.

[5] Glazova N Y, Manchenko D M, Volodina M A, et al. Semax, synthetic ACTH(4-10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats[J]. Neuropeptides, 2021,86.DOI:10.1016/j.npep.2020.102114.

[6] Hadarceva K, Belyaeva E. Semax-application prospect (brief overview message).[J]. Clinical Medicine and Pharmacology, 2021.DOI:https://api.semaxnticscholar.org/CorpusID:245468513.

[7] Lebedeva I S, Panikratova Y R, Sokolov O Y, et al. Effects of Semax on the Default Mode Network of the Brain[J]. Bulletin of Experimental Biology and Medicine, 2018,165(5):653-656.DOI:10.1007/s10517-018-4234-3.

[8] Boyarshinova O S, Perepelkina O V, Markina N V, et al. Audiogenic Epilepsy in Young Mice of Different Strains after Neonatal Semax Treatment[J]. Bulletin of Experimental Biology and Medicine, 2008,146(1):86-88.DOI:10.1007/s10517-008-0212-5.

[9] Puspita R. Semax for Epilepsy Treatment[M]. 2020.DOI:10.31219/osf.io/hcn3g.

[10] Glazova N Y, Manchenko D M, Vilensky D A, et al. Effects of Semax in the Rat Models of Acute Stress[J]. Journal of Evolutionary Biochemistry and Physiology, 2023,59(1):200-212.DOI:10.1134/S0022093023010179.

[11] Ashmarin I P, Nezavibatko V N, Myasoedov N F, et al. Nootropic analogue of adrenocorticotropin 4-10-semax (the experience of design and investigation over 15 years)[J]. Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I P Pavlova, 1997,47(2):420-430. https://pubmed.ncbi.nlm.nih.gov/9173745/