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Semax: An Exotic Nootropic & Neurotrophic Factor

Semax is a 7 amino acid peptide with the following sequence: Met-Glu-His-Phe-Pro-Gly-Pro.

While you may be familiar with the term nootropic, you may not have come across a related category of neuroactive compounds called “neurotrophic factors”. This similar but distinct category of biomolecules is comprised of peptides and small proteins that control cell proliferation, survival, and differentiation of neurons. Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) are all members. Neurotrophic factors are absolutely crucial during physiological development, and they remain important during adulthood especially in the aftermath of injury in order to promote regeneration of the nervous system [1].

Neurotrophic factors have been extensively explored for their roles in supporting the survival, proliferation and maturation of certain kinds of neuronal cells. They have been shown to improve neural regeneration in neurodegerative diseases, such as Alzheimer’s Disease, Parkinson’s, and Huntington’s disease [2]. Recent researches have indicated that neurotrophic factors can be found in the tissue-specific adult stem cell niche and promote tissue regeneration outside of the nervous system all throughout your body. These research discoveries suggest that neurotrophic factors can serve as potential therapeutic candidates in adult tissue regeneration, and Semax is well positioned to be one of the first neurotrophic factors to take the market by storm.

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Semax Compound

Let’s take a look at some of the intriguing research findings that reveal Semax’s unique neuroprotective effects on the body, including the following:

  1. Improving cerebral circulation [3]
  2. Stimulating attention and operative memory [4]
  3. Treatment of ischemic brain stroke [5]–[7]
  4. Induced regeneration of damaged nerves [8]
  5. Enhancement of neural connectivity (ie. brain wiring) [9], [10]
  6. Therapy of peptic ulcer [11]
  7. Protection of memory/learning in the context of heavy metal poisoning [12]
  8. Accelerates healing of pancreas after acute pancreatitis [13]

Effective treatment of patients at different stages of stroke

In 2018, scientists sought to determine the efficacy of Semax for the treatment of patients with ischemic brain stroke [4]. One hundred and ten patients (43 men, 67 women, average age 58 years) were examined. All patients were divided into early (89±9 days) and late (214±22 days) rehabilitation groups according to how recently they suffered from a stroke. Each group was subdivided into those who received Semax or placebo. Standard regimen of Semax included 2 courses (6000 mcg/day) for 10 days with a 20-day interval. Plasma BDNF levels, motor performance on the British Medical Research Council scale and Barthel index (https://www.physio-pedia.com/Barthel_Index) were assessed in all groups.

Administration of Semax, regardless of the timing of rehabilitation, increased BDNF plasma levels which remained high during the whole study period. Administration of Semax and high BDNF levels accelerated the improvement and the final outcome of Barthel score index. There was a positive correlation between BDNF plasma levels and Barthel score, as well as a correlation between early rehabilitation and motor performance improvement.

This groundbreaking study concluded that early rehabilitation and administration of Semax increase BDNF plasma level, improved functional recovery, and recovered motor performance in patients who recently suffered from ischemic brain stroke.

Neural network enhancement confirmed by fMRI 

Numerous clinical and experimental studies have confirmed high efficiency of Semax in neurology and psychiatry [7],[14]. The neurophysiological mechanisms of these effects, however, remain unclear. Thus, scientists wanted to directly study the effects of Semax on the neuronal network of the brain using functional magnetic-resonance imaging (fMRI) which measures blood flow in different part of the brain. 

The use of functional magnetic-resonance imaging (fMRI) is based on shifts in the blood oxygenation parameters, which are assumed to reflect the dynamics of relevant neuronal activity. One of highly prevalent approaches to these studies is analysis of the relationships between the studied parameters in various brain locations and detection of the functionally specific neuronal networks associated with certain brain structures that conduct specific functions (ie. memory, emotion, etc). The default mode network (DMN) of the brain represents a group of structures (ie. the frontal cortex, parietal cortex, and lateral cortex) with the maximum functional relations at your resting state, in the absence of any kind of external task (ie. when you’re not concentrating or performing a task). This network is associated with processes of information about both your inner status and your environment: processing of information about the status of the organism and free flow of thoughts (about past, future, etc.) with emotions experienced by the host, and also what’s known as “episodic” memory.

The study was carried out on two groups of healthy volunteers (11 men and 13 women). Resting state fMRI was carried out 3 times: directly before and 5 and 20 min after intranasal 1% Semax (14 subjects) or placebo (10 subjects). Strikingly, Semax caused an increase in spatial volumes of DMN brain regions, which was the result of the involvement of a greater number of neuronal populations in the network (as a result of synchronization of neuron “firing” activity). Thus, by increasing blood flow in DMN regions, Semax is able to permit better communications between neurons [8].

Improving quality of life for patients with Motor Neuron Diseases (MND’s)

In 2007, scientists conducted a clinical trial assessing quality of life in 27 patients with definite, probable and possible diagnosis of motor neuron diseases (MND’s) treated with Semax (1% solution). Motor Neuron Diseases are a group of progressive neurological disorders that destroy motor neurons, the cells that control skeletal muscle activity such as walking, breathing, speaking, and swallowing. This group includes diseases such as amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, Kennedy’s disease, and post-polio syndrome.

Normally, messages or signals from nerve cells in the brain (upper motor neurons) are transmitted to nerve cells in the brain stem and spinal cord (lower motor neurons) and from them to muscles in the body. Upper motor neurons direct the lower motor neurons to produce muscle movements.

When the muscles cannot receive signals from the lower motor neurons, they begin to weaken and shrink in size (muscle atrophy or wasting). The muscles may also start to spontaneously twitch. These twitches (fasciculations) can be seen and felt below the surface of the skin.

When the lower motor neurons cannot receive signals from the upper motor neurons, it can cause muscle stiffness (spasticity) and overactive reflexes. This can make voluntary movements slow and difficult. Over time, individuals with MNDs may lose the ability to walk or control other movements.

To determine the efficacy of Semax to improve quality of life in patients with MND’s, scientists devised an open-label clinical trial of Semax (1% solution) conducted in sequential groups of patients. The drug was administered intranasally in two 10-day-long courses with 2-weeks break in daily dose of 12 mg. Sixty days before enrollment, and on days 1, 10, 24, 34 and 48, patients were assessed by the Norris ALS, the ALS Functioning Rating Scale and the ALSAQ-40 quality of life in the ALS scale. At the conclusion of the 2-month study, Semax was shown to significantly improve the total estimate of life quality due to the improvement of emotional state and motivation in MND patients with the maximal effect on day 10. This finding suggests that it is feasible to administer Semax in complex MND palliative therapy.

Engaging the “gut-brain axis” for peptic ulcer therapy

One of the more surprising benefits of Semax is its ability to normalize gut-brain neuronal signaling leading to improvement of symptoms for patients suffering from peptic ulcer. In the last two decades much attention has been focused on the mutual influence of the gastrointestinal tract and Central Nervous System (CNS), the so-called “gut-brain axis”. This communication is made possible by a dense neural network which consists of the afferent nerves sending information from gut to the brain and vice versa.

It is now clear that the gut-brain axis is active in both physiological and pathological conditions. It is well known that stomach dysfunction is a risk factor for behavioral disorders. Moreover, psychological distress, as manifested by anxiety and depression, is associated with functional gastrointestinal disorders via the limbic system [15], [16]. Furthermore, psychological distress is involved in the regulation of visceral pain.

The gut-brain axis has long been suspected to be involved in the mechanisms underlying gastric damage and protection, and A recent observational 11-years long study, showed a correlation between stress and the onset of ulcers [17].

To study how Semax affects patients with ulcers, scientists examined 32 patients aged 59-81 years old with documented chronic peptic ulcers prior to study enrollment. The patients were divided into two groups, and the group that was administered 1% Semax three times per day intranasally or placebo. By day 14, 89.5% of patients who received Semax experienced substantial ulcer healing vs 30.1% of patients in the control group [11].

Umbrella Labs Semax Solution

We use lyophilization (ie. freeze-drying) i to enhance the stability of peptides since the molecular reactivity of peptides in the solid state is reduced [18]. Our lyophilized peptide is stable for weeks at room temperature, as has been observed with other peptide therapeutics developed for inhalation [19]. However, it is nonetheless still advisable to refrigerate your lyophilized Umbrella Semax upon delivery, and certainly before you dissolve it. Once dissolved, it should always be kept cold and dark to minimize degradation (ie. don’t let the bottle warm up on your countertop after each use).

Semax contains a methione (Met) amino acid residue, which is sensitive to oxidation especially in the presence of water [20]. Since the oxidation of Semax results in decreased potency, it is essential that steps are taken to maximize the longevity of dissolved Semax by employing an antioxidant approach. A common water-soluble food-grade antioxidant used for preservation is ascorbic acid, which is a form of vitamin C. In fact, recent research at Stanford University demonstrates that nasal spray biocompatibility and shelf-stability is best when using a pH-buffered citric acid solution rather than employing conventional preservatives that can irritate nasal membranes [21]. Thus, we leverage the strong antioxidant capacity of ascorbic acid in our Umbrella nasal spray solution to ensure dissolved peptide stability while maintaining biocompatibility and limiting irritation caused by chemical preservatives commonly found in other nasal sprays.

Conclusion

Semax is a fascinating neuroprotective peptide that offers unparalleled insurance against neurodegeneration from both internal and external assaults to your brain. Given the fact that Semax’s effect on cognition is subtle, it is not a nootropic of choice for those seeking a psychotropic experience. However, for anyone seeking proven neurological protection without adverse effects, Semax is becoming the neurotrophic factor of choice for the most discerning individuals.

References

  1. H. B. Stolp, “Neuropoietic cytokines in normal brain development and neurodevelopmental disorders,” Mol. Cell. Neurosci., 2013.
  2. K. Heese, W. L. Jin, and N. Inoue, “Nerve growth factor, neural stem cells and Alzheimer’s disease,” NeuroSignals. 2006.
  3. J. K. Buitelaar, H. van Engeland, J. M. van Ree, and D. de Wied, “Behavioral effects of Org 2766, a synthetic analog of the adrenocorticotrophic hormone (4-9), in 14 outpatient autistic children,” J. Autism Dev. Disord., 1990.
  4. I. P. Asmarin et al., “[A nootropic adrenocorticotropin analog 4-10-semax (l5 years experience in its design and study)].,” Zh. Vyssh. Nerv. Deiat. Im. I P Pavlova, 1997.
  5. E. I. Gusev, M. Y. Martynov, E. V. Kostenko, L. V. Petrova, and S. N. Bobyreva, “The efficacy of semax in the tretament of patients at different stages of ischemic stroke,” Zhurnal Nevrol. i Psihiatr. Im. S.S. Korsakova, 2018.
  6. E. V. Medvedeva, V. G. Dmitrieva, S. A. Limborska, N. F. Myasoedov, and L. V. Dergunova, “Semax, an analog of ACTH(4−7), regulates expression of immune response genes during ischemic brain injury in rats,” Mol. Genet. Genomics, 2017.
  7. I. P. Ashmarin, V. N. Nezavibatko, N. G. Levitskaya, V. B. Koshelev, and A. A. Kamensky, “Design and investigation of an ACTH(4-10) analogue lacking D-amino acids and hydrophobic radicals,” Neurosci. Res. Commun., 1995.
  8. G. S. Polunin, S. M. Nurieva, D. L. Baiandin, N. L. Sheremet, and L. A. Andreeva, “Opredelenie terapevticheskoi éffektivnosti novogo otechestvennogo preparata ‘Semaks’ pri zabolevaniiakh zritel’nogo nerva.,” Vestn. Oftalmol., 2000.
  9. I. S. Lebedeva et al., “Effects of Semax on the Default Mode Network of the Brain,” Bull. Exp. Biol. Med., vol. 165, no. 5, pp. 653–656, Sep. 2018.
  10. W. Li, X. Mai, and C. Liu, “The default mode network and social understanding of others: What do brain connectivity studies tell us,” Front. Hum. Neurosci., 2014.
  11. I. O. Ivanikov, M. E. Brekhova, G. E. Samonina, N. F. Myasoedov, and I. P. Ashmarin, “Therapy of peptic ulcer with semax peptide,” Bull. Exp. Biol. Med., 2002.
  12. A. N. Inozemtsev, S. B. Bokieva, O. V. Karpukhina, K. Z. Gumargalieva, A. A. Kamensky, and N. F. Myasoedov, “Semax prevents learning and memory inhibition by heavy metals,” Dokl. Biol. Sci., 2016.
  13. Y. I. Ivanov and V. V. Yasnetsov, “Effects of semax and mexidol on the course of acute pancreatitis in rats,” Eksp. i Klin. Farmakol., 2000.
  14. S. J. Tsai, “Semax, an analogue of adrenocorticotropin (4-10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndrome,” Med. Hypotheses, 2007.
  15. M. P. Jones et al., “A multidimensional model of psychobiological interactions in functional dyspepsia: A structural equation modelling approach,” Gut, 2013.
  16. N. Clauwaert et al., “Associations between gastric sensorimotor function, depression, somatization, and symptom-based subgroups in functional gastroduodenal disorders: Are all symptoms equal?,” Neurogastroenterol. Motil., 2012.
  17. S. Levenstein, S. Rosenstock, R. K. Jacobsen, and T. Jorgensen, “Psychological stress increases risk for peptic ulcer, regardless of helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs,” Clin. Gastroenterol. Hepatol., 2015.
  18. M. G. Fakes, M. V. Dali, T. A. Haby, K. R. Morris, S. A. Varia, and A. T. M. Serajuddin, “Moisture sorption behavior of selected bulking used in lyophilized products,” PDA J. Pharm. Sci. Technol., 2000.
  19. S. Hengsawas Surasarang, G. Florova, A. A. Komissarov, S. Shetty, S. Idell, and R. O. Williams, “Formulation for a novel inhaled peptide therapeutic for idiopathic pulmonary fibrosis,” Drug Dev. Ind. Pharm., 2018.
  20. X. Liang, A. Kaya, Y. Zhang, D. T. Le, D. Hua, and V. N. Gladyshev, “Characterization of methionine oxidation and methionine sulfoxide reduction using methionine-rich cysteine-free proteins,” BMC Biochem., 2012.
  21. W. R. Ryan and P. H. Hwang, “Safety of a preservative-free acidified saline nasal spray: A randomized, double-blind, placebo-controlled, crossover clinical trial,” Arch. Otolaryngol. – Head Neck Surg., 2010.

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