Abstract
A thorough review of Semax, the synthetic heptapeptide analog of ACTH(4-10) developed in Russia, covering its molecular structure, neurotrophic mechanisms, clinical applications in stroke and cognitive enhancement, and regulatory landscape.
Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro, designed as a stabilized analog of the adrenocorticotropic hormone fragment ACTH(4-10). Originally developed in the 1980s at the Institute of Molecular Genetics of the Russian Academy of Sciences under the leadership of Nikolai Myasoedov, Semax was created to capture the nootropic and neuroprotective properties of ACTH fragments while eliminating their hormonal (steroidogenic) effects. The addition of the Pro-Gly-Pro tripeptide to the C-terminus of ACTH(4-7) dramatically enhanced metabolic stability and biological potency, yielding a compound with a remarkably broad spectrum of neurological activities.
The molecular weight of Semax is approximately 813 daltons, making it small enough for efficient absorption through nasal mucosa, which became the primary route of administration in clinical practice. The peptide's stability in biological fluids is substantially greater than that of native ACTH fragments, with the Pro-Gly-Pro extension providing resistance to aminopeptidase and carboxypeptidase degradation. Despite this enhancement, Semax retains a relatively short plasma half-life and is typically administered intranasally two to three times daily to maintain therapeutic concentrations.
The mechanism of action of Semax is multifaceted and continues to be elucidated through ongoing research. At its core, Semax functions as a potent neurotrophic factor modulator. Research has demonstrated that Semax significantly upregulates brain-derived neurotrophic factor (BDNF) expression in multiple brain regions, including the hippocampus, frontal cortex, and basal forebrain. BDNF is critical for neuronal survival, synaptic plasticity, and memory consolidation, and its upregulation represents one of the most therapeutically relevant mechanisms of Semax. Additionally, Semax has been shown to increase nerve growth factor (NGF) and neurotrophin-3 (NT-3) expression, creating a comprehensive neurotrophic milieu that supports neuronal health and function.
Beyond neurotrophic factor modulation, Semax influences multiple neurotransmitter systems. Research documents effects on dopaminergic, serotonergic, and cholinergic transmission. Semax enhances dopamine and serotonin turnover in key brain regions, which may underlie its cognitive-enhancing and mood-modulating properties. The peptide also modulates the expression of genes involved in immune function, inflammation, and vascular regulation within the central nervous system.
One of the most extensively studied clinical applications of Semax is in ischemic stroke. Russian clinical trials involving over 300 patients demonstrated that intranasal Semax administered at 12 mg per day (6 mg twice daily) during the acute phase of ischemic stroke significantly improved neurological outcomes. Treated patients showed accelerated recovery of motor function, speech, and cognitive abilities compared to standard therapy alone. The neuroprotective mechanism in stroke involves BDNF-mediated neuronal survival, anti-inflammatory effects, and modulation of the immune response in the peri-infarct zone. Genomic studies revealed that Semax modulates the expression of over 1,800 genes in the ischemic brain, with effects spanning neurotrophic signaling, inflammation, apoptosis, and neurotransmitter metabolism.
Cognitive enhancement represents another major area of Semax research. Studies in healthy volunteers demonstrated improvements in attention, memory consolidation, and information processing speed following intranasal Semax administration. A clinical study in patients with cognitive impairment of vascular origin showed significant improvements in memory, attention, and overall cognitive function after 10-day treatment courses with Semax at doses of 600 micrograms per day intranasally. The cognitive effects appear to involve both acute enhancement of neurotransmitter function and longer-term neurotrophic support.
Semax has also been investigated for its effects on the immune system. Research revealed that Semax can modulate innate and adaptive immune responses, with potential applications in immune-mediated neurological conditions. The peptide influences the expression of cytokines, chemokines, and immune cell surface markers in both central and peripheral immune compartments.
In ophthalmology, Semax has been studied for optic nerve disease, particularly in glaucomatous neuropathy. A study in patients with early-stage open-angle glaucoma showed that intranasal Semax improved visual field parameters and retinal ganglion cell function, likely through neurotrophic support of the optic nerve.
The safety profile of Semax is remarkably favorable based on extensive clinical use in Russia since its approval in 2001. The peptide is classified as a nootropic drug (not a controlled substance) and is available by prescription for stroke recovery, cognitive disorders, and optic nerve pathology. Common side effects are mild and transient, including nasal mucosa irritation with intranasal administration, occasional headache, and mild dizziness. No serious adverse events have been reported in clinical trials or post-marketing surveillance. The absence of hormonal effects, despite being derived from ACTH, has been confirmed in multiple studies showing no effect on cortisol levels or adrenal function at therapeutic doses.
An important variant is N-Acetyl Semax (NASA), which features an acetyl group on the N-terminal methionine. This modification further enhances metabolic stability and may improve blood-brain barrier penetration. N-Acetyl Semax Amidate (NASA Amidate) includes both N-terminal acetylation and C-terminal amidation, representing the most metabolically stable form. These analogs are primarily available through research chemical suppliers rather than as approved medications.
Semax received regulatory approval in Russia in 2001 and is available as a 0.1 percent and 1 percent intranasal solution under the trade name Semax. It has not received regulatory approval in the United States, European Union, or other Western jurisdictions, where it is classified as a research chemical. Despite this, Semax has generated considerable international interest in the nootropics community and among researchers studying neuroprotection and cognitive enhancement.
