Semax

Semax is a rationally designed synthetic peptide based on the N-terminal fragment of adrenocorticotropic hormone (ACTH). While ACTH(4-10) retains the neurotrophic activity of the parent hormone without its steroidogenic effects, the addition of a Pro-Gly-Pro tripeptide to the C-terminus of ACTH(4-7) dramatically improves proteolytic resistance and extends the duration of central nervous system activity. This design yielded a compound with potent nootropic and neuroprotective properties. Approved in Russia since 2011 in both 0.1% and 1% intranasal formulations, Semax is prescribed for cognitive enhancement in healthy individuals, treatment of cognitive dysfunction following cerebrovascular events, and as adjunctive therapy in ischemic stroke recovery. Its mechanism centers on robust upregulation of neurotrophic factors—particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)—making it one of the few peptide agents with demonstrated neurotrophic factor-inducing capabilities in vivo. Beyond its established cognitive applications, Semax has attracted research interest for its anti-inflammatory effects in the central nervous system, its influence on gene expression profiles in brain tissue, and its potential in optic nerve and retinal neuroprotection. The peptide represents a compelling example of structure-activity relationship optimization in neuropeptide pharmacology. All information presented here is for educational and research purposes only.

Semax enhances cognitive function and provides neuroprotection through multiple synergistic mechanisms: **BDNF and NGF Upregulation**: The most well-characterized action of Semax is its robust stimulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) gene expression in the hippocampus, cortex, and basal forebrain. This effect is sustained well beyond the peptide's plasma half-life and underlies its pro-cognitive and neuroprotective properties through TrkB and TrkA receptor signaling cascades. **Melanocortin Receptor Activation**: As an ACTH fragment analog, Semax interacts with melanocortin receptors (MC3R and MC4R) in the central nervous system. These receptors are involved in synaptic plasticity, attention, learning, and memory consolidation, and their activation contributes to Semax's nootropic effects. **Anti-inflammatory CNS Effects**: Semax has been demonstrated to suppress the expression of pro-inflammatory cytokines (TNF-α, IL-1β) and chemokines in brain tissue following ischemic insult, while upregulating anti-inflammatory mediators. This neuroinflammatory modulation is critical to its neuroprotective efficacy in stroke models. **Neurovascular Protection**: Research demonstrates that Semax improves cerebral blood flow and protects the blood-brain barrier integrity during ischemic conditions, reducing infarct volume and preserving penumbral tissue in animal models of stroke. **Gene Expression Modulation**: Transcriptomic analyses reveal that Semax influences the expression of hundreds of genes in brain tissue, including those involved in neurotransmitter signaling, ion channel function, cell survival pathways (PI3K/Akt), and epigenetic regulation, indicating a broad reprogramming of neuroprotective gene networks.

Semax has been the subject of extensive research in both preclinical and clinical settings: **Ischemic Stroke Recovery**: Clinical trials in Russia have demonstrated that intranasal Semax (1%) administered in the acute phase of ischemic stroke significantly improves neurological outcomes, reduces infarct progression, and accelerates functional recovery compared to standard-of-care alone. The neuroprotective effect correlates with suppression of inflammatory gene expression in peripheral blood cells. **Cognitive Enhancement in Healthy Subjects**: Controlled studies using psychometric testing batteries have shown that Semax (0.1%) improves attention, short-term memory, and cognitive flexibility in healthy volunteers, with effects measurable for days after a course of administration. **BDNF and Neurotrophic Effects**: Quantitative PCR and ELISA studies in rodent models demonstrate that a single intranasal dose of Semax produces a 1.5- to 3-fold increase in BDNF mRNA in the hippocampus and cortex within 30 minutes, with elevated protein levels persisting for up to 24 hours. **Optic Neuroprotection**: Clinical research has explored Semax for glaucomatous optic neuropathy, with studies reporting improved visual field parameters and retinal nerve fiber layer preservation following 10-day intranasal treatment courses. **Transcriptomic Profiling**: Microarray studies of rat brain tissue reveal that Semax modulates the expression of over 200 genes in the hippocampus, with significant enrichment in pathways related to neurotransmission, immune response, vascular function, and cell survival.

Research and clinical protocols for Semax have employed the following parameters: **Standard Nootropic Dose (0.1% Solution)**: The approved Russian protocol for cognitive enhancement utilizes 2–3 drops (approximately 200–300 mcg total) per nostril, administered 2–3 times daily, for courses of 10–14 days. **Neuroprotective Dose (1% Solution)**: For acute ischemic stroke and severe cognitive impairment, the 1% formulation is used at higher total daily doses (6000–12000 mcg/day intranasally), administered in divided doses under clinical supervision. **Research Protocols**: Preclinical studies have employed intranasal doses of 50–500 mcg/kg and intraperitoneal doses of 100–1000 mcg/kg in rodent models. **Duration and Cycling**: Clinical protocols typically employ 10–14 day courses with intervals between courses. Some protocols for chronic conditions utilize repeated courses. **Note**: These are research and clinical reference ranges from Russian medical practice. Semax is not approved for therapeutic use outside of Russia. Optimal dosing for diverse populations has not been established through international Phase III trials.

Semax has demonstrated a favorable tolerability profile in clinical and research settings: **Clinical Safety Data**: In Russian clinical trials across multiple indications, Semax at both 0.1% and 1% concentrations was well tolerated. No serious adverse events were attributed to the peptide in published reports. **Reported Effects**: - Mild, transient nasal mucosal irritation with intranasal use - Occasional mild headache during initial administration - No evidence of hormonal disruption despite ACTH-derived structure (no cortisol elevation) - No reported dependence, tolerance, or withdrawal phenomena **Theoretical Considerations**: - Effects of chronic long-term use beyond established treatment courses are not well characterized - Melanocortin receptor activation theoretically could influence appetite and energy homeostasis, though clinically significant effects have not been reported - Comprehensive drug interaction studies are limited **Research Limitations**: While safety data from decades of Russian clinical use is extensive, the absence of large-scale international trials means the full safety profile by modern global regulatory standards remains to be confirmed.