Semax: ACTH Derivative Neuropeptide

Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is a synthetic heptapeptide derived from the ACTH(4-10) fragment of adrenocorticotropic hormone. Developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, Semax retains the neurotrophic properties of the ACTH(4-10) sequence while lacking the steroidogenic (cortisol-stimulating) activity of full-length ACTH.

The Pro-Gly-Pro C-terminal extension — the same stabilizing motif used in Selank — confers resistance to aminopeptidases and carboxypeptidases, extending the biological half-life beyond that of the native ACTH(4-10) fragment. Semax has a molecular weight of approximately 813.97 Da and is water-soluble.

Semax has been studied primarily for its effects on BDNF expression, cognitive function, and neuroprotection in rodent models. It represents a class of melanocortin-derived peptides that exert CNS effects independent of adrenal steroid pathways.

Semax acts through several interconnected pathways in the central nervous system.

**BDNF upregulation:** The most consistently reported molecular effect of Semax is upregulation of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in rodent hippocampal and cortical tissue. BDNF is a key mediator of synaptic plasticity, neuronal survival, and learning-related long-term potentiation. Multiple independent studies have confirmed that Semax increases BDNF mRNA and protein levels, with effects persisting for hours after a single administration.

**Melanocortin signaling:** As an ACTH derivative, Semax interacts with the melanocortin system, particularly MC3 and MC4 receptors expressed in the CNS. These receptors are involved in neuronal energy metabolism, synaptic function, and neuroimmune signaling. Importantly, Semax does not activate MC2 receptors (the adrenal ACTH receptor), which explains its lack of steroidogenic activity.

**Monoaminergic modulation:** Semax influences dopaminergic and serotonergic neurotransmission in a region-specific manner. In rodent models, it modulates dopamine turnover in the striatum and prefrontal cortex, and serotonin metabolism in the hippocampus. These effects likely contribute to its observed influence on attention, motivation, and memory processes in behavioral paradigms.

**Neuroprotective mechanisms:** In ischemia and excitotoxicity models, Semax has been shown to modulate expression of immediate early genes (c-Fos, Arc) and antiapoptotic factors (Bcl-2), suggesting engagement of endogenous neuroprotective programs.

Semax has been investigated in a range of rodent models relevant to cognitive function and neuroprotection.

N-Acetyl Semax Amidate (sometimes called Adamax) is a modified form of Semax with an N-terminal acetyl group and a C-terminal amide. These modifications further protect the peptide from enzymatic degradation and may enhance CNS penetration after intranasal administration.

Preclinical comparisons between Semax and N-Acetyl Semax are limited, but the modified form is reported to have a longer duration of action in some rodent behavioral models. The acetylation of the N-terminal methionine also protects against oxidation, which is a common degradation pathway for methionine-containing peptides.

Researchers selecting between the two forms should consider their specific experimental requirements. Standard Semax has a larger published literature and more established concentration ranges, while N-Acetyl Semax may offer advantages in protocols requiring extended activity duration or improved metabolic stability.

Semax has been administered by several routes in preclinical studies, with intranasal delivery being the most common.

**Intranasal administration:** This is the predominant route in the literature, as it provides relatively rapid CNS access via the olfactory epithelium. Typical rodent concentrations range from 50-600 mcg/kg. Peak BDNF upregulation in hippocampal tissue occurs approximately 1-3 hours after intranasal delivery.

**Stability and handling:** Reconstituted Semax should be stored at 2-8°C and used within 14 days. The methionine residue at position 1 is susceptible to oxidation — minimize air exposure and consider N-Acetyl Semax for protocols where oxidative stability is critical. Lyophilized material is stable at -20°C for 12-18 months.

**Behavioral testing timelines:** Cognitive effects (e.g., Morris water maze improvement) typically require subchronic administration (5-10 days) before behavioral testing. Neuroprotective effects in ischemia models are assessed with acute or peri-ischemic administration windows.

**Endpoint selection:** Given Semax's broad molecular profile, include both behavioral endpoints (learning, memory, anxiety) and molecular markers (BDNF protein/mRNA, monoamine levels, immediate early gene expression) to capture the full scope of compound activity.

*All materials are for research use only.*