Semax, a synthetic analog of ACTH(4-10) with nootropic properties: a review

This comprehensive review compiles decades of research on Semax, a synthetic heptapeptide derived from the ACTH(4-10) fragment with a Pro-Gly-Pro extension for enhanced stability. Developed in Russia, Semax represents an innovative approach to developing nootropics based on endogenous peptide fragments.

The review details multiple nootropic and neuroprotective effects documented in preclinical and clinical studies:

• Improved learning and memory consolidation across various behavioral paradigms
• Enhanced sustained and selective attention
• BDNF upregulation (brain-derived neurotrophic factor), one of the key mechanisms
• Modulation of neurotrophin gene expression in the hippocampus and cortex

The molecular mechanisms discussed include:

• Activation of melanocortin MC3 and MC4 receptors in the central nervous system
• Modulation of the dopaminergic, serotonergic, and cholinergic systems
• Antioxidant and anti-inflammatory effects in neural tissue
• Influence on immediate early gene expression (c-fos, c-jun)

A highlighted aspect is the absence of corticotropic activity of Semax — despite being derived from ACTH, the peptide does not affect cortisol levels, eliminating undesirable endocrine effects. The review also addresses relevant pharmacokinetic aspects, such as intranasal administration allowing direct CNS access via the olfactory nerve. Semax is approved in Russia and Ukraine as a nootropic and neuroprotective medication, representing one of the few nootropic peptides with formal regulatory approval.