Semax

Semax is a synthetic heptapeptide consisting of the ACTH(4-7) fragment (Met-Glu-His-Phe) extended with a Pro-Gly-Pro C-terminal tripeptide that confers resistance to enzymatic degradation. Unlike full-length ACTH, Semax lacks steroidogenic activity because the adrenal-stimulating domain resides in the N-terminal ACTH(1-3) sequence, which is absent. This allows Semax to selectively activate central nervous system pathways without affecting cortisol production.

Semax enhances the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus, basal forebrain, and cortex through activation of the TrkB and TrkA receptor tyrosine kinase pathways. These neurotrophins are critical for synaptic plasticity, long-term potentiation, and neuronal survival. Semax also modulates the melanocortin system, acting on MC4R receptors in the brain to influence learning, memory consolidation, and attentional processing.

Additionally, Semax has demonstrated neuroprotective effects through inhibition of oxidative stress pathways, reduction of nitric oxide synthase overexpression in ischaemic tissue, and modulation of inflammatory gene expression. It enhances cerebral blood flow and has been shown to reduce infarct volume in animal models of stroke.

Semax was developed in the 1980s at the Institute of Molecular Genetics of the Russian Academy of Sciences by a team including Nikolai Myasoedov and Isaak Ashmarin. The original design concept was to isolate the nootropic fragment of ACTH (residues 4-7, previously shown to enhance attention and memory without hormonal effects) and stabilise it against rapid enzymatic degradation.

The addition of the Pro-Gly-Pro extension increased the peptide's half-life from minutes to several hours, enabling practical therapeutic use. Semax was approved in Russia in 2001 as a nasal spray for the treatment of cognitive disorders, stroke recovery, and peptic ulcer disease. It was added to the Russian List of Vital and Essential Drugs. Research has demonstrated efficacy in improving cognitive function in stroke patients, enhancing memory and attention in healthy subjects, and providing neuroprotection in ischaemic brain injury models. Its dual nootropic and neuroprotective profile has sustained research interest across neuroscience disciplines.