Semax: ACTH(4-10) Analogue — Neuroprotection & Cognitive Function

Semax is a synthetic heptapeptide of sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), derived from the ACTH(4-7) fragment with the Pro-Gly-Pro tripeptide added for enzymatic stability. Developed at the Institute of Molecular Genetics of the Russian Academy of Sciences by Myasoedov and colleagues, it is described in the literature as a nootropic and neuroprotective peptide, approved for clinical use in Russia.

Semax acts as a melanocortin analogue without corticotropic activity: it does not stimulate cortisol release. Transcriptome (RNA-Seq) studies in tMCAO cerebral ischemia models (Filippenkov et al. 2020, PMID 32580520) document that Semax suppresses pro-inflammatory genes and activates neurotransmission genes — an inverse pattern to untreated ischemia. Additionally, it modulates BDNF and NGF in the hippocampus and cortex.

Semax (MEHFPGP) is derived from ACTH(4-7) with a primarily nootropic and neuroprotective profile — studies focus on cognition, ischemic stroke, and BDNF. Selank (TKPRPGP) is derived from endogenous tuftsin with a primarily anxiolytic profile — phase III clinical trials document anxiety reduction without sedation. Both share the PGP addition for stability. The literature describes combined use for cognition + anxiety indications.

In Russia, Semax has approval from the Ministry of Health for use in ischemic stroke and neurasthenic syndromes, marketed as Semax 0.1% (intranasal solution). It has no FDA (USA), EMA (Europe), or ANVISA (Brazil) approval. The evidence base consists predominantly of preclinical studies and Russian clinical trials not replicated at scale by independent Western centers.

Preclinical studies in the tMCAO rat model form the primary evidence base: Sudarkina et al. (2021, PMID 34201112) document that Semax increases active CREB in subcortical structures and reduces MMP-9, c-Fos and active JNK — suppressing inflammation and activating recovery pathways. Filippenkov et al. (2020, PMID 32580520) identified 394 differentially expressed genes. In Russia, the peptide is used clinically as an adjunct in acute stroke based on local studies.

Glazova et al. (2020, PMID 33418449) demonstrated that Semax reversed learning impairment and anxiety induced by neonatal SSRI (fluvoxamine) exposure in rats, normalizing brain monoamines. Other Russian studies document learning improvement in maze and object recognition models. Evidence is preclinical; independent controlled clinical trials in humans for cognitive endpoints are scarce in the Western literature.

The intranasal route predominates in Russian studies — discussed in the literature as capable of partially bypassing the blood-brain barrier via olfactory and trigeminal routes, allowing higher relative CNS concentration. Intranasal half-life is described as ~30 minutes. Systemic half-life is ~2 minutes due to protease degradation. The intranasal route is considered superior for CNS effects at the doses studied (Manchenko et al. 2010, PMID 21268834).

Vyunova et al. (2016, PMID 27921334) proposed the "synacton" concept: Semax, after metabolic cleavage, generates active fragments (HFPGP and PGP) that have their own neuronal membrane binding sites. These fragments, together with the parent molecule, form a bioregulator complex acting in sequence — explaining the diversity of clinical effects described for a single molecule. Fragments EHFPG and HFPGP exhibited the highest competitive activity for Semax binding sites.

No. Semax is derived from the ACTH(4-7) fragment, which corresponds to the behavioral activity region of the molecule — without the domains responsible for activating the MC2R receptor in the adrenal gland. Studies document that Semax does not stimulate cortisol release or other adrenal hormones, differentiating it from full ACTH and analogues with preserved corticotropic activity.

Medvedeva et al. (2017, PMID 28255762) performed transcriptome analysis in rat cerebral cortex with focal ischemia: Semax increased interferon signaling, antigen presentation and immunoglobulin genes. The PGP (Pro-Gly-Pro) component attenuated post-ischemic immune activation, suggesting that Semax's neuroinflammatory effects are mediated by neuroimmune crosstalk involving both components of the molecule.

Preclinical studies in rats describe that Semax increases BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) expression in the hippocampus and cortex. BDNF activation is associated with hippocampal neurogenesis, synaptic plasticity and neuronal survival. This mechanism is considered relevant for both neuroprotective effects in stroke and the nootropic effects described in cognitive models.

Russian literature describes combined use of Semax + Selank: Semax (ACTH(4-10) analogue, nootropic) complements Selank (tuftsin analogue, anxiolytic), both developed at the same institute and sharing heptapeptide structure with PGP. The rationale is to combine cognitive effects (Semax) with anxiolytic effects without sedation (Selank), without redundant pharmacological overlap, given that the primary mechanisms are distinct.