Selank and Semax: cognitive peptides and neuroprotection research

Selank and Semax occupy a unique position in the peptide research landscape. Both were developed at the Institute of Molecular Genetics of the Russian Academy of Sciences in the 1980s and 1990s, and both have accumulated a body of preclinical and limited clinical data that is considerably larger than most Western researchers realise — primarily because much of it was published in Russian-language journals and has only recently been translated and indexed in major databases.

Both peptides are administered intranasally, exploiting the olfactory and trigeminal nerve pathways that provide direct access to the central nervous system without requiring systemic administration or passage across the blood-brain barrier. This route of administration significantly reduces the effective dose required compared to parenteral routes and produces more rapid CNS effects.

Selank: anxiolytic activity and immune modulation

Origin and structure

Selank is a synthetic heptapeptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro) derived from the human immunoglobulin G (IgG) fragment. It was developed as a longer-acting, more stable analogue of the endogenous tetrapeptide tuftsin. Unlike most short peptides, Selank demonstrates unusual metabolic stability — it is cleaved in the body to produce active metabolites (including the tripeptide Pro-Gly-Pro) that retain biological activity, giving it a longer effective duration than its molecular size would suggest.

Mechanisms

Selank's primary CNS effects appear to be mediated through modulation of GABAergic neurotransmission. It does not bind GABA-A receptors directly but modulates their sensitivity to endogenous GABA — producing anxiolytic effects without the sedation, tolerance development, or dependence liability associated with benzodiazepines.

Additionally, Selank upregulates expression of BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) in hippocampal and cortical regions, effects that are associated with improved synaptic plasticity and neuroprotection against stress-induced neuronal damage.

A third mechanism is immunomodulatory: Selank influences the balance of Th1/Th2 immune responses and upregulates expression of several interleukins. This immune effect is considered relevant in the context of neuroinflammation models.

Research findings

Preclinical studies document consistent anxiolytic effects across multiple animal models of anxiety, including elevated plus maze, forced swim test, and restraint stress paradigms. Unlike diazepam controls, Selank-treated animals showed anxiolysis without impairment of locomotor activity or memory consolidation — a profile that suggests selective action on anxiety circuitry rather than general CNS depression.

In memory and learning models, Selank administration before or during training improved retention in passive avoidance tasks and accelerated extinction of conditioned fear responses. The BDNF upregulation likely contributes to these effects through enhanced long-term potentiation.

Semax: ACTH-derived cognitive enhancement

Origin and structure

Semax is a synthetic heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) based on the 4-10 fragment of ACTH (adrenocorticotropic hormone). The ACTH 4-7 sequence (Met-Glu-His-Phe) is the active core responsible for cognitive effects, which were first observed when scientists noted that full ACTH had memory-enhancing properties beyond its adrenal actions. The Pro-Gly-Pro C-terminal extension was added to improve stability and CNS penetration.

Critically, Semax has no adrenocortical activity — it does not stimulate cortisol secretion despite its ACTH structural origin. This makes it useful for studying ACTH's CNS effects in isolation from its peripheral hormonal actions.

Mechanisms

Semax's best-characterised mechanism is the upregulation of BDNF and its receptor TrkB in hippocampal and prefrontal cortical regions. BDNF is one of the most important growth factors for synaptic plasticity, learning and memory consolidation, and neuroprotection against ischaemic and excitotoxic injury.

Semax also modulates dopaminergic neurotransmission in prefrontal circuits, effects associated with working memory and executive function. In serotonin pathway studies, Semax treatment was associated with increased 5-HT turnover in limbic structures — potentially contributing to its reported effects on mood and anxiety.

Research findings

Semax has been studied extensively in models of ischaemic brain injury, where its BDNF-upregulating and neuroprotective effects are most clearly demonstrated. In rodent stroke models, post-ischaemia Semax administration reduced infarct volume, improved functional recovery scores, and increased neuronal survival in the penumbra zone compared to controls.

In cognitive research models without injury, Semax improved performance in spatial navigation tasks, object recognition, and working memory paradigms. Effects were most pronounced in aged subjects — consistent with BDNF's role in reversing age-related declines in synaptic plasticity.

How they differ and why they are stacked

Selank and Semax are mechanistically complementary:

• Selank reduces anxiety-like behaviour primarily through GABAergic modulation; Semax enhances cognitive performance primarily through BDNF and dopaminergic pathways.
• Selank has more pronounced effects on stress resilience and immune regulation; Semax has more pronounced effects on learning, memory, and neuroprotection.
• Combined, they address both the anxiolytic and the cognitive enhancement dimensions of nootropic research without receptor system overlap — a textbook case for rational stack design.

Sex-specific considerations

Both GABAergic sensitivity and BDNF baseline expression are modulated by sex hormones. Estrogen upregulates BDNF in hippocampal tissue, meaning female models typically start with a higher BDNF baseline. This compresses the apparent effect size of Semax in female subjects — not because the peptide is less active, but because it is elevating an already higher baseline. Progesterone metabolites (neurosteroids) interact directly with GABA-A receptors in ways that modulate Selank's anxiolytic effects depending on hormonal cycle phase.

Researchers designing cognitive studies with these compounds should include cycle-controlled female cohorts or use ovariectomised models with hormone replacement to enable clean comparison.

Selank and Semax represent a category of research compounds that are well-characterised in the preclinical literature but whose translation to broader Western research has been limited by language barriers. As that barrier lowers, their utility in cognitive and neuroprotective research is becoming increasingly recognised.

References

• Uchakina, O.N. et al. (2008). Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Bulletin of Experimental Biology and Medicine, 146(4), 458–460.
• Dolotov, O.V. et al. (2006). Semax, an analogue of ACTH 4-10 with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Behavioural Brain Research, 168(1), 144–149.
• Shadrina, M.I. et al. (2010). Expression analysis of neuroprotective SEMAX peptide action. Annals of the New York Academy of Sciences, 1199, 214–221.