Semax and BDNF: Neurotrophin Signaling and Cognitive Enhancement Mechanisms

Semax is a synthetic heptapeptide derived from the ACTH (adrenocorticotropic hormone) sequence with a modified C-terminus for enhanced stability and CNS activity.

Structural Details

• Sequence: Met-Glu-His-Phe-Pro-Gly-Pro (ACTH 4-10 with C-terminal Pro-Gly-Pro)
• Molecular Weight: 813.9 Da
• Origin: ACTH(4-10) fragment plus tripeptide extension
• Development: Created at the Institute of Molecular Genetics, Russian Academy of Sciences

Key Modifications

• PGP Extension: The Pro-Gly-Pro C-terminus prevents degradation and enhances CNS penetration
• No Hormonal Activity: Unlike ACTH, Semax does not stimulate cortisol release
• CNS Selectivity: Actions confined to cognitive and neuroprotective effects

Administration

Semax is typically administered intranasally, allowing direct access to the CNS via the olfactory epithelium. This route bypasses the blood-brain barrier and minimizes systemic exposure.

BDNF (brain-derived neurotrophic factor) is the most abundant neurotrophin in the brain and essential for cognitive function.

BDNF Functions

• Neuronal Survival: Prevents apoptosis and supports neuron viability
• Synaptic Plasticity: Essential for long-term potentiation (LTP) and memory formation
• Neurogenesis: Promotes birth of new neurons in hippocampus
• Dendrite Growth: Stimulates dendritic arborization and spine formation
• Neurotransmission: Modulates release and sensitivity to glutamate, GABA, serotonin, dopamine

BDNF and Cognition

BDNF is critical for:

• Learning: Hippocampal BDNF required for spatial and contextual learning
• Memory Consolidation: Converts short-term to long-term memories
• Cognitive Flexibility: Prefrontal cortex BDNF supports executive function
• Mood Regulation: Low BDNF associated with depression; antidepressants increase BDNF

BDNF Decline

BDNF levels decline with age, stress, and in neurodegenerative diseases—making BDNF upregulation a therapeutic target.

Semax robustly increases BDNF expression through multiple mechanisms.

Gene Expression Effects

• BDNF mRNA: Semax increases BDNF gene transcription in hippocampus and cortex
• Time Course: Effects seen within hours and persist after treatment
• Regional Specificity: Most pronounced in hippocampus (memory) and prefrontal cortex (executive function)

Proposed Mechanisms

• Melanocortin Pathway: Semax may activate MC4 receptors, linked to BDNF expression
• CREB Activation: Phosphorylated CREB binds BDNF promoter, increasing transcription
• Activity-Dependent: Effects may require neuronal activity for full expression
• NGF Synergy: Semax also increases NGF (nerve growth factor), which may amplify BDNF effects

Protein Production

Beyond mRNA, Semax increases mature BDNF protein:

• Enhanced translation of BDNF transcripts
• Increased processing of pro-BDNF to mature BDNF
• Enhanced secretion of BDNF from neurons

BDNF exerts its effects primarily through the TrkB (tropomyosin receptor kinase B) receptor.

TrkB Activation

When BDNF binds TrkB:

1. Receptor dimerization and autophosphorylation
2. Recruitment of adaptor proteins (Shc, PLC-γ, PI3K)
3. Activation of downstream signaling cascades

Key Downstream Pathways

• MAPK/ERK: Promotes neuronal survival, gene expression, synaptic plasticity
• PI3K/Akt: Inhibits apoptosis, enhances protein synthesis, supports metabolism
• PLCγ/Ca2+: Modulates synaptic transmission and plasticity

Synaptic Effects

• LTP Enhancement: BDNF/TrkB signaling is required for late-phase LTP
• AMPA Receptor Trafficking: Increases synaptic AMPA receptors
• Spine Morphology: Promotes mature mushroom spine formation
• Synaptic Protein Synthesis: Local translation of synaptic proteins

Semax Amplification

By increasing BDNF levels, Semax amplifies all of these TrkB-mediated effects, enhancing synaptic plasticity and cognitive function.

Semax's BDNF-mediated effects translate to observable cognitive benefits.

Cognitive Enhancement

• Memory: Improved retention and recall in animal learning tasks
• Attention: Enhanced focus and reduced attentional lapses
• Learning Speed: Faster acquisition of new information
• Executive Function: Better planning and cognitive flexibility

Neuroprotection

Semax protects against various neural insults:

• Ischemia: Reduced infarct volume in stroke models
• Hypoxia: Protection against oxygen deprivation
• Oxidative Stress: Enhanced antioxidant capacity
• Excitotoxicity: Reduced glutamate-induced damage

Clinical Observations

In Russia, Semax is approved for:

• Stroke recovery (improved functional outcomes)
• Optic nerve disease (reduced vision loss)
• Cognitive disorders
• Peptic ulcers (peripheral effects)

Anxiolytic Effects

Through serotonin and dopamine modulation, Semax may reduce anxiety without sedation—potentially through BDNF effects on limbic circuits.