Semax: Mechanism of Action

Mechanism of Action

Receptor Targets and Binding

Specific binding sites for Semax have been identified in basal forebrain membranes. Binding is reversible, specific, and time-dependent, with a dissociation constant (K_d) of 2.4 ± 1.0 nM and maximal binding capacity (B_max) of 33.5 ± 7.9 fmol/mg protein.[9] This binding strictly requires calcium ions (Ca²⁺) and is blocked by manganese ions (Mn²⁺), characteristic of G-protein-coupled receptor interactions.[10]

In receptor assays, Semax acts as a competitive antagonist of α-melanocyte-stimulating hormone (α-MSH) at the MC4 and MC5 melanocortin receptors. No antagonism was observed at MC3.[11] Additionally, Semax inhibits enzymes responsible for enkephalin degradation (IC₅₀ = 10 μM).[12]

BDNF/TrkB Signaling Cascade

Semax stimulates tyrosine phosphorylation of TrkB receptors (the high-affinity receptor for BDNF), producing a 1.5–1.6-fold increase in TrkB phosphorylation in the hippocampus within 3 hours of administration.[9] In glial cell cultures, BDNF mRNA increased 8-fold and NGF mRNA 5-fold within 30 minutes.[13] In vivo, Semax increased hippocampal BDNF protein by 1.4-fold and exon III BDNF mRNA by 3-fold.[14]

Neurotransmitter Modulation

Semax activates the dopaminergic and serotonergic systems. It increases extracellular levels of 5-HIAA (a serotonin metabolite) in the striatum by approximately 25%.[1] While it does not alter basal dopamine levels alone, it significantly potentiates dopamine release induced by D-amphetamine.[1] Semax also regulates intracellular calcium homeostasis, preventing Ca²⁺ deregulation under glutamate excitotoxicity conditions.[10]

Gene Expression and Transcription

Genome-wide transcriptional analysis following ischemia-reperfusion demonstrated that Semax modulates 394 differentially expressed genes. It upregulates neurotransmission-related genes including Gpr6, Drd2, Hes5, and Gpr88, while downregulating pro-inflammatory genes such as Il1b, Il6, and Ccl6.[15][16]

Pharmacokinetic Paradox

Despite a relatively short plasma elimination half-life of approximately 1–2 hours, the experimental effects of a single intranasal dose persist for 20–24 hours.[5] Intranasal bioavailability is reported at 60–70%, with rapid CNS penetration across the blood-brain barrier.[17]