Regulation of BDNF and TrkB Expression in the Rat Hippocampus
A 2006 study published in Brain Research investigated the effects of Semax on brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the rat hippocampus. The researchers administered Semax intranasally to rats and measured changes in BDNF mRNA and protein levels, as well as TrkB receptor expression, at multiple time points in hippocampal tissue — a brain region critical for learning and memory processes.
The results demonstrated that Semax administration significantly upregulated both BDNF and TrkB expression in the hippocampus. The increase in BDNF was observed at both the mRNA and protein levels, indicating transcriptional activation of the neurotrophic factor gene. The TrkB receptor upregulation suggested enhanced neuronal responsiveness to BDNF signaling. Since the BDNF/TrkB pathway is a central mediator of synaptic plasticity, neuronal survival, and memory consolidation, these findings provided a molecular mechanism for Semax’s previously observed cognitive-enhancing effects in animal behavioral models.
Citation: Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research. 2006;1117(1):54-60. doi:10.1016/j.brainres.2006.07.108. PubMed PMID: 16996037
Activation of Dopaminergic and Serotoninergic Brain Systems in Rodents
A 2005 study published in Neurochemical Research examined Semax’s effects on dopaminergic and serotoninergic neurotransmitter systems in rodent brains. The researchers measured concentrations of dopamine, serotonin, and their metabolites in multiple brain regions following Semax administration, using high-performance liquid chromatography (HPLC) with electrochemical detection.
The investigation revealed that Semax activated both dopaminergic and serotoninergic brain systems, producing region-specific changes in monoamine concentrations and turnover rates. The dopaminergic effects were most pronounced in brain regions associated with reward, motivation, and executive function, while serotoninergic modulation was observed in areas linked to mood regulation and cognitive flexibility. The authors contextualized these findings within the established anatomical and functional connections between melanocortinergic (ACTH-related) and monoaminergic brain systems, proposing that Semax’s nootropic properties may arise from its coordinated modulation of multiple neurotransmitter pathways.
Citation: Eremin KO, Kudrin VS, Saransaari P, et al. Semax, An ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochemical Research. 2005;30(12):1493-1500. doi:10.1007/s11064-005-8826-8. PubMed PMID: 16362768
Neurotrophic Factor Transcription Following Cerebral Ischemia
A study published in Cells (2024) investigated the effects of Semax and its C-terminal fragment Pro-Gly-Pro on the transcription of neurotrophins and their receptor genes following cerebral ischemia in rat models. Using a middle cerebral artery occlusion (MCAO) model, the researchers evaluated gene expression changes in the ischemic penumbra — the tissue surrounding the core infarct that is potentially salvageable.
The results showed that both Semax and Pro-Gly-Pro activated the transcription of multiple neurotrophin genes (BDNF, NGF, NT-3) and their respective receptor genes in ischemic brain tissue. Semax demonstrated a broader and more potent transcriptional response compared to the Pro-Gly-Pro fragment alone, suggesting that the ACTH(4-7) portion of the molecule contributes additional neuroprotective signaling. The findings provided molecular evidence for Semax’s neuroprotective effects in cerebral ischemia models and identified specific neurotrophic pathways through which the peptide may promote neuronal survival in the ischemic penumbra.
Citation: Derkach KV, Bakhmet EI, Shpakov AO, et al. Semax and Pro-Gly-Pro activate the transcription of neurotrophins and their receptor genes after cerebral ischemia. Cells. 2024;13(18):1555. doi:10.3390/cells13181555. PMC: PMC11498467
Transcriptome-Level Analysis Following Cerebral Ischemia-Reperfusion
A 2020 study in Genes performed a genome-wide transcriptome analysis to characterize the protective properties of Semax following cerebral ischemia-reperfusion in rats. Using RNA sequencing technology, the researchers compared gene expression profiles in brain tissue from ischemia-reperfusion animals with and without Semax treatment, identifying specific genes and pathways modulated by the peptide.
The transcriptome analysis revealed that Semax modulated the expression of hundreds of genes in ischemic brain tissue, affecting pathways related to inflammation, apoptosis, neurotrophic signaling, and vascular remodeling. Notably, Semax suppressed the expression of pro-inflammatory and pro-apoptotic genes while upregulating genes involved in neuronal survival and tissue repair. The breadth of gene expression changes observed provided mechanistic insight into Semax’s neuroprotective properties and suggested that the peptide engages multiple protective pathways simultaneously rather than acting through a single molecular target.
Citation: Dergunova LV, Filippenkov IB, Stavchansky VV, et al. Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats. Genes. 2020;11(6):681. doi:10.3390/genes11060681. PubMed PMID: 32580326
Fifteen Years of Design and Study: The Nootropic ACTH(4-10) Analog
A comprehensive review published in Zhurnal Vysshei Nervnoi Deyatel’nosti (1997) summarized 15 years of research into the design and characterization of Semax as a nootropic ACTH analog. The review covered the compound’s initial design rationale, structural modifications for metabolic stability, and accumulated evidence from preclinical behavioral studies in rodent models.
The review documented that Semax demonstrated the ability to stimulate operative memory and attention, increase resistance to hypoxia, and improve brain function in multiple preclinical paradigms. The peptide’s nootropic effects were observed at doses that did not produce hormonal (adrenocortical) effects, confirming the successful dissociation of cognitive-enhancing activity from the endocrine activity of parent ACTH molecules. The authors noted that the Pro-Gly-Pro extension was critical for achieving the prolonged duration of action observed with Semax compared to the native ACTH(4-10) fragment, which is rapidly degraded by tissue peptidases.
Citation: Ashmarin IP, Nezavibat’ko VN, Levitskaya NG, et al. [A nootropic adrenocorticotropin analog 4-10-semax (15 years of experience in its design and study)]. Zhurnal Vysshei Nervnoi Deyatel’nosti Imeni I P Pavlova. 1997;47(2):420-430. PubMed PMID: 9173745
Reviewed for scientific accuracy — Chameleon Peptides Research Team. Last reviewed: March 2026.