What is Semax?

Semax is the synthetic heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, also written as ACTH(4-7)PGP and described in the literature as a synthetic regulatory peptide and an ACTH(4-10) analogue [2][7]. It is a peptide drug candidate in the neuroprotective class, derived from the ACTH(4-7) sequence extended with the C-terminal tripeptide Pro-Gly-Pro [5][6]. The evidence block for this page does not supply a CAS number, molecular formula or molecular weight, so none is stated here.

The work reviewed below centres on peptide action at the level of copper-ion handling and redox chemistry, on gene-expression responses in ischaemic brain tissue, and on receptor-linked signalling in injury and stress models [2][5][6][8][9].

Research Studies

Semax and copper-catalysed reactive oxygen species in amyloid-beta systems (in vitro)

In vitro work examined whether Semax could interfere with copper-driven oxidation of amyloid-beta (aβ). The paper reports that Semax has a high affinity for Cu(II) ions and that it was able to extract Cu(II) from Cu(II)-aβ species and to influence the redox behaviour of the complex [2]. The stated rationale is that Cu(II)/Cu(I) redox cycling of the Cu(II)-aβ complex can generate reactive oxygen species (ROS) through Fenton-like chemistry, and that this ROS production is postulated to contribute to neurotoxicity in Alzheimer's disease [2]. The reported findings are from in vitro experiments; they are not clinical outcomes.

Semax and amyloidosis in a transgenic Alzheimer's disease animal model

A study assessed Semax and a derivative in a transgenic animal model of Alzheimer's disease, looking at behavioural characteristics and the development of amyloidosis [1]. The paper frames the work against the absence of remedies that are both effective and sufficiently safe for the disease process, and against interest in natural peptide drugs [1]. The findings are from an animal model; no human outcome is reported in the evidence block.

Semax and gene expression in rat frontal cortex after transient middle cerebral artery occlusion

Using RNA-Seq, researchers identified differentially expressed genes associated with ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP in the penumbra-associated region of the rat frontal cortex at 24 h after transient middle cerebral artery occlusion (tMCAO) [5]. The peptides significantly reduced profile disturbances caused by ischaemia across a large set of genes [5]. A companion analysis examined the same peptides in the penumbra-associated frontal cortex at 24 h after tMCAO, following earlier work at 4.5 h in the ipsilateral frontal cortex [6]. Both reports are rat studies.

Semax and intracellular calcium dynamics in rat brain neurons

An electrophysiology study examined the effect of Semax on spontaneous fluctuations of intracellular calcium ion concentration in pyramidal neurons on hippocampal slices, and on proton-induced increases in intracellular calcium in cerebellar granule cells on cerebellar slices [7]. This is an ex vivo rat brain slice preparation; the findings describe calcium dynamics in that preparation and are not clinical results.

Semax and the mu opioid receptor gene Oprm1 after spinal cord injury in female mice

Work in female mice investigated Semax in the context of spinal cord injury, where lysosomal membrane permeabilization is exacerbated and contributes to neuronal cell death, and where ubiquitination may affect lysosomal membrane stability and function [8]. The study is described as targeting the mu opioid receptor gene Oprm1 to promote deubiquitination and functional recovery [8]. The findings are from a mouse model of spinal cord injury.

Semax and antidepressant-like and antistress effects in male rats under chronic unpredictable stress

A study of ACTH(4-10) synthetic analogues, including Semax and Melanotan II, examined antidepressant-like and antistress effects in male rats in a model of chronic unpredictable stress [9]. The paper situates the work against limitations of current antidepressant therapy and against the role of stressful events and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in the pathogenesis of depression [9]. The reported effects are behavioural and endocrine findings in male rats.

Semax and therapeutic peptide mechanisms in gerontology

A narrative review of therapeutic peptides in gerontology covers mechanisms, clinical applications, evidence base and safety profiles of peptides with demonstrated or potential applications in healthy aging and age-related conditions, targeting hallmarks of aging that include metabolic dysfunction, telomere attrition, tissue repair impairment and hormonal decline [4]. Semax appears within this broader peptide-therapeutics literature rather than as the subject of a dedicated clinical trial in the evidence block.

Semax and therapeutic peptide signalling pathways in orthopaedics

A review of therapeutic peptides in orthopaedics describes peptides as adjuncts that modulate molecular signalling networks, naming PI3K/Akt, mTOR, MAPK, TGF-β and AMPK as pathways through which peptides influence tissue regeneration [10]. This is a review-level statement about the peptide class and its signalling context, not a Semax-specific experimental result.

What the evidence does and does not show

Across the studies above, the Semax findings come from in vitro systems, ex vivo rat brain slices, and animal models including transgenic Alzheimer's disease mice, rats subjected to tMCAO, female mice with spinal cord injury, and male rats under chronic unpredictable stress [1][2][5][6][7][8][9]. The evidence block contains no human clinical trial of Semax, and no human dose, pharmacokinetic parameter or safety endpoint for Semax. Statements about pathway involvement in orthopaedics and about gerontological applications are review-level and class-level rather than Semax-specific [4][10].

Sources

• [1] The Potential of the Peptide Drug Semax and Its Derivative for Correcting Pathological Impairments in the Animal Model of Alzheimer's Disease. https://europepmc.org/article/PMC/PMC12755871
• [2] Semax, a Copper Chelator Peptide, Decreases the Cu(II)-Catalyzed ROS Production and Cytotoxicity of aβ by Metal Ion Stripping and Redox Silencing. https://europepmc.org/article/PMC/PMC12151629
• [4] Therapeutic peptides in gerontology: mechanisms and applications for healthy aging. https://europepmc.org/article/PMC/PMC13095733
• [5] Genes That Associated with Action of ACTH-like Peptides with Neuroprotective Potential in Rat Brain Regions with Different Degrees of Ischemic Damage. https://europepmc.org/article/PMC/PMC12249733
• [6] ACTH-like Peptides Compensate Rat Brain Gene Expression Profile Disrupted by Ischemia a Day After Experimental Stroke. https://europepmc.org/article/PMC/PMC11673339
• [7] The Effect of Peptide Semax, an ACTH(4-10) Analogue, on Intracellular Calcium Dynamics in Rat Brain Neurons. https://pubmed.ncbi.nlm.nih.gov/41171324/
• [8] Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice. https://pubmed.ncbi.nlm.nih.gov/40692165/
• [9] Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. https://pubmed.ncbi.nlm.nih.gov/39442746/
• [10] Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions. https://europepmc.org/article/PMC/PMC12753158

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