Semax

Mechanism (as reported)

Across provided studies, Semax-related findings include modulation of inflammatory/immune gene expression in ischemic brain models (PMIDs: 24661604, 34097675, 34201112), copper/metal-associated effects relevant to amyloid-β assembly and ROS production (PMIDs: 35080861, 40496623), and in a spinal cord injury model a reported interaction with μ-opioid receptor signaling leading to downstream changes involving USP18 and ubiquitination/deubiquitination-linked pathways (PMID: 40692165).

Key findings (each cites a source)

• A review of therapeutic peptides for orthopaedics describes neuroactive peptides (including semax) as being associated with brain-derived neurotrophic factor and HGF/c-Met pathway effects relevant to neuroplasticity, while noting a lack of clinical trials. [PMID 41490200]
• In a spinal cord injury mouse study, Semax was reported to improve functional recovery and inhibit lysosomal membrane permeabilization (LMP)-related pyroptosis and neuroinflammation, alongside decreased oxidative stress. [PMID 40692165]
• In the same spinal cord injury study, Semax was reported to regulate USP18, and USP18 knockdown was reported to confirm a role for USP18 in Semax’s spinal cord injury-related recovery effects. [PMID 40692165]
• In the spinal cord injury study, μ-opioid receptor (Oprm1) was reported as a Semax target based on network pharmacology and docking, with Semax’s functional recovery proposed to involve μ-opioid receptors regulating USP18 and downstream deubiquitination of FTO-associated ubiquitination/deubiquitination-linked processes (as described in the abstract). [PMID 40692165]
• In artificial membrane models, Semax was reported to prevent amyloid-β : Cu2+ complex formation and to exhibit anti-aggregating and protective properties, with results suggesting interference with Aβ fibrillogenesis of Aβ:Cu2+ complexes. [PMID 35080861]
• In vitro experiments were reported to show that Semax (described as having high affinity for Cu(II)) could extract Cu(II) from Cu(II)-amyloid-β species, influence redox cycling, decrease copper-catalyzed ROS production, and show cytoprotective properties against copper-catalyzed oxidation–induced oxidative stress in SH-SY5Y cells. [PMID 40496623]
• In a rat focal ischemia genome-wide transcriptional analysis, Semax was reported to predominantly enhance expression of immune-system related genes, with changes in chemokine and immunoglobulin gene groups, and also to alter vascular-system related gene expression at multiple time points. [PMID 24661604]
• In a rat cerebral ischemia-reperfusion model protein-expression profiling study, Semax was reported to upregulate active CREB in subcortical structures at 24 h after tMCAO and to downregulate MMP-9 and c-Fos in adjacent tissue, with additional downregulation of active JNK, as described in the abstract. [PMID 34201112]
• In a qRT-PCR study of reversible ischemia, Semax was reported to decrease mRNA levels of proinflammatory mediators including Il1a, Il1b, Il6, Ccl3, and Cxcl2, compensating for increases induced by ischemia-reperfusion; the authors concluded the protective effect may be due to anti-inflammatory effects (per the abstract). [PMID 34097675]
• In a transgenic APPswe/PS1dE9/Blg mouse model of Alzheimer’s disease, Semax and a Semax derivative were reported to improve cognitive performance in behavioral tests and to reduce the number of amyloid inclusions in cortex and hippocampus, based on histological examination. [PMID 41479572]
• Research described in the Alzheimer’s disease mouse study supports the authors’ conclusion that Semax and its derivative have a high potential for developing therapeutic/corrective strategies for Alzheimer’s disease (as stated in the abstract). [PMID 41479572]