Semax

In 110 adults after ischaemic stroke, split into early (89 +/- 9 days) and late (214 +/- 22 days) rehabilitation groups and each into semax and no-semax subgroups, semax raised plasma BDNF, which remained elevated throughout, and both accelerated improvement and improved final Barthel index. There was no placebo arm and no blinding is described; the authors credit early rehabilitation together with semax rather than semax alone.¹⁴

In 30 patients treated during the acute period of hemispheric ischaemic stroke, compared with a control group of 80 patients whose strokes were analogous in severity and lesion location and who received conventional therapy, adding semax to combined intensive therapy was reported to have some influence on the rate of restoration of damaged neurological functions, increasing the regression of general cerebral and focal - especially motor - disorders as assessed by clinical rating scales, EEG monitoring with mapping and somatosensory evoked potentials; the study was a non-randomised controlled clinical trial.¹⁵

In 24 healthy volunteers (mean age 43.9 +/- 9.5 years) scanned by resting-state fMRI before and 5 and 20 minutes after intranasal dosing, the 14 given semax showed a greater volume of the rostral medial frontal subcomponent of the default mode network than the 10 given placebo. The session measured network topography only; no cognitive, behavioural or clinical outcome was recorded.¹⁶

In an uncontrolled, open-label sequential-group trial in 27 patients with motor neuron disease, semax did not alter the course of chronic partial denervation on serial needle electromyography or the clinical trajectory on the Norris ALS and ALS Functional Rating Scales. It did significantly improve the total ALSAQ-40 quality-of-life score through emotional state and motivation, maximal at day 10. There was no control or placebo group.¹⁷

In rats, basal forebrain cell membranes bound tritium-labelled Semax specifically, reversibly and only in the presence of calcium (Kd 2.4 +/- 1.0 nM, 33.5 +/- 7.9 fmol of binding sites per mg protein), and intranasal doses of 50 and 250 ug/kg raised BDNF protein in the basal forebrain at 3 hours while leaving cerebellar BDNF unchanged.⁷

In rats with focal photoinduced ischaemia of the prefrontal cortex, intranasal Semax given for 6 days decreased the volume of cortical infarction and improved retention and performance of a conditioned passive avoidance response. The report gives the direction of effect only, with no effect sizes or comparator values in its abstract.¹⁸

In female C57BL/6 mice with a T9-T10 contusion spinal cord injury, Semax improved functional recovery on Basso scores, footprint analysis and inclined-plane testing and inhibited lysosomal membrane permeabilisation-related pyroptosis by decreasing oxidative stress, with matching effects in a parallel PC12 cell neuroinflammation model. RNA sequencing implicated the deubiquitinase USP18, and knockdown confirmed that USP18 mediates the recovery.⁶

In APPswe/PS1dE9/Blg transgenic mice modelling Alzheimer's disease, open field, novel object recognition and Barnes maze testing showed that both Semax and a derivative improved cognitive function, and histology showed a reduced number of amyloid inclusions in the cortex and hippocampus. The abstract reports the direction of effect only, without effect sizes or a stated comparator.¹⁹

In primary neuronal and glial cultures from rat basal forebrain, Semax increased survival of cholinergic neurons approximately 1.5- to 1.7-fold and stimulated choline acetyltransferase activity at 100 nM, while leaving GABAergic and total neuron-specific-enolase-positive neuron numbers unaffected and, across 1 nM to 10 uM, not affecting glial proliferation.²⁰

In cell-free chemistry and in cultured human SH-SY5Y neuroblastoma cells, Semax extracted Cu(II) from Cu(II)-amyloid-beta species, influenced their redox cycling, decreased the associated reactive oxygen species production and protected cells against oxidative stress induced by copper-catalysed oxidation of amyloid-beta; an earlier equilibrium and cell study likewise found reduced copper-induced cytotoxicity by MTT assay in SH-SY5Y and RBE4 endothelial cells.^5,12

In rats subjected to transient middle cerebral artery occlusion, RNA sequencing identified 394 genes differentially expressed by more than 1.5-fold in Semax-treated brains versus saline at 24 hours, with inflammatory genes suppressed and neurotransmission genes activated - the opposite direction to the changes ischaemia-reperfusion produced on its own.⁹

In the same rat transient middle cerebral artery occlusion model examined at protein level 24 hours after occlusion, Semax upregulated active CREB in subcortical structures including the focus of ischaemic damage, downregulated MMP-9 and c-Fos in the adjacent frontoparietal cortex and downregulated active JNK in both tissues, matching the anti-inflammatory direction seen in the transcriptome.⁴