Semax (ACTH(4-7)–Pro-Gly-Pro) in Animal Models of Neurological Injury: A Research Summary

Semax is a synthetic peptide analogue built on the ACTH(4-10) / ACTH(4-7) fragment extended with a Pro-Gly-Pro tail, and the published literature summarised here is almost entirely preclinical [1][2]. The studies below were conducted in rats and mice; none of the records cited in this guide is a controlled human trial, and the rodent findings should not be read as human outcomes. The most frequently examined model is incomplete global cerebral ischemia produced by bilateral occlusion or ligation of the common carotid arteries in rats. In one such rat study, ischemia was followed by elevated nitric oxide (NO) generation and increased indices of lipid peroxidation in cerebral cortex; Semax, but not glycine, was reported to abate the rise in nitric oxide and to restore neurological functioning in the ischemic animals, while glycine was ineffective on both measures [1]. A companion rat study using the same bilateral carotid occlusion model reported an approximately twofold increase in NO production and a moderate rise in secondary lipid peroxidation products, a correlation between cortical NO content and the degree of neurological disturbance, and prevention of both the neurological disturbances and the excess cortical NO production in Semax-treated animals [2]. Other rodent work compared Semax with conventional reference agents. In rats with brain ischemia induced by bilateral ligation of the common carotid arteries, both Semax and mexidol were reported to reduce neurological deficit scores and increase survival; the authors noted that mexidol showed a linear dose–effect relationship across the range tested whereas the effect of Semax diminished as the dose was raised, an inverted relationship worth noting when interpreting preclinical comparisons [3]. The same report described course administration of Semax and mexidol before injury as reducing neurological deficit and amnesia in a step-down passive avoidance task in rats subjected to brain ischemia caused by gravitational overload [3]. Semax has also served as the comparator compound in screening work on other peptides: in a rat and mouse study of a new tripeptide mixture, Semax was used as the reference drug against which neuroprotective effects in rat brain ischemia, antihypoxic effects in mice in hermetic and altitude chamber tests, antiamnesic effects against scopolamine-induced amnesia in rats and electroshock-induced amnesia in mice, and changes in transcallosal evoked potential amplitude in rat brain were benchmarked, with the new mixture reported as more effective than Semax on those endpoints [4]. An earlier rat study examined the ACTH(4-7)-Pro-Gly-Pro peptide in seizure models rather than ischemia. Using amygdaloid kindling and audiogenic epilepsy in rats, including a strain susceptible to audiogenic seizures, the peptide was described as having an anticonvulsant profile in the kindling preparation; in the audiogenic epilepsy test it lowered the seizure threshold and did not prevent motor convulsions, so the direction of effect differed between the two models [5]. Two rat studies extended the question beyond the brain to cardiac ischemia, explicitly framing their hypothesis on the earlier observation that Semax reduced neurological deficit and NO hyperproduction in rat brain after acute cerebral hypoperfusion [6][7]. In acute myocardial infarction induced by left coronary artery occlusion, Semax was reported to cause no change in cardiac function but to prevent the ischemia-induced ultrastructural changes in cardiomyocytes, alongside a blunting of the increase in plasma nitrate concentrations seen in untreated infarcted rats [6]. In a longer 28-day rat protocol after coronary occlusion, the infarcted group developed cardiac hypertrophy with disproportionate growth of contractile filaments relative to mitochondria, reduced mean arterial pressure and contractile function, and raised left ventricular end-diastolic pressure; Semax did not alter cardiac work but partially prevented the rise in end-diastolic pressure and attenuated cardiomyocyte hypertrophy and the contractile-to-mitochondrial imbalance [7]. Taken together, the retrieved record is a preclinical one centred on rodent ischemia models, with nitric oxide generation and lipid peroxidation recurring as the mechanistic readouts [1][2][6], behavioural and neurological deficit scoring as the functional readouts [1][2][3][4], and model-dependent divergence in the seizure literature [5]. Several of the reports are English-abstract records from Russian-language journals [2][3][6][7], and the non-monotonic dose–response noted for Semax in one ischemia study [3] is a methodological consideration for researchers designing further animal work.