A.A. Kamensky

Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus

The heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is an analog of the adrenocorticotropin fragment (4-10) which after intranasal application has profound effects on learning and exerts marked neuroprotective activities. Here, we found that a single application of Semax (50 microg/kg body weight) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosporylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively, in the rat hippocampus. Semax-treated animals showed a distinct increase in the number of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system.

The Heptapeptide SEMAX stimulates BDNF Expression in Different Areas of the Rat Brain in vivo

N-terminal fragments of adrenocorticotropic hormone (ACTH) and different types ( α , β and γ ) of melanocyte-stimulating hormone (MSH) form the family of melanocortin peptides exerting a marked action on the functions of the central nervous system (CNS). Peptides from this family possess neurotrophic, nootropic and neuroprotective properties [1]. The heptapeptide SEMAX (Met–Glu–His–Phe–Pro–Gly–Pro) is an analog of the ACTH(4–10) fragment completely devoid of any hormonal activity present in the full-length ACTH molecule. It shown to stimulate the learning and memory formation processes in laboratory animals [2, 3]. As a regulator of CNS functions, this peptide, if administered at very small doses (15–50 μ g/kg), produces a marked nootropic effect [4, 5]. It also stimulates forebrain functions by increasing selective attention at the moment of information reception, improving memory consolidation and raising the learning ability [4]. At the cellular level, SEMAX has a neuroprotective effect, preventing the death of cholinergic neurons in culture, and stimulates an activity of choline acetyl transferase [6, 7].

Semax, an analogue of adrenocorticotropin (4–10), binds specifically and increases levels of brain‐derived neurotrophic factor protein in rat basal forebrain

The heptapeptide Semax (Met‐Glu‐His‐Phe‐Pro‐Gly‐Pro) is an analogue of the N‐terminal fragment (4–10) of adrenocorticotropic hormone which, after intranasal application, has profound effects on learning and memory formation in rodents and humans, and also exerts marked neuroprotective effects. A clue to the molecular mechanism underlying this neurotropic action was recently given by the observation that Semax stimulates the synthesis of brain‐derived neurotrophic factor (BDNF), a potent modulator of synaptic plasticity, in astrocytes cultured from rat basal forebrain. In the present study, we investigated whether Semax affects BDNF levels in rat basal forebrain upon intranasal application of the peptide. In addition, we examined whether cell membranes isolated from this brain region contained binding sites for Semax. The binding of tritium‐labelled Semax was found to be time dependent, specific and reversible. Specific Semax binding required calcium ions and was characterized by a mean± SEM dissociation constant (KD) of 2.4 ± 1.0 nm and a BMAX value of 33.5 ± 7.9 fmol/mg protein. Sandwich immunoenzymatic analysis revealed that Semax applied intranasally at 50 and 250 µg/kg bodyweight resulted in a rapid increase in BDNF levels after 3 h in the basal forebrain, but not in the cerebellum. These results point to the presence of specific binding sites for Semax in the rat basal forebrain. In addition, these findings indicate that the cognitive effects exerted by Semax might be associated, at least in part, with increased BDNF protein levels in this brain region.

Heptapeptide semax attenuates the effects of chronic unpredictable stress in rats.

353 Chronic stress is a risk factor of a number of pathol ogies, including depressive disorders [1], with a high degree of comorbidity of depression and anxiety disor ders [2]. In addition, in many patients with these pathologies, disturbance of cognitive functions has been observed [3]. In experiments on animals, it has been demonstrated that, in rats, chronic stress also causes cognitive disturbances and behavioral disor ders, including an elevated level of anxiety and depres sive like behavior [4]. It is suggested that functional and structural changes in several brain regions (first of all, the hippocampus, prefrontal cortex, and amygdala) caused by an unbalanced level of glucocor ticoids because of chronic stress may underlie these disorders [1]. Another important factor involved in these pathologies is brain derived neurotrophic factor (BDNF), whose expression in the hippocampus is decreased in depression and can be increased with the use of antidepressants [5]. At the same time, the increase in the BDNF level in the amygdala is related to an increase in the anxiety level [5]. In addition, BDNF plays an important role in learning and mem ory formation, and a decrease in its level in the hip pocampus deteriorates cognitive functions [1].

Influence of semax on the emotional state of white rats in the norm and against the background of cholecystokinin-tetrapeptide action

The effects of the adrenocorticotropic hormone (ACTH(4–10)) analog, Semax (MEHFPGP), on the level of anxiety and depression in white rats have been studied in the normal state and against the back-ground of cholecystokinin-tetrapeptide (CCK-4) action. Semax was injected intranasally in doses of 50 and 500 μg/kg 15 min before the testing. CCK-4 was administered intraperitoneally in a dose of 400 μg/kg 40 min before the testing. The level of anxiety was estimated in the elevated plus-maze test, and the degree of depression, in the forced swimming test. Semax administration did not influence the emotional state of animals in the normal state. The CCK-4 injection led to an increase in anxiety and depression in rats. Semax normalized the animal behavior disturbed by the CCK-4 administration, which attests to its anxiolytic and antidepressant effects at elevated levels of anxiety and depression.

Behavioral Effects of Original Tetrapeptide, an Analog of N-Terminal Nociceptin Fragment

The study examined the effect of an analog to N-terminal nociceptin fragment AcOH × Phe-Gly-Gly-Phe-NH2 on the behavior of albino rats. This tetrapeptide (5 μg/kg intraperitoneally) signifi cantly enhanced motor and exploratory activity in mature rats and in 42-day pups and produced opposite effects in 21-day rat pups, which attests to the complex dynamics of maturation of nervous structures involved in the realization of nociceptin action.

The analog of arginine-vasopressin (6-9) fragment, Ac-D-SPRG, exhibits antidepressant action in rats in case of intranasal injection

The antidepressant properties of newly synthesized analog of arginine-vasopressin fragment analog, Ac-D-SPRG, were tested using Porsolt’s swimming test on white rats. It was demonstrated that this substance when injected intranasally decreases the depression in comparison with the control group.

Semax prevents learning and memory inhibition by heavy metals

Separate and joint effect of Semax, ascorbic acid, lead diacetate, and ammonium molybdate on avoidance conditioning in rats was studied. It was established that the heavy metal salts inhibited the avoidance response, and the peptide counteracted this inhibition as strongly as ascorbic acid or to a comparable degree. These findings confirm the antioxidant properties of Semax.

P.1.g.062 The new nociceptin analogue PheGlyGlyPheValGlyPro: dose-dependent effects on pain sensitivity and locomotor activity in rat

antipsychotic (extended-release paliperidone palmitate). The study has been approved by the Ethical Committee of the University of Medicine and Pharmacy of Craiova and was conducted according to ethical regulations for the research on animals. Method: We have studied on Wistar rats the neuroprotective effects of the two long-acting antipsychotics (haloperidol decanoate vs. paliperidone palmitate) against a control group (N0) during 14 days. The study groups included 8 adult, male rats with weight between 200 and 250 grams. They were kept during the entire study in a stress-free environment with optimal parameters of temperature, humidity and food. The substances were administered in intramuscular injections on Day 0: group N1 − haloperidol decanoate (0.5mg/kg), group N2 − paliperidone palmitate (0.5mg/kg) and control group N0 − saline solution. During the 14 days of the study, the subjects were monitored for extrapyramidal signs and behavioral changes. The rats were sacrificed on Day 15 and biological material from the frontal cortex and hippocampus was prepared with specific histological techniques of coloration and fixation: hematoxyline-eosine, trichromicGS, PAShematoxyline, toluidine blue, methylen blue for Nissle corpuscles. Results: The observations during the 14 days revealed extrapyramidal manifestations of medium intensity only within group N1 and avoidant behavior more obvious in group N1 compared with group N2. The assessment of neuroprotection employed optical microscopy and involved the cytoarchitecture of the frontal cortex, dentate gyrus and hippocampus. The histological studies showed significant changes in group N1 (haloperidol decanoate) with large neuronal losses in the layers I, II and III of the frontal cortex, areas of intense vacuoliosation and picnocytosis, as well as microbleedings and vessels of neoformation. In group N2, the changes in frontal cortex were minimal with only a few areas of vacuolisation and vessels of neoformation. The hippocampal area was significantly destructured in group N1, with an evident loss of neural interconnects in area CA1CA3, as well as microbleedings in the dentate gyrus. Many hippocampal structures were affected by picnocytosis to the level of complete neuronal destruction. Changes induced by paliperidone at hippocampal level were also minimal, without picnocytosis or neuronal destruction. Conclusions: On animal mode, haloperidol decanoate demonstrates a significant loss of neuroprotection compared with paliperidone palmitate, as most vulnerable areas are the frontal cortex and hippocampus with close correlation with a possible disturbance of the cortical-subcortical circuits. The new longacting antipsychotic, paliperidone palmitate, suggests the premises of a superior neuroprotection.

Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment

The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4–6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax.