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The Neuroprotective Effects of Semax in Conditions of MPTP-Induced Lesions of the Brain Dopaminergic System


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This report describes studies cf the effects of the ACTH(4-10) analog Semax (MEHFPGP) on the behavior of white rats with lesions to the brain dopaminergic system induced by the neurotoxin MPTP. Neurotoxin was given as single i.p. doses of 25 mg/kg. Neurotoxin injections were shown to decrease movement activity and increase anxiety in the animals. Daily intranasal administration of Semax at a dose of 0.2 mg/kg decreased the severity of MPTP-induced behavioral disturbances. The protective activity of Semax in MPTP-induced lesions of the brain dopaminergic system may be associated with both its modulating effect on the dopaminergic system and the neurotrophic action of the peptide.
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ACTH/MSH-like peptides, collectively known as
“melanocortins,” represent a class of endogenous regula-
tory peptides currently subject to active study. This class
of peptides includes adrenocorticotrophic hormone
(ACTH), melanocyte-stimulating hormone (MSH), and
their fragments and synthetic analogs. These compounds
are interesting because peptides of this class have marked
actions on central nervous system (CNS) function. The
first data on the neurotrophic effects of melanocortins
were obtained from studies of their effects on animal
behavior. These studies showed that these peptides act on
learning, motivational processes, and the concentration
and attention abilities of animals. The behavioral effects
of melanocortins are not associated with their hormonal
activity, but result from their direct actions on the CNS
[9]. Structural-functional studies identified the amino acid
sequence for a minimal ACTH fragment retaining its
behavioral activity. The most marked effects on behavior
were seen with the fragment ACTH(4–10) – Met-Glu-His-
Phe-Arg-Trp-Gly, which retains the behavioral effects of
the whole molecule. Tetrapeptide ACTH(4–10) has almost
the same activity [4, 11].
The literature now contains many reports on the effects
of melanocortins on nervous tissue development and regen-
eration processes [12]. Peptides of this class promote neu-
ron survival and the growth of neurites in tissue cultures
[19]. It has also been demonstrated that ACTH, MSH, and
their fragments and analogs have neurotrophic and neuro-
protective influences on the central and peripheral nervous
systems during early ontogenesis and in neuronal damage
in adult animals. Peripheral administration of melanocortins
during the neonatal period accelerates maturation of the
neuromuscular system, affects CNS development, and leads
to long-term changes in animal behavior [18]. In peripheral
nerve lesions in adult animals, administration of
melanocortins accelerates nerve regeneration and muscle
reinnervation, as demonstrated by electrophysiological,
morphological, biochemical, and functional tests [21].
Positive influences of melanocortins have also been noted
in experiments with central nervous system lesions induced
both by transection of various parts of the brain and by
administration of neurotoxins. Peripheral administration of
ACTH fragments and their analogs accelerates functional
recovery after damage to the hippocampus, labyrinthecto-
my, and bilateral lesions and section of the fornix. In addi-
tion, it has been demonstrated that administration of the
ACTH(4–9) analog ORG 2766 has marked protective
actions in lesions to the substantia nigra due to administra-
Neuroscience and Behavioral Physiology, Vol. 34, No. 4, 2004
The Neuroprotective Effects of Semax in Conditions of
MPTP-Induced Lesions of the Brain Dopaminergic System
N. G. Levitskaya, E. A. Sebentsova, L. A. Andreeva,
L. Yu. Alfeeva, A. A. Kamenskii, and N. F. Myasoedov
2004 Plenum Publishing Corporation
Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 88, No. 11, pp. 1369–1377,
November, 2002. Original article submitted June 11, 2002.
This report describes studies of the effects of the ACTH(4–10) analog Semax (MEHFPGP) on the behav-
ior of white rats with lesions to the brain dopaminergic system induced by the neurotoxin MPTP.
Neurotoxin was given as single i.p. doses of 25 mg/kg. Neurotoxin injections were shown to decrease
movement activity and increase anxiety in the animals. Daily intranasal administration of Semax at a dose
of 0.2 mg/kg decreased the severity of MPTP-induced behavioral disturbances. The protective activity of
Semax in MPTP-induced lesions of the brain dopaminergic system may be associated with both its mod-
ulating effect on the dopaminergic system and the neurotrophic action of the peptide.
KEY WORDS: ACTH fragments, Semax, dopaminergic system, MPTP, rats.
Institute of Molecular Genetics, Russian Academy of Sciences,
123182 Moscow, Russia; Faculty of Biology, M. V. Lomonosov
Moscow State University, 119899 Moscow, Russia.
tion of the neurotoxin 6-OHDA. Animals given the peptide
showed accelerated recovery of behavioral, morphological,
and biochemical parameters as compared with controls [6].
Thus, extensive experimental data have now been
accumulated providing evidence of the neurotrophic influ-
ences of melanocortins on the developing and regenerating
nervous system. Use of short ACTH fragments and their
analogs lacking hormone activity allows the endocrine
properties of the hormones to be separated from their neu-
rotrophic effects. Structural-functional studies have demon-
strated that as in the case of the behavioral effects, the neu-
rotrophic activity is due to the N-terminal part of the ACTH
molecule [12]. Immunochemical methods have demonstrat-
ed the existence of an endogenous ACTH(4–10) fragment
in the rat brain during the early neonatal period. In adult
animals, immunoreactivity to ACTH(4–10) has been noted
after lesioning of the nervous system. It has been suggested
that the endogenous ACTH(4–10) fragment is formed in the
brain during the period of nervous system development and
during the regeneration of nerve tissue [7].
A significant disadvantage of natural melanocortins is
their short duration of action. Many investigators have tried
to create highly effective analogs of ACTH fragments by
introducing various modifications of the primary structure
of the molecule. These experiments resulted in the develop-
ment of analogs of natural peptides lacking hormonal
effects but having marked neurotrophic activity and high
protease stability. Examples of such compounds include the
ACTH(4–9) analogs ORG 2766 and HOE-427, as well as
the ACTH(4–10) analog BIM 22015, which have been
shown to have high levels of behavioral, neurotrophic, and
neuroprotective activity in in vivo and in vitro experiments.
These peptides improve learning and memory, accelerate
regeneration of peripheral nerves after transection, and have
neuroprotective actions in various models of pathology [16,
17, 20]. Preliminary clinical studies have supported the data
obtained in animal experiments. However, none of the syn-
thetic analogs listed above has yet been introduced into
clinical practice. The ACTH(4–10) heptapeptide analog
Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has been devel-
oped and studied at the Institute of Molecular Genetics,
Russian Academy of Sciences and the Faculty of Biology,
Moscow State University. Studies of the physiological
activity of this peptide have demonstrated that it improves
memory and attention, has antihypoxic and antihemorrhag-
ic effects, and promotes decreases in the severity of the clin-
ical and neurophysiological manifestations of experimental
ischemic insult. Thus, Semax retains the spectrum of activ-
ity of natural ACTH fragments and the effects are manifest
for prolonged periods [8]. Semax is currently used in med-
icine as a nootropic agent. Clinical studies have shown its
high efficacy in the treatment of cognitive/memory disor-
ders of different origins and in the prophylaxis and treat-
ment of post-anesthesia memory impairments [1].
Administration of Semax has marked positive actions in the
treatment of stroke [3]. Recent studies have established that
the peptide can increase the lifetime of nerve cells in pri-
mary cultures from rat embryo brain [2].
Studies of the neurotrophic effects of Semax continue,
using a variety of experimental models, the aim being to
widen the spectrum of its clinical application. The present
study addresses the effects of Semax on an MPTP-induced
model of parkinsonism. Parkinson’s syndrome arises as a
result of damage to and degeneration of a proportion of the
dopaminergic neurons in the substantia nigra, leading to
decreases in dopamine levels in the striatum [13]. These
lesions can be modeled experimentally by administration of
the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine), which specifically damages dopaminergic
neurons in the substantia nigra, inducing the development
of parkinsonian symptoms. Biochemical and structural
changes induced by systemic administration of MPTP are
accompanied by disorders of behavioral reactions and the
development of depressive behavior [14]. The aim of the
present work was to study the efficacy of Semax in condi-
tions of MPTP-induced lesions to the brain dopaminergic
Studies were performed on male white mongrel rats
weighing 180–230 g. Animals were kept in standard ani-
mal-house conditions and all experiments were performed
between 11:00 and 18:00. Lesions of the dopaminergic sys-
tem were induced by single injections of MPTP (25 mg/kg,
i.p., in physiological saline). Animals received intranasal
Semax at doses of 0.05 and 0.2 mg/kg 30 min after neuro-
toxin administration. Semax was subsequently given daily
for four days one hour after testing. Each series of experi-
ments involved four groups of animals (18–20 rats per
group); controls received i.p. physiological saline and
intranasal water; the Semax group received i.p. physiologi-
cal saline and intranasal Semax; the MPTP group received
i.p. MPTP and intranasal water; the combined treatment
group received i.p. MPTP and intranasal Semax.
One day after MPTP administration, the animals’
behavior was measured in an open field test (in stress-free
conditions) followed by testing in the burrow box 1 test.
Rats were subsequently tested once daily using the follow-
ing methods: an elevated maze test at two days, burrow box
2 at three days, and in the open field test (stressful version)
at four days.
Open Field Test (OFT). The experimental chamber
was a round arena 80 cm in diameter with a wooden floor
divided by two concentric circles and eight diameters. A
500-W electric lamp was placed 80 cm above the arena,
along with a domestic electric bell and a red 15-W lamp.
For testing, animals were placed in the center of the arena
and horizontal movement activity was monitored visually
Levitskaya, Sebentsova, Andreeva, et al.400
for 2 min, with measurments of excursion length, number of
sector crossings, vertical movement activity (number of
rearings), the number of excursions to the center of the
arena, and grooming (number of washes). Two versions of
the test were performed: the “stress-free” version (in silence
and with the red lamp) and the “stressful” (with the bright
light and bell).
Burrow Box (BB). The experimental apparatus con-
sisted of a square arena with round openings in the floor,
which was divided into squares. Two different experimental
chambers were used – BB1 and BB2. BB1 was a wooden
chamber of size 40 × 40 × 30 cm with 13 openings in the
floor, which was divided into nine squares. BB2 was a
metal chamber of size 47 × 47 × 27 cm with 16 openings,
the floor being divided into 16 squares. The use of two dif-
ferent chambers allowed the animals’ responses to new
experimental situations to be studied in both cases. For test-
ing, rats were placed in the corner of the chamber and the
following measures were recorded visually for 3 min: the
latent period of leaving the start square, horizontal move-
ment activity (excursion length, number of segment cross-
ings), the number of openings investigated, vertical move-
ment activity (number of rearings), and grooming.
Experiments were performed in the quiet with illumination
from the red lamp.
Elevated Cross Maze (ECM). The experimental
chamber was a cross maze (arm length 35 cm, wall height
20 cm). Two opposite arms were dark and closed; the other
two were illuminated and open. The maze was located at a
height of 50 cm from the floor. Rats were placed in the cen-
ter of the maze and the following measures were recorded
for 3 min: the latent period of entering the closed arm, the
total time spent in the light, the number of excursions from
the closed arms, the number of times the animals hung from
the open arms of the maze, and the number of rearings.
Results were analyzed statistically using parametric
(ANOVA) and non-parametric (Wilcoxon–Mann–Whitney
and Fisher) tests run on Statistica. Data were plotted as
mean ± standard error of the mean.
The animals’ behavior was tested one day after MPTP
administration and the first dose of Semax using the open
field and burrow box 1. Two doses of Semax produced no
significant changes in the measures recorded. The MPTP
injection induced significant decreases in horizontal and ver-
tical movement activity in the open field as compared with
controls. Semax (0.05 mg/kg) after MPTP did not alter the
effects of the neurotoxin. Rats given Semax (0.2 mg/kg)
after neurotoxin also showed a significant decrease in excur-
sion length in the open field, though the number of rearings
was insignificantly greater than the level seen in rats given
MPTP only. There were no significant differences in this
parameter either in relation to controls or the levels in rats
given MPTP only (Fig. 1). Studies of the animals’ behavior
in burrow box 1 also revealed decreases in excursion length
and number of rearings after MPTP. Semax (0.05 mg/kg)
after neurotoxin produced no significant changes in the ani-
mals’ behavior as compared to animals given MPTP alone.
However, the number of rearings in this group was slightly
lower than in the MPTP group, though there was no signifi-
cant difference from controls. Horizontal and vertical activ-
The Neuroprotective Effects of Semax in Conditions of MPTP-Induced Lesions 401
Fig. 1. Behavioral parameters in rats in the open field test (stress-free version, one day after MPTP
administration). Vertical axes: A) excursion length, cm; B) number of rearings. 1) Controls; 2) Semax
(0.2 mg/kg); 3) MPTP; 4) MPTP + Semax. *Significant differences from control,
significant dif-
ferences from MPTP group.
ity in rats given MPTP and Semax (0.2 mg/kg) reached the
control level and was significantly different from the level in
rats given neurotoxin only (Fig. 2).
Animals were tested in the elevated cross maze two
days after MPTP (by this time, the rats had received two
injections of Semax). Animals given Semax (both doses)
showed no significant changes in behavioral parameters in
the maze as compared with controls. Animals given MPTP
showed significant decreases in the total time spent in the
illuminated part of the maze and the number of times they
hung from the open arms compared with controls. In addi-
tion, the number of excursions from the closed arms showed
no significant difference from control (p = 0.99). Semax
(0.05 mg/kg) after MPTP produced no increase in the num-
ber of hangings from the arms of the maze compared with
animals given neurotoxin alone. In animals given MPTP
and Semax (0.2 mg/kg), parameters such as the total time
spent in the light, the number of excursions from the closed
arms, and hangings from the maze arms were significantly
higher than values in the group given MPTP and were no
different from those in controls (Fig. 3).
Animals were tested in burrow box 2 three days after
MPTP. Semax (both doses) produced so significant changes
in parameters. Rats given neurotoxin showed significant
Levitskaya, Sebentsova, Andreeva, et al.402
Fig. 2. Behavioral parameters in animals in the burrow box 1 test (one day after administration of MPTP).
For further details see caption to Fig. 1.
Fig. 3. Behavioral parameters in animals in the elevated cross maze test (two days after MPTP). Vertical axes: A) time spent in open arms, sec;
B) number of excursions from closed arms; C) number of hangings from the maze arms. For further details see caption to Fig. 1.
reductions in horizontal and vertical movement activity, as
well as increases in the latent period of leaving the start
square, as compared with controls. Semax (0.05 mg/kg)
produced no significant increase in excursion length or the
number of rearings compared to the group given MPTP.
Rats given Semax (0.2 mg/kg) after neurotoxin
showed a significant increase in excursion length and a
decrease in the latent period compared with animals given
MPTP only. In addition, the number of rearings in this
group was not significantly different from that in rats given
neurotoxin (p = 0.07) (Fig. 4).
Animals were tested in the stressful version of the
open field test four days after MPTP. Chronic administra-
tion of Semax (both doses) had no effect on the animals’
behavior in this test. Rats given MPTP showed significant
decreases in excursion length and the number of excursions
to the center of the field as compared with controls. Semax
(0.05 mg/kg) had no effect on behavioral changes induced
by MPTP. Rats given Semax (0.2 mg/kg) also showed a sig-
nificant decrease in excursion length compared with con-
trols, like the MPTP group, though the number of excur-
sions to the center of the field made by this group was
The Neuroprotective Effects of Semax in Conditions of MPTP-Induced Lesions 403
Fig. 4. Behavioral parameters of animals in the burrow box 2 test (three days after MPTP). Vertical axes: A) latent period of leaving the
start square, sec; B) excursion length, cm; C) number of rearings. For further details see caption to Fig. 1.
Fig. 5. Behavioral parameters of animals in the open field test (stressful version) four days after MPTP. Vertical
axes: A) excursion length, cm; B) number of excursions to the center. For further details see caption to Fig. 1.
significantly greater than in rats given neurotoxin only and
was no different from the level in controls (Fig. 5).
Studies of the animals’ behavior in the open field and
burrow box tests showed that MPTP led to decreases in hor-
izontal and vertical movement activity as compared with
controls. Neurotoxin-induced changes in the rats’ behav-
ioral parameters in the elevated cross maze test provided
evidence for an increase in the level of anxiety. The
decrease in the number of excursions to the center of the
arena in the stressful version of the open field test seen in
rats given MPTP may also be associated with increases in
anxiety. These data lead to the conclusion that single doses
of MPTP (25 mg/kg) induce decreases in movement and
orientational-investigative activity in rats and increase the
level of anxiety. The behavioral changes persisted for at
least four days after neurotoxin administration.
Semax (0.05 mg/kg) given after MPTP in some cases
decreased the extent of behavioral disorders induced by
neurotoxin. However, none of the experiments showed sig-
nificant differences between this group of animals and those
given MPTP only.
Semax (0.2 mg/kg) after MPTP-induced lesioning of the
dopaminergic system to a significant extent normalized the
animals’ behavior. Rats of this group were characterized by
higher levels of motor and orientational activity and decreased
levels of anxiety as compared with animals given MPTP only.
Thus, daily intranasal administration of Semax
(0.2 mg/kg) promoted functional recovery in animals with
lesions to the dopaminergic system of the brain, having
protective effects in the MPTP-induced model of parkin-
sonism. Semax (0.05 mg/kg) was virtually ineffective in
this model.
ACTH-like peptides are known to have modulating
effects on the brain dopaminergic system [10] – they
increase dopamine concentrations in various brain struc-
tures, activating the synthesis and release of the transmitter
in response to external stimuli. Previous studies have
demonstrated that administration of Semax weakens behav-
ioral abnormalities in animals induced by the dopamine
receptor blocker haloperidol, which may be associated with
increases in transmitter release [5]. The modulating influ-
ence of Semax on the brain dopaminergic system may
underlie the neuroprotective effects of the peptide in MPTP-
induced lesions. Increases in the synthesis and release of
dopamine by undamaged neurons may lead to increases in
the transmitter concentration in the striatum to the level typ-
ical of the asymptomatic stage of parkinsonism.
Semax has also been shown to increase neuron sur-
vival in primary cultures from the basal nuclei of the fore-
brain and to increase the expression of the genes encoding
the neurotrophic factors NGF and BDNF in glial cell cul-
tures [15]. Thus, the effects seen here may be associated
with the neurotrophic activity of Semax, due to weakening
of damage and restoration of the function of reversibly
damaged nigrostriatal dopamine-synthesizing neurons.
Thus, the neuroprotective effects of Semax in
MPTP-induced lesions to the brain dopaminergic system
may be based on both compensatory processes needed for
functional recovery and increases in neuron survival.
This study was supported by the Russian Fund for
Basic Research (Grant No. 01-04-48767).
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... At the next stage, the developed test system was used to test two known neuroprotectors with different mechanisms of action: nomifensine, an inhibitor of the DA membrane transporter involved in the penetration of specific toxins (MPP+, 6-HDA) into DA-ergic neurons, followed by oxidative stress and subsequent neuronal death; and SEMAX, a fragment of the adrenocorticotropic hormone, a Met-Glu-His-Phe-Pro-Gly-Pro peptide that can act either as an inducer of the synthesis of endogenous neurotrophic factors or an antioxidant, depending on the way of its administration [5,6]. ...
... SEMAX can stimulate the production of endogenous neurotrophic factors and act as an antioxidant [5,6]. To separate these two effects, we used two experiment designs. ...
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Degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease begins from the axonal terminals in the striatum and, then, in retrograde fashion, progresses to the cell bodies in the substantia nigra. Investigation of the dynamics of axonal terminal degeneration may help in the identification of new targets for neuroprotective treatment and be used as a tool for testing potential drugs. We have shown that the degeneration rate of dopaminergic axonal terminals changes over time, and that the striatal dopamine concentration is the most sensitive parameter to the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This model was validated using neuroprotectors with well-known mechanisms of action: the dopamine transporter inhibitor nomifensine and SEMAX peptide that stimulates the secretion of endogenous neurotrophic factors or acts as an antioxidant. Nomifensine was shown to almost completely protect dopaminergic fibers from the toxic effect of MPTP and maintain the striatal dopamine concentration at the control level. However, SEMAX, slightly but reliably, increased striatal dopamine when administered before MPTP treatment, which indicates that it is more effective as an inductor of endogenous neurotrophic factor secretion rather than as an antioxidant.
... studies have demonstrated that this peptide improves memory and attention and has antihypoxic and neuroprotective effects; in addition, it affects the development of the central nervous system and decreases pain sensitivity (Ashmarin et al., 1995;Levitskaya et al., 2004Levitskaya et al., , 2008. Acute administration of Semax has a normalizing effect on the emotional state; chronic Semax administration has an anxiolytic effect under normal conditions and reduces the adverse effects of chronic unpredictable stress (Vilensky et al., 2007;Levitskaya et al., 2010;Yatsenko et al., 2013). ...
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The effect of acute restrained stress on cognitive functions and anxiety-like behavior in white rats has been studied; furthermore, the influence of the fragment ACTH(4–10) analog Semax on the stress effects was evaluated. It was shown that stress exposure leads to impaired retention of previously acquired food-motivated maze task as well as reduced anxiety-like behavior in the elevated plus maze in rats. Preliminary intraperitonial administration of Semax (0.1 mg/kg) attenuates cognitive impairment caused by acute restrained stress, but it does not affect stress-induced changes in anxiety.
... The test area was formed by a round field 80 cm in diameter with wooden floor ruled into 16 equal sectors subdivided by two concentric circles; the height of the area barrier was 40 cm. For measure ment of spontaneous motor activity, each animal was placed into the center of the area and the number of hor izontal transitions between sectors was registered for 2 min [21,22]. Observations began 90 sec after applica tion of the preparations. ...
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The brain is protected by a physiological blood-brain barrier (BBB) against toxins and some metabolites circulating in the blood. At the same time, the BBB limits penetration into the brain of many neuroactive drugs. Efficient ways to increase BBB permeability for delivery of drugs of different chemical nature into the brain are unknown. This work deals with delivery into the brain of 10(-2) M dopamine, a substance that does not penetrate the BBB under normal circumstances. It was studied in two independent experiments: (i) penetration of (3)H-labeled dopamine from its mixture with 10(-5) M H2O2 into hypothalamus and striatum structures of intact rat brain, and (ii) effect of unlabeled dopamine from a mixture with H(2)O(2) on the rat motor activity in a haloperidol catalepsy model. It was shown that (i) at the third minute after nasal application of the dopamine + H(2)O(2) mixture, the dopamine level increases 45-fold in the hypothalamus and almost 30-fold in the striatum and (ii) motility of animals in the catalepsy haloperidol model is recovered 90 sec after intranasal introduction of dopamine. No such effects were observed after replacement of H(2)O(2) by 0.9% NaCl solution. Thus, it was shown on the example of dopamine that its introduction into the nasal cavity simultaneously with H(2)O(2) provides for rapid delivery of the drug into the brain. These results expand our knowledge concerning the biological role of exoROS in modulating BBB permeability and may contribute to the development of a new therapeutic strategy for neurological diseases.
Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4–10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1–14, a time period equivalent to 27–40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15–28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development.
It was shown, that photochemically induced thrombosis of blood vessels in prefrontal areas of the cortex lead to the formation of well-defined infarct zone. Bilateral prefrontal cortex injury impair acquisition of the Morris water-maze on postoperative days 20-24. Chronic treatment of brain-injuried rats with peptide semax, a synthetic analogue of ACTH(4-7), at a dose of 250 μg/kg (intranasal, once a day) during six days after photothrombosis resulted in restoration of spatial learning ability. The observed long-lasting antiamnesic effects of the semax are probably caused by its strong neuroprotective action, and ability to induce synthesis of nerotrophic factors.
The more recent history and main experimental data for the Krushinsky-Molodkina (KM) audiogenic rat strain are presented. The strain selection started in late 1940. Now this strain is inbred, and two new strains are maintained in a laboratory in parallel. These strains originated from KM×Wistar hybrids and were bred (starting from 2000) for no-seizure and intense audiogenic seizure phenotypes, respectively. The experimental evidences of audiogenic seizure physiology were accumulated in parallel with (and usually ahead of) data on other audiogenic-prone strains. The peculiar feature of the KM strain is its vulnerability to brain hemorrhages. Thus, the KM strain is used not only as a genetic model of seizure states, but also as a model of blood flow disturbances in the brain. This article is part of a Special Issue entitled: "Genetic Models-Epilepsy". Copyright © 2015 Elsevier Inc. All rights reserved.
The spatial and electron structure of the heptapeptide molecule Gly-Glu-His-Phe-Pro-Gly-Pro were investigated using semiempirical methods. By theoretical conformational analysis method has been investigated the low-energy conformations, geometric and energetic parameters of this molecule. By quantum-chemical method of CNDO/2 has been determined sharing electronic density and value of dipole moments of this molecule.
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The heptapeptide Semax (MEHFPGP) is an analog of the fragment ACTH(4–10) with long-lasting actions. The aim of the present work was to study the effects of Semax on learning ability and pain sensitivity in white rats given different doses via the intraperitoneal and intranasal routes. The nootropic effects of Semax were studied in a test based on the acquisition of a conditioned passive avoidance reaction to pain stimulation. Pain sensitivity was assessed in a hindpaw compression test. The results showed that i.p. Semax had nootropic and analgesic actions. Dose-response characteristics were different for these different effects. Intranasal Semax was more effective in improving learning in animals than i.p. Semax but had no effect on pain sensitivity. Our results provide evidence that different mechanisms and brain structures are involved in mediating the nootropic and analgesic effects of Semax.
We studied the effects of a single semax administration to rats on the activity of carboxypeptidase H, a basic carboxypeptidase involved in the final stage of formation of biologically active peptides from their precursors. We found that the drug induced a long-term increase in the activity of carboxypeptidase, which lasted for 24 h. We believe that this change in the activity of the enzyme studied may serve as one of the factors that mediate semax action. Keywordssemax–carboxypeptidase H–neuropeptides–brain–adrenal glands
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The biological activity of an ACTH(4-10) analogue, Semax (MEHFPGP), has been studied. This peptide was shown to have a beneficial effect on the functions of the central nervous system. Semax accelerated the learning process in animals and had a prolonged effect in comparison to ACTH(4-10). It increased the resistance of rats exposed to hypobaric and circulatory hypoxia. Semax had a protective effect against the development of haemorrhagic stroke in rats. Experiments with volunteers and clinical investigations with Semax are currently being carried out. The data obtained underscore the potential of Semax as a stimulator of memory and mental functions and as a potential antihypoxic and antistroke drug.
Epinephrine, derived from the adrenal medulla, enhances memory storage for several forms of learning. One physiological action of this hormone is to liberate hepatic glucose stores. This experiment tested the possibility that glucose could itself enhance memory. Rats were water deprived, pretrained to drink, pretrained to drink in the behavioral apparatus, and then trained in a one-trial inhibitory (passive) avoidance task. Immediately after the training footshock, the animals each received an injection of glucose (1.0–500 mg/kg). When tested for retention 24 h later, the animals which received 10 or 100 mg/kg doses of glucose exhibited enhanced retention performance; higher and lower doses had no significant effect on the memory tests. Also, glucose injections (100 mg/kg) delayed by 1 h after training had no effect on the retention tests. These findings suggest that the increase in plasma glucose levels subsequent to epinephrine injection may contribute to the effects of epinephrine on memory. In addition, the results suggest that peripheral glucose levels may exert important influences on memory storage.
ACTH-like neuropeptides have been investigated in various paradigms such as cognition, neuronal damage and neuronal excitation. All their effects may be collectively described as modulation of neural plasticity. However, the mechanism of action accounting for these effects remains to be demonstrated. This report is an overview of the data and has incorporated some additional findings of the influence of the ACTH4-9 analog, Org2766, on neuronal excitation, especially in the hippocampus. An interaction with NMDA receptors may account for the various aspects of plasticity. Based on recent findings demonstrating that the ACTH4-9 analog counteracts both the NMDA antagonist, AP5, and NMDA-induced explosive running behavior, the hypothesis is put forward that glutamatergic neurotransmission is involved in behavioral changes induced by the ACTH4-9 analog.
The transfer of ebiratide into the brain was examined in rats. Its brain levels after intravenous administration (2-20 mg/kg), determined by radioimmunoassay, peaked at 5 min and declined almost in parallel with the plasma levels. Brain/plasma ratios (B/P) were constantly about 0.05 ml/g at all doses. Brain distribution study at 5 min after 125I-ebiratide at an effective dose (0.4 microgram/kg) revealed that unchanged ebiratide had larger B/P than the metabolites and region selectivity. The combined use with unlabeled ebiratide resulted in marked decreases in B/P, particularly in the hippocampus, suggesting a specific uptake of this peptide.
(1) The availability of short amino acid sequences of the naturally occurring ACTH 1-39 molecule has made it possible to separate the corticotropic characteristics of the parent molecule from its neurotrophic effects. Potent neurotrophic fragments are ACTH 4-10, an analog of ACTH 4-9 (Org 2766), and alpha-MSH (ACTH 1-13), peptide fragments that do not evoke corticosteroid secretion, yet clearly affect both the development and regeneration of peripheral nerve. (2) Early postnatal administration of either ACTH 4-10 or Org 2766 accelerates the neuromuscular development of the immature rat, increasing the contractile strength of the EDL muscle and inducing more rapid muscle contractions. Grasping strength and motor activity are increased; these are all changes indicative of more rapid neuromuscular maturation. Prenatal peptide treatment elicits a more complex pattern of response since administration early in gestation (GD 3-12) accelerates neuromuscular development whereas later administration (GD 13-21) decelerates maturation. (3) ACTH peptides have a similar accelerating effect on the morphology of the developing neuromuscular junction. At two weeks of age, nerve arborization is conspicuously increased by postnatal administration of either ACTH 4-10 or Org 2766, as is nerve terminal branching within the endplate itself. However, this is preceded by an initial depression of nerve branching in the 7-day-old rat pup. We conclude that while the developing neuromuscular system is sensitive to ACTH peptides, this susceptibility is age-related. The crucial role of these peptides may be limited to very brief, defined periods during which the peptides may interact with trophic or growth-associated substances, each of which may have its own decisive, circumscribed time frame of influence. (4) Perinatal administration of ACTH peptides affects CNS development. One measurable indication of this is an acceleration of eye opening. Early exposure to ACTH peptides has long-lasting effects on behavior, apparent when these animals are tested as adults. Increased spontaneous motor activity, heightened states of arousal and agitation, and changes in social behavior have been reported. Certain avoidance responses and tests of visual discrimination in male rats are improved by neonatal treatment with alpha-MSH. Overall motor activity is increased and the normal period of hyperactivity is initiated earlier. Male sexual behavior is decreased and sexually dimorphic behaviors in males are eliminated. alpha-MSH may alter the development of its own dopaminergic feedback circuitry while ACTH affects serotonin levels in the preoptic nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)