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Transcriptomic response of rat hippocampus and spleen cells to single and chronic administration of the peptide selank

  • Institute of Molecular Genetics of National Research Centre «Kurchatov Institute»


A new direction in designing new drugs able to effectively reduce anxiety without having side effects is the use of endogenous regulatory peptides. Research� ers of the Institute of Molecular Genetics, Russian Academy of Sciences, and the Zakusov Research Institute of Pharmacology, Russian Academy of Med� ical Sciences, have created the preparation selank, the effective substance of which is a synthetic peptide, an analogue of the short fragment Thr–Lys–Pro–Arg of the heavy chain of human immunoglobulin G, elon� gated at the C terminus with the tripeptide Pro–Gly– Pro. It was shown that selank has a stable nootropic and anxiolytic effects, facilitate brain cell survival in hypoxia, and exhibits an antiviral effect [3, 10].
ISSN 16076729, Doklady Biochemistry and Biophysics, 2010, Vol. 430, pp. 5–6. © Pleiades Publishing, Ltd., 2010.
Origi nal Russian Text © T. A. Kolomin , M.I. Shadr ina, Ya.V. A gniullin, S.I. Shram, P.A. Slominskii, S.A. Lim borska, N. F. Myasoed ov, 2010, published in Doklady Akademii Nauk,
2010, Vol. 430, No. 1, pp. 127–129.
A new direction in designing new drugs able to
effectively reduce anxiety without having side effects is
the use of endogenous regulatory peptides. Research
ers of the Institute of Molecular Genetics, Russian
Academy of Sciences, and the Zakusov Research
Institute of Pharmacology, Russian Academy of Med
ical Sciences, have created the preparation selank, the
effective substance of which is a synthetic peptide, an
analogue of the short fragment Thr–Lys–Pro–Arg of
the heavy chain of human immunoglobulin G, elon
gated at the
terminus with the tripeptide Pro–Gly–
Pro. It was shown that selank has a stable nootropic
and anxiolytic effects, facilitate brain cell survival in
hypoxia, and exhibits an antiviral effect [3, 10].
Recent studies showed that many peptides, semax
in particular, can modulate genome expression [1, 13].
Since the peptide selank also belongs to the regulatory
peptide family, it was of interest to assess its effect on
the genome expression. For this purpose, we per
formed a search for the genes whose expression in the
rat hippocampus and spleen changes under the influ
ence of this peptide.
Experiments were performed with male Wistar
rats weighing, on average, 260 g. The animals were
divided into three groups (eight animals in each): the
control group (C), the group with single administra
tion (SA) of selank, and the group with chronic
administration (CA) of selank. Rats of two groups, C
and SA, were intranasally administered with water
once a day for five days, and the animals of group CA
were intranasally administered with aqueous selank
solution (200
g/kg body weight). On 6 day, the rats
of group SA were intranasally administered with
aqueous selank solution (200
g/kg). One hour later,
the animals were decapitated. Total RNA was iso
lated from the hippocampus and spleen using the
Total RNA Isolation System (Promega,
United States), which was then used to synthesize the
first strand of cDNA with the RevertAid
H Minus
First Strand cDNA Synthesis Kit (Fermentas,
The effect of selank of gene expression in rat hip
pocampus was studied using the SBC–R–RC–100–
13 microtemplate comprising 12000 genes (Shanghai
, China). The level of expression of certain
genes was quantitated by realtime PCR in an
RealTime QPCR System (Stratagene
Equipment, United States) using the SYBR Green I
dye (Sintol, Russia) and RT
qPCR Primer Assay
Green primers (Super Array, United States).
The obtained values of the threshold reaction cycles
) were normalized relative to the
gene encoding the ribosomal protein L3. The results
were statistically processed using the Relative Expres
sion Software Tool384, version 2 software [8].
At the first stage of the study, we hybridized the hip
pocampal RNA on the microtemplate. The results of
these experiments showed that both single and chronic
administration of selank caused a twofold change in
the expression of five genes (table). Taking into
account the fact that selank exhibits a pronounced
antiviral activity, the study of the mechanism of action
of this peptide on the expression of these five genes in
the rat spleen was of particular interest.
The quantitative assessment showed that the effect of
selank on the expression of the five selected genes in the
spleen is much stronger than in the hippocampus. In the
spleen, an increase in the expression of all five genes was
observed. The most significant increase (by a factor of
over 4.5) was observed after a single administration of
selank. In the case of chronic administration, the effect
of the peptide was less pronounced: the expression of the
selected genes increased at most twice (table).
It should be noted that the direction of the effect of
selank on the expression of
in rat hippocampus and spleen was opposite. In the
hippocampus, the
expression after a single and
chronic selank administration and the
expression after a single selank administration signifi
Transcriptomic Response of Rat Hippocampus and Spleen Cells
to Single and Chronic Administration of the Peptide Selank
T. A. Kolomin, M. I. Shadrina, Ya. V. Agniullin, S. I. Shram, P. A. Slominskii,
S. A. Limborska, and
N. F. Myasoedov
Received June 2, 2009
Institute of Molecular Genetics,
Russian Academy of Sciences, pl. Akademika Kurchatova 46,
D182, Moscow, 123182 Russia
KOLOMIN et al.
cantly decreased. In the spleen, conversely, the expres
sion of these genes increased, especially after a single
selank administration.
The greatest change in gene expression was
observed in the spleen for three genes—
, and
after a single selank administra
tion. The maximum (70fold) increase in expression
was detected for the
gene. This gene encodes
an integral glycoprotein involved in the regulation of
transmembrane signaling [4]. The
gene is a
key autoantigen in insulindependent diabetes melli
tus and may have a pathogenic role in the development
of this disease [11].
The expression of
increased 16 times after a single selank administration.
gene encodes the calciumsensitive protein
that crosslinks Factin fibrils and plays a key role in the
maintenance of the cytoplasm viscosity and elasticity
required for the preservation of the integrity of macro
molecules associated with the plasma membrane [12].
The discovered change in the
expression is
of special interest because this gene is involved in the
regulation of inflammatory processes. The
gene encodes the specific serpentinetype fractalkine
receptor that is involved in leukocyte maturation,
transfer, and recirculation as well as in the initiation of
local inflammation as a result of involvement of
inflammatory cells in chemotaxis [5, 9]. The interac
tion of fractalkine with CX3CR1 may serve as a regu
lator of the relationship between neurons and micro
glial and be involved in microglia activation and
migration [7]. There are data indicating that CX3CR1
functions as a neuroprotector and can inhibit apopto
sis [6]. In addition, it was shown that CX3CR1 may
function as a coreceptor for HIV1 penetration into
the cell [2].
Our results indicate that selank may participate in
the regulation of inflammatory processes in the body.
The complex biological effect of selank on the body at
least partially may be determined by the systemic
effect of this peptide on the genome expression. This
mechanism of action of peptides opens new vistas for
directional changes of transcriptional profile under
the influence of oligopeptides, homologues of natural
biologically active peptides. However, further studies
of the mechanisms of action of peptides, including
selank, on various systems of the body and the pro
cesses in them are required.
This study was supported by the Russian Founda
tion for Basic Research (project no. 090401237a),
the program “Molecular and Cellular Biology” of the
Russian Academy of Sciences, and the State Contract
no. 02.512.11.2245.
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Relative changes in gene expression in the rat hippocampus and spleen caused by single (SA) and chronic (CA) adminis
tration of the peptide selank relative to the control
Gene Gene name Hippocampus Spleen
Actinin 1 0.42* 0.49* 15.96** 1.97**
Chemokine (CX
C) receptor 1 0.46* 2.77* 15.93** 1.87**
Fibroblast growth factor 7 2.35* 2.23* 8.15** 2.08**
Receptorlike protein tyrosine phosphatase N2 2.61* 3.01* 70.36** 1.09
Sodium and chloridedependent transporter XTRP3 3.98* 2.13* 4.47* 1.19
< 0.05; **
< 0.01.
... Concomitantly, administration of a single intranasal dose of Selank (200 μg/kg) changed the mRNA levels of 36 genes, and a curative administration of Selank (200 μg/kg once a day for 5 days) changed the mRNA levels of 20 genes. The expression level of six genes (Actn1, Cx3cr1, Fgf7, Kng1, Ptprn2, and Slc6a20) changed after both single and curative introduction of Selank [184]. ...
... The third cluster included 15 genes encoding proteins involved in the cellular transport system: Arfgap1, Atp5a1, Cacna1g, Clcnka, Gria4, Grid2, Kcnj4, Scamp5, Scn3b, Slc1a2, Slc5a7, Slc6a20, Slc8a3, Trpc1, and Tomm20. Of these, 10 are involved exclusively in ion transport and ion homeostasis for cell support: Atp5a1, Cacna1g, Clcnka, Gria4, Grid2, Kcnj4, Scn3b, Slc5a7, Slc8a3, and Trpc1 [184,187]. ...
... Significantly higher levels of the Cx3cr1 mRNA were detected in the frontal cortex and cerebellum after a single Selank injection, whereas multidirectional changes in the mRNA level of this gene were observed in these regions of the brain after curative administration of the peptide. In the rat cerebellum, a significant decrease was observed in the mRNA levels of the Ptprn2 gene, which is widely expressed in the brain and is involved in the growth and differentiation of nerves [184]. Together with its anxiolytic and nootropic actions, Selank elicits a pronounced immunomodulatory activity [179,180]. ...
... Previously, it was shown that Selank causes a marked change in the expression of genes involved in inflammatory processes in the hippocampus and spleen of rodents (Kolomin et al., 2010(Kolomin et al., , 2011(Kolomin et al., , 2014. Our results have confirmed at the molecular level that the clinical effects observed after the introduction of Selank are related to its antiviral activity (Ershov et al., 2009;Andreeva et al., 2010). ...
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Clinical studies have shown that Selank had an anxiolytic effect comparable to that of classical benzodiazepine drugs, which can enhance the inhibitory effect of GABA by allosteric modulation of GABAA receptors. These data suggest that the molecular mechanism of the effect of Selank may also be related to its ability to affect the performance of the GABAergic system. To test this hypothesis, we studied the changes in expression of 84 genes involved in the functioning of the GABAergic system and in the processes of neurotransmission in the culture of neuroblastoma IMR-32 cells using qPCR method. As test substances, in addition to Selank, we selected the major GABAA receptor ligand, GABA, the atypical antipsychotic, olanzapine, and combinations of these compounds (Selank and GABA; Selank and olanzapine). We found no changes in the mRNA levels of the genes studied under the effect of Selank. The combined effect of GABA and Selank led to nearly complete suppression of changes in expression of genes in which mRNA levels changed under the effect of GABA. When Selank was used in conjunction with olanzapine, the expression alterations of more genes were observed compared with olanzapine alone. The data obtained indicate that Selank has no direct effect on the mRNA levels of the GABAergic system genes in neuroblastoma IMR-32 cells. At the same time, our results partially confirm the hypothesis that the peptide may affect the interaction of GABA with GABAA receptors. Our data also suggest that Selank may enhance the effect of olanzapine on the expression of the genes studied.
... A pronounced change in the expression of the genes involved in inflammatory processes in the brain was observed. In particular, the use of both Selank administration schemes led to a significant change in the expression of the Cx3cr1 gene, which ensures local inflammation in the brain via the regulation of microglial activation and migration (Kolomin et al., 2010(Kolomin et al., , 2013. ...
We studied the effects of Selank on the condition of the colon wall in Wistar male rats subjected to restraint stress. Selank was injected intraperitoneally in doses of 80, 250, and 750 μg/kg 15 min before stress exposure. In rats subjected to stress, signs of atrophy, inflammatory reaction, and changes in the number and functional activity of mast cells were observed against the background of increased corticosterone level. Selank administration led to a decrease in corticosterone levels, reduced pathomorphological manifestations of stress exposure, and accelerated adaptation. These effects were presumably realized due to multifunctional biological effects of Selank.
Here we present a review of studies on the effects of peptides with neuroprotective properties on gene transcription in nerve cells. The few published works in this area clearly demonstrate massive changes in cell transcriptomes induced by peptides under normal conditions and under conditions of experimental brain ischemia. These changes significantly affect signaling and metabolic pathways, affecting various body systems and confirming the multiple target actions of peptides. The importance of noncoding RNAs in the regulation of these processes is shown, and we discuss the prospects of research for determining the main mechanisms of peptide regulation, which is necessary for the further development of drugs with targeted neuroprotective effects.
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A study of the immunomodulating effect of selank showed that both the total peptide and its fragment significantly change the expression of the genes for chemokines, cytokines, and their receptors in mouse spleen 6 and 24 h after single administration. Changes in the mRNA level of the majority of the genes under study were observed after the administration of Gly-Pro, which was earlier identified as a selank pharmacophore, a minimum fragment with anitiviral activity.
Previous studies have shown that synthetic tuftsin analogue Selank causes a transcriptomic response in the rat hippocampus and in spleen cells and may participate in the regulation of inflammatory processes in the body. In this work we studied the effect of Selank and two of its fragments on the expression of genes involved in processes of inflammation. We analyzed the expression of 84 genes involved in processes of inflammation (e.g., chemokines, cytokines, and its receptors) in mouse spleen 6 and 24 h after Selank single intraperitoneal injection (100 μg/kg) using real-time PCR method. We found significant changes in the expression of 34 genes involved in inflammation processes. The detailed analysis of quantitative data showed that the Bcl6 gene, which plays a main role in the formation and development of the immune system, exhibited significant changes in its expression levels in response to injection of each of the peptides. Also, we observed expression changes for Bcl6 target and corepressor genes under the influence of Selank and its fragments. Our results showed that Selank and its fragments caused a number of alterations in the expression of genes involved in inflammation. The data obtained confirmed the participation of Selank in the processes of regulation of inflammation in the body. The complex biological effect of Selank may be partially determined by the systematic effect of this peptide on genomic expression.
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Objective To examine the expression of the novel CX3C chemokine fractalkine (Fkn) and its receptor (CX3CR1) in rheumatoid arthritis (RA) and rat adjuvant-induced arthritis (AIA), a model of RA.Methods Immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), reverse transcriptase–polymerase chain reaction (RT-PCR), and chemotaxis assays were used.ResultsIn rat AIA, synovial tissue (ST) macrophages, fibroblasts, endothelial cells, and dendritic cells were Fkn immunopositive, whereas lymphocytes did not significantly express Fkn. Significant staining for CX3CR1 was found in ST macrophages, fibroblasts, and dendritic cells, whereas only a small percentage of endothelial cells stained for CX3CR1 in rat AIA. We immunolocalized Fkn to RA ST macrophages, fibroblasts, endothelial cells, and dendritic cells. We also found intense ST macrophage and dendritic cell staining for CX3CR1 in RA ST. Flow cytometry analysis of RA synovial fluid (SF) and peripheral blood revealed a greater percentage of monocytes expressing Fkn and CX3CR1 compared with T cells. By ELISA, we found significantly elevated soluble Fkn (sFkn) levels in RA SF compared with SF from patients with osteoarthritis or other forms of arthritis. By RT-PCR, we found enhanced expression of Fkn and CX3CR1 mRNA on day 18 in rat AIA, a time of pronounced inflammation in the rat joint. Soluble Fkn–depleted RA SF showed significantly decreased chemotactic activity for monocytes compared with sham-depleted RA SF.Conclusion These results indicate that Fkn and its receptor are both expressed in RA and in rat AIA, and that sFkn is up-regulated in RA SF. Furthermore, our data suggest a new role for Fkn in monocyte chemotaxis in the inflamed RA joint.
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Fractalkine is a multimodular human leukocyte chemoattractant protein and a member of the chemokine superfamily. Unlike other human chemokines, the chemokine domain of fractalkine has three amino acids between two conserved cysteines, referred to as the CX3C motif. Both plasma membrane-associated and shed forms of fractalkine have been identified. Here, we show that the recombinant 76-amino acid chemokine domain of fractalkine is a potent and highly specific chemotactic agonist at a human orphan receptor previously named V28 or alternatively CMKBRL1 (chemokine beta receptor-like 1), which was shown previously to be expressed in neutrophils, monocytes, T lymphocytes, and several solid organs, including brain. CMKBRL1/V28 also functioned with CD4 as a coreceptor for the envelope protein from a primary isolate of HIV-1 in a cell-cell fusion assay, and fusion was potently and specifically inhibited by fractalkine. Thus CMKBRL1/V28 is a specific receptor for fractalkine, and we propose to rename it CX3CR1 (CX3C chemokine receptor 1), according to an accepted nomenclature system.
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Recent in vitro and in vivo studies have shown that the chemokine fractalkine is widely expressed in the brain and localized principally to neurons. Central nervous system expression of CX(3)CR1, the only known receptor for fractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that fractalkine regulates cellular communication between neurons (that produce fractalkine) and microglia (that express its receptor). Here we show, for the first time, that hippocampal neurons also express CX(3)CR1. Receptor activation by soluble fractalkine induces activation of the protein kinase Akt, a major component of prosurvival signaling pathways, and nuclear translocation of NF-kappaB, a downstream effector of Akt. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120(IIIB), an effect blocked by anti-CX(3)CR1 antibodies. Experiments with two different inhibitors of the phosphatidylinositol 3-kinase, a key enzyme in the activation of Akt, and with a phospholipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of fractalkine. These data show that neuronal CX(3)CR1 receptors mediate the neurotrophic effects of fractalkine, suggesting that fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.
Leukocyte trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. Fractalkine, a novel transmembrane molecule with a CX3C-motif chemokine domain atop a mucin stalk, induces both adhesion and migration of leukocytes. Here we identify a seven-transmembrane high-affinity receptor for fractalkine and show that it mediates both the adhesive and migratory functions of fractalkine. The receptor, now termed CX3CR1, requires pertussis toxin–sensitive G protein signaling to induce migration but not to support adhesion, which also occurs without other adhesion molecules but requires the architecture of a chemokine domain atop the mucin stalk. Natural killer cells predominantly express CX3CR1 and respond to fractalkine in both migration and adhesion. Thus, fractalkine and CX3CR1 represent new types of leukocyte trafficking regulators, performing both adhesive and chemotactic functions.
A receptor-type protein tyrosine phosphatase, PTP NE-6, was identified from rat olfactory epithelial cDNA and cloned from a rat brain cDNA library. PTP NE-6 mRNA is abundant in brain and expressed at lower levels in olfactory tissue and adrenal gland. In situ hybridization demonstrates that PTP NE-6 mRNA is expressed throughout the brain, with highest levels in the medial habenula and at intermediate levels in layer IV of cortex, medial geniculate nucleus, inferior colliculus, hypothalamus, and thalamus. The predicted amino acid sequence demonstrates that PTP NE-6 contains a single catalytic domain that diverges from the consensus protein tyrosine phosphatase catalytic domain by expressing an aspartate instead of the conserved alanine residue in the catalytic site. Recombinantly expressed PTP NE-6 does not exhibit detectable phosphatase activity. Upon mutation of the aspartate to the consensus alanine, phosphatase activity toward p-nitrophenyl phosphate is observable with a kcat value of 3.7 s−1 and a Km of 980 µM. These data demonstrate that the inactivity of native PTP NE-6 toward p-nitrophenyl phosphate is due to the divergent aspartate in the catalytic site and not to variant amino acids within the phosphatase domain.
Localization of the mRNAs for fractalkine, a CX3C chemokine, and for its receptor CX3CR1 was investigated in the rat brain. In situ hybridization study revealed that fractalkine mRNA was dominantly expressed in neuronal cells particularly in the olfactory bulb, cerebral cortex, hippocampus, caudate putamen and nucleus accumbens. In vitro study using enriched neuronal or glial culture supported the dominant expression of fractalkine mRNA in neurons. On the other hand, CX3CR1 mRNA was dominantly expressed in glial cells throughout the whole brain. The in vitro study suggested the cells expressing CX3CR1 mRNA are microglia, not astrocytes or neurons. Fractalkine appears to function as a signal molecule from neuron to microglia.
The stability of standard gene expression is an elementary prerequisite for internal standardisation of target gene expression data and many so called housekeeping genes with assumed stable expression can exhibit either up- or down-regulation under some experimental conditions. The developed, and herein presented, software called BestKeeper determines the best suited standards, out of ten candidates, and combines them into an index. The index can be compared with further ten target genes to decide, whether they are differentially expressed under an applied treatment. All data processing is based on crossing points. The BestKeeper software tool was validated on four housekeeping genes and 10 members of the somatotropic axis differentially expressed in bovine corpora lutea total RNA. The BestKeeper application and necessary information about data processing and handling can be downloaded on
Phogrin is an integral glycoprotein primarily expressed in neuroendocrine cells. The predominant localization of phogrin is on dense-core secretory granules, and the lumenal domain has been shown to be involved in its efficient sorting to the regulated secretory pathway. Here, we present data showing that a leucine-based sorting signal [EExxxIL] within the cytoplasmic tail contributes its steady-state localization to secretory granules. Deletion mutants in the tail region failed to represent granular distribution in pancreatic beta-cell line, MIN6, and anterior pituitary cell line, AtT-20. A sorting signal mutant with two glutamic acids substituted into alanines (EE/AA) is primarily accumulated in the Golgi area instead of secretory granules, and another mutant (IL/AA) is trapped at the plasma membrane due to a defect in endocytosis. We further demonstrate that the leucine-based sorting signal of phogrin specifically interacts with both adaptor protein (AP)-1 and AP-2 clathrin adaptor complexes in vitro. These observations, along with previous studies, suggest that distinct domains of phogrin mediate proper localization of this transmembrane protein on secretory granules.
Here a new approach of the elucidation of paths of proteolytic biodegradation of physiologically active peptides, based on the use of a peptide with isotopic label at all amino acid residues and the enrichment of HPLC samples with unlabeled peptide fragments in UV-detectable concentration, has been proposed. The method has been applied for the investigation of degradation dynamics of the neuroactive heptapeptide MEHFPGP (Semax) in the presence of plasma membranes, and cultures of glial and neuronal cells obtained from the rat basal forebrain. The splitting away of ME and GP, and formation of pentapeptides are the predominant processes in the presence of all tested objects, whereas the difference in patterns of resulting peptide products for glial and neuronal cells has been detected. In conclusion, the approach applied allows analyzing physiologically active peptide concentrations in biological tissues and degradation pathways of peptides in the presence of targets of their action.
TP-7 is a synthetic analogue of tuftsin. It has a structure of tuftsin, to which three natural L-amino-acids Pro-Gly-Pro are attached. This heptapeptide improves learning and memorization and causes antidepressant and anxiolytic effect. It is possible to use TP-7 in the future to optimize cognitive functions and as a potential new anxioselective, fast-acting and easy-dosed drug. Therefore, it was purposeful to study such properties of the heptapeptide as its influence on anxiety-fear and body weight under a long-term treatment regimen. The experiment was performed on 24 preselected Wistar rats with the use of Rodina's method. There were three experimental groups of animals with high initial emotional reactivity: passive control group (P), active control group (A, receiving distilled water) and group treated with TP-7 at the dose of 0.3 mg/kg (T). The rats of A and T groups received intraperitoneal injections every day. The experiments were conducted 15 min after the administration of the drug, one and two days after initial testing day, then 1, 2, 3 and 4 weeks after that. The heptapeptide reduced the anxiety-phobic states significantly starting from the second day of drug application. The observed effects persisted throughout four weeks of the experiment, which confirmed effective long-term anxiolytic properties of the heptapeptide. TP-7 did not cause any changes in the body mass by itself.