The living record of
peptide science.

The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family.

Biochem Pharmacol

Sean M Davidson, Aneta E Rybka, Paul A Townsend

The urocortins are members of the corticotropin releasing hormone (CRH) family of peptide hormones. The archetypal member of this family, CRH, plays an important role in regulating thermogenesis and homeostasis by acting centrally and systemically in target organs via its two receptors CRH-R1 and CRH-R2. However, by virtue of their much greater relative affinity for CRH-R2, the physiological effects of the urocortin peptides are largely restricted to peripheral organs such as the heart. A powerful cytoprotective effect of urocortin peptide administration against ischemia and reperfusion injury has been demonstrated in isolated cardiomyocyte models, as well as in the intact heart both in vitro and in vivo. Extremely promising data has shown the beneficial effect of treating pacing-induced heart failure in sheep with urocortin molecules. Though the efficacy and specificity of these molecules in humans is not yet established, molecular dissection of the cytoprotective pathways activated by urocortin peptides suggests that the beneficial effects may be separable from potentially deleterious effects.

Response of growth and myogenic factors in human skeletal muscle to strength training.

Br J Sports Med

Y Liu, M Heinichen, K Wirth +2 more

To investigate the response to different strength training techniques of growth and myogenic factors in human skeletal muscle, with particular emphasis on satellite cell (SC) activation.

[A comparative study of noopept and piracetam in the treatment of mild and moderate cognitive impairment in patients with organic brain diseases of vascular and traumatic origin].

Zh Nevrol Psikhiatr Im S S Korsakova

G G Neznamov, E S Teleshova

[Compensatory and antiamnestic effects of heptapeptide Selank in monkeys].

Zh Evol Biokhim Fiziol

The work presents results of study of role of heptapeptide Selank--an anxiolytic from group of biologically active peptides--in compensation of disturbed psychic and homeostatic functions in monkeys. New data have been obtained which indicate that an intranasal administration of Selank produces long-term changes of the monkeys' behavior disturbed during neurosis: elimination of fear and aggression and an increase of orientational-explorative activity as well as facilitation of handling reactions and communicational relations. It has been established that on the background of the Selank there occurs a long compensation of disturbed psychic functions (processes of memory) and of homeostatic parameters. It has been shown that unlike the earlier studied neurohormones (thyroliberin and ACTH4-10), the antistressor Selank effects do not depend on the type of neurotic disturbances and have long-term compensatory character. Comparison of the data obtained on monkeys with results of similar studies on the more low-organized mammals (rodents) allow suggesting that the new peptide preparation Selank is a promising agent for correction of various psychoemotional disturbances (alarm- and depression-like disorders).

[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice].

Zh Vyssh Nerv Deiat Im I P Pavlova

K Iu Sarkisova, I I Kozlovskiĭ, M M Kozlovskaia

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

Creatine supplementation augments skeletal muscle carnosine content in senescence-accelerated mice (SAMP8).

Rejuvenation Res

Wim Derave, Glenys Jones, Peter Hespel +1 more

The histidine-containing dipeptides (HCD) carnosine and anserine are found in high concentrations in mammalian skeletal muscle. Given its versatile biologic properties, such as antioxidative, antiglycation, and pH buffering capacity, carnosine has been implicated as a protective factor in the aging process. The present study aimed to systematically explore age-related changes in skeletal muscles HCD content in a murine model of accelerated aging. Additionally, we investigated the effect of lifelong creatine supplementation on muscle HCD content and contractile fatiguability. Male senescence-accelerated mice (SAMP8) were fed control or creatine-supplemented (2% of food intake) diet from the age of 10 to 60 weeks. At week 10, 25, and 60, tibialis anterior muscles were dissected and analysed for HCD and taurine content by HPLC. Soleus and EDL muscles were tested for in vitro contractile fatigue and recovery. From 10 to 60 weeks of age, muscular carnosine (-45%), taurine (-24%), and total creatine (-42%) concentrations gradually and significantly decreased. At 25 but not at 60 weeks, oral creatine supplementation significantly increased carnosine (+88%) and anserine (+40%) content compared to age-matched control-fed animals. Taurine and total creatine content were not affected by creatine supplementation at any age. Creatine-treated mice showed attenuated muscle fatigue (soleus) and enhanced force recovery (m. extensor digitorum longus [EDL]) compared to controls at 25 weeks, but not at 60 weeks. From the present study, we can conclude that skeletal muscle tissue exhibits a significant decline in HCD content at old age. Oral creatine supplementation is able to transiently but potently increase muscle carnosine and anserine content, which coincides with improved resistance to contractile fatigue.

Galanin in Alzheimer's disease: neuroinhibitory or neuroprotective?

Cell Mol Life Sci

S E Counts, S E Perez, E J Mufson

Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.

[Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].

Zh Nevrol Psikhiatr Im S S Korsakova

A A Zozulia, G G Neznamov, T S Siuniakov +11 more

Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.

[Compensatory effect of selank on the mnestic functions disturbed by neurotoxic damage of the noradrenergic system of the rat brain].

Eksp Klin Farmakol

I I Kozlovskiĭ, Iu F Belozertsev, T P Semenova +2 more

It has been shown that the peptide anxiolytic drug Selank recovers learning and memory impaired by damage of the noradrenergic (NA) brain system in Wistar rats after injection of the NA-synthesis inhibitor disulfiram, administration of neurotoxic compound 6-OHDA, or a combined induction of hypoxic hypoxia and hypercapnia. The main component of the Selank action is the stimulation of the search reflex aimed to distinguish an adequate adaptive response in the first trials of the learning session. The enhancement of memory consolidation and retrieval shows evidence for stimulation of the brain motivation mechanisms impaired by the NA system damage.

[Genotype-dependent mice behavior in cognitive tasks. Effect of noopept].

Zh Vyssh Nerv Deiat Im I P Pavlova

A P Bel'nik, R U Ostrovskaia, I I Poletaeva

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.

Inhibiting myostatin with follistatin improves the success of myoblast transplantation in dystrophic mice.

Cell Transplant

Basma F Benabdallah, Manaf Bouchentouf, Joel Rousseau +5 more

Duchenne muscular dystrophy is a recessive disease due to a mutation in the dystrophin gene. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the myostatin signal with an antagonist, follistatin. Three different approaches were studied to overexpress follistatin in the muscles of mdx mice transplanted with myoblasts. First, transgenic follistatin/mdx mice were generated; second, a follistatin plasmid was electroporated in mdx muscles, and finally, follistatin was induced in mdx mice muscles by a treatment with a histone deacetylase inhibitor. The three approaches improved the success of the myoblast transplantation. Moreover, fiber hypertrophy was also observed in all muscles, demonstrating that myostatin inhibition by follistatin is a good method to improve myoblast transplantation and muscle function. Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy.

Discovery that a melanocortin regulates sexual functions in male and female humans.

Peptides

Mac E Hadley

Melanocortins (MCs) are multifunctional peptide hormones that regulate a diversity of physiological functions. MCs have been implicated in sexual function in animals. We document here that a MC analog, Melanotan II (MTII), can enhance sexual function in human males (erectile activity) and females (increased levels of sexual desire and genital arousal). Unlike other sexual-enhancement drugs, MTII works at the level of the brain, thus eliciting a rather natural sexual response with minimal or no undesirable side effects. The actions of the peptide were discovered accidentally while studying the effects of the peptide and related analogs on human skin pigmentation (tanning).

Dipeptide preparation Noopept prevents scopolamine-induced deficit of spatial memory in BALB/c mice.

Bull Exp Biol Med

A P Belnik, R U Ostrovskaya, I I Poletaeva

The effect of original nootropic preparation Noopept on learning and long-term memory was studied with BALB/c mice. Scopolamine (1 mg/kg) impaired long-term memory trace, while Noopept (0.5 mg/kg) had no significant effect. Noopept completely prevented the development of cognitive disorders induced by scopolamine (blockade of muscarinic cholinergic receptors). Our results confirmed the presence of choline-positive effect in dipeptide piracetam analogue Noopept on retrieval of learned skill of finding a submerged platform (spatial memory). We conclude that the effectiveness of this drug should be evaluated in patients with Alzheimer's disease.

Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.

FASEB J

Masashi Nakatani, Yuka Takehara, Hiromu Sugino +9 more

Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, follistatin, follistatin-related proteins, and myostatin antibodies. Although follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from follistatin, which does not affect activin signaling. The dissociation constants (K(d)) of follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (K(d)) of a follistatin-derived myostatin inhibitor, designated FS I-I, to activin and myostatin are 64.3 microM and 46.8 nM, respectively. Transgenic mice expressing FS I-I, under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. Hyperplasia and hypertrophy were both observed. We crossed FS I-I transgenic mice with mdx mice, a model for Duchenne muscular dystrophy. Notably, the skeletal muscles in the mdx/FS I-I mice showed enlargement and reduced cell infiltration. Muscle strength is also recovered in the mdx/FS I-I mice. These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.

Selank and its metabolites maintain homeostasis in the gastric mucosa.

Bull Exp Biol Med

T S Pavlov, G E Samonina, Z V Bakaeva +2 more

Antiulcer properties of a synthetic anxiolytic Selank and in vivo formed metabolites of this compound were studied on 3 experimental models of ulceration. The test peptides decreased the area of experimental gastric ulcers.

Loss of muscle strength during aging studied at the gene level.

Rejuvenation Res

Geoffrey Goldspink

Age-related muscle wasting and increased frailty is a major socioeconomic as well as a major medical problem. In our quest to extend the quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and prevent them falling and breaking bones that are brittle because of osteoporosis. Muscles generate the mechanical strain that contributes to the maintenance of other musculoskeletal tissues and a vicious cycle is established when the muscles start to produce less force resulting in more bone loss and weakening of tendons. Another aspect that is less well appreciated is that muscle acts as a dynamic, metabolic store. In a traumatic situation, muscle provides amino acids to aid tissue repair processes and maintaining acid-base balance. At the present time there are strategies in addition to exercise for preventing age-related muscle wasting and these are briefly reviewed. Here, more attention is paid to the role of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and the discovery of mechano-growth factor (MGF). This is derived from the IGF-1 gene by alternative splicing and in the young is responsible for increasing contractile strength in response to exercise by activating the muscle satellite (stem) cells that kick-start local muscle repair and induce hypertrophy. Recent studies including gene transfer of this part of the IGF-1 gene and unique MGF peptides offer the prospect of treating muscle wasting during the aging process as well as muscle cachexia associated with many diseases.

The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.

J Psychopharmacol

Rita U Ostrovskaya, Marina A Gruden, Natalya A Bobkova +7 more

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

Melanocortin receptors, melanotropic peptides and penile erection.

Curr Top Med Chem

Stephen H King, Alexander V Mayorov, Preeti Balse-Srinivasan +3 more

Penile erection is a complex physiologic event resulting from the interactions of the nervous system on a highly specialized vascular organ. Activation of central nervous system melanocortinergic (MC) receptors with either endogenous or synthetic melanotropic ligands may initiate and/or facilitate spontaneous penile erection. While the CNS contains principally the MC3 and MC4 receptor subtypes, there is conflicting data as to which receptor mediates erection. Although the MC4R is emerging as the principle effector of MC induced erection, the role of the MC3R is poorly understood. Manipulation of each receptor subtype with newly synthesized receptor specific agonists and antagonists, as well as knockout mice, has elucidated their individual contributions. Novel data from our laboratories suggests that antagonism of forebrain MC3R may enhance melanocortin-induced erections. Furthermore, melanocortin agents may interact with better-studied systems such as oxytocinergic pathways at the hypothalamic, brainstem or spinal level. Current therapies for erectile dysfunction target end organ vascular tissue. Manipulation of MC receptors may provide an alternative, centrally mediated therapeutic approach for erectile and other sexual dysfunctions. The non-specific "superpotent" MC agonist, PT-141, which is the carboxylate derivative of MT-II, has reached phase II human trials. Through their centrally mediated activity, melanocortin agonists have potential to treat erectile dysfunction as well as possible applications to the unmet medical needs of decreased sexual motivation and loss of libido.

Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.

Bull Exp Biol Med

V K Meshavkin, N V Kost, O Yu Sokolov +3 more

Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.

Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C.

J Mol Endocrinol

H Douglas Falls, Brian D Dayton, Dennis G Fry +6 more

Ghrelin, a 28 amino acid, octanoylated peptide, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In addition to various endocrine functions, including stimulation of GH release, ghrelin has been characterized as an important regulator of energy homeostasis. Ghrelin administration has been shown to increase adiposity in rodents and stimulate food intake in humans. Studies suggest that these orexigenic effects are mediated primarily through GHS-R expression in hypothalamic and pituitary neuronal pathways. In this context, GHS-R has been recognized as a potential target for the treatment of GH deficiency and body weight disorders. Cell lines provide convenient in vitro systems to identify and characterize potential pharmacophores and to analyze GHS-R functional activity. While recombinant cell lines that overexpress GHS-R have served as effective research tools for these studies, such cell lines may differ in signaling response to ghrelin compared with hypothalamic or pituitary cells expressing GHS-R. We show here that a cell line derived from a rat anterior pituitary adenoma, RC-4B/C, expresses endogenous GHS-R as judged by reverse transcriptase-PCR. In a Ca(2+)mobilization assay, RC-4B/C cells demonstrate a dose-dependent increase in intracellular [Ca(2+)] on stimulation with rat ghrelin and a related peptide agonist, hexarelin (EC(50), 1.0 nM and 1.7 nM respectively), but are unresponsive to treatment with inactive des-octanoyl rat ghrelin. A subclone, RC-4B/C.40, with a more robust and stable ghrelin response, was isolated from the parental population of cells to allow further analysis of GHS-R signal transduction. Using pertussis toxin and the phospholipase C inhibitor U-73122, we show that ghrelin signals through the Gq pathway in the RC-4B/C.40 cells. We also demonstrate that the ghrelin-induced rise of intracellular [Ca(2+)] in RC-4B/C.40 cells involves initial Ca(2+)release from intracellular stores followed by a sustained elevation that occurs via influx of extracellular Ca(2+) through ion channels. In addition, unlike observations reported in recombinant cell systems, the RC-4B/C.40 cells do not exhibit a high level of GHS-R constitutive activity as determined in a phosphatidylinositol hydrolysis assay. Overall, the data presented here suggest that the RC-4B/C parental and RC-4B/C.40 cells provide novel in vitro systems for the characterization of GHS-R pharmacophores and ghrelin signaling.