mystery of yawning
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
1 juin 2012
Bull Exp Biol Med.
2011;151(4):429-431
Effects of Pro-Gly-Pro tripeptide
on the dopamine system
 
Meshavkin VK, Batishcheva EY, Kost NV, Sokolov OY, Trufanova AV, Samonina GE.
 
Laboratory of Pathophysiology, Center of Mental Health, Russian Academy of Medical Sciences, Moscow, Russia.

Chat-logomini

 
Abstract
 
Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D(2)and D(3)receptors.
 
 
Glyprolines is a recently discovered family of bioactive peptides consisting of glycine (Gly) and proline (Pro). One of them, Pro-Gly-Pro tripeptide, redu ces blood clotting and inhibits ulcer formation in the sto mach [8]; its preclinical studies have been carried out. The effects of PGP on CNS activity were de monstrated in animal experiments, primarily the stress-protective effect. The drug prevents increase in anxiety and suppression of orientation and exploratory ac ti vity of stressed rats [5]. Presumably, the direct effects of glyprolines on the CNS structures involved in the formation of response to stress play the key role in these effects. These characteristics are assumed to be essential for the realization of other effects of glyprolines, for example, their antiulcerogenic effect on the gastric mucosa under conditions of stress inducing ulcer formation [8]. In addition, PGP exhibited a neuroprotective effect in vitro on nerve cell culture under conditions of oxidative stress [6] and in vivo on hypoxic animals [9]. Presumably, the effect of PGP on hypoxic resistance is due to blood fl ow stimulation and more rapid saturation of tissues with oxygen as a result of glyproline preinjection. Incorporation of glyproline in the C-terminal structure of other bioactive peptides improves the resistance of the resultant molecule to proteases, stimulates and even modulates the physiological effects of the initial peptide, as exemplifi ed by such drugs as Semax (Met-Glu-His-Phe-Pro-Gly-Pro) with marked nootropic and neurotropic effects and Selanc (Thr-Lys-Pro-Arg-Pro-Gly-Pro) anxiolytic. Despite great variety of detected forms of biological activities of glyprolines, the neurochemical mechanism of their action received little attention. We studied the interactions of PGP with the dopamine system at the behavioral and receptor levels.
 
 
RESULTS
The curves of 3H-spiperone exclusion from sites of its specifi c binding to the membrane fraction of striatal cells, where the density of D2 dopamine receptors is maximum, with sulpiride (selective ligand of these receptors) and PGP are presented in Figure 1. The curve of 3H-spiperone exclusion with sulpiride reaches a plateau without attaining 50% binding level. This indicates the presence of receptors other that D2 in the striatum binding spiperone. The maximum exclusion of 3H-spiperone with PGP reaches 90%, 50% exclusion being attained at peptide concentration of 9 nM.
 
Hence, PGP presumably interacts not only with D2, but also with some other spiperone receptors and its affi nity for them is by an order of magnitude lower than that of spiperone. Spiperone is a nonselective ligand of 5-HT1 and 5-HT2 serotonin receptors, D2 dopamine receptors (D2, D3, D4), and of ?1 adrenoceptors. In our study under conditions optimal for 3H-spiperone reactions with 5-HT2 receptors in the frontal cortex (the brain site with the highest density of these receptors [10]), PGP in concentrations up to 100 ?M virtually did not modify binding of 3H-spiperone. Independent experiments also showed that tritium-labeled PGP specifi cally bound to the basal nuclear membranes, but not to other compartments of rat forebrain [4].
 
The results suggest that PGP reacts with D2 dopamine receptors and adrenoreceptors. This is confi rmed by the data on the capacity of PGP and its fragments to reduce the tone of the aorta, elevated by norepinephrine [2]. PGP in a dose of 10 mg/kg reduced behavioral manifestations of drug-induced hyperactivation of the dopamine system in vivo. This effect was observed in the verticalization test refl ecting the increase of dopaminergic transmission in the cerebral mesolimbic structures induced by injection of high doses of apomorphine (5 mg/kg; Table 1). Apomorphine in a medium dose (0.75 mg/kg) stimulated dopaminergic transmission in the nigrostriatal system, thus causing stereotypy. Under these conditions PGP in a dose of 10 mg/kg decreased the duration and number of stereotypical movements in rats by 20%.
 
It is assumed that psychomimetics stimulate motor and stereotypical activities of experimental animals through postsynaptic D1 and D2 dopamine receptors, while D3 receptor stimulation inhibits locomotion [12,13]. On the other hand, it was shown that the yawning phenomenon is primarily caused by stimulation of presynaptic D3 receptors, while D2 autoreceptors mediate its inhibition [11]. The PGP reduced the number of yawns by 35% in rats (Table 1), this indicating blocking of presynaptic D3 receptors. Hence, our study detected the PGP capacity to react with D2 dopamine receptors in vitro and block apomorphine reactions with post- and presynaptic dopamine receptors of D2 and D3 types in vivo. Opposite effects me dia ted by these receptors can be responsible, along with other factors, for just 20-30% realization of behavioral effects of PGP.
 
Very low efficiency of PGP in vivo can be also due to its pharmacokinetics. It enters unchanged into the circulation and crosses the blood-brain barrier [3]. However, just one thousandth of the injected peptide reaches the brain and is gradually hydrolyzed with the formation of GP as the main metabolite [1]. The neurotropic effects of this dipeptide on stressed animals are no less pronounced than the effects of PGP [5]. GP is the main metabolite of Selanc, a synthetic peptide anxiolytic [1]. We also observed a depriming effect of Selanc in verticalization test, but this peptide did not modify 3H-spiperone binding to D2 receptors in vitro [7]. Summing up these data, we think that not only PGP, but also its GP fragment are characterized by dopamine-blocking effects.
 
It is assumed that the development of positive symptoms in schizophrenia is associated with hyperactivation of the dopamine system, while blocking of dopamine receptors is the main mechanism of pharmacological effect of neuroleptics. PGP unites the characteristics of a D2 receptor antagonist with the neuroprotective [6,9] and nootropic [5] effects, and hence, can be regarded as a candidate antipsychotic drug effective for therapy of positive symptoms and cognitive disorders in schizophrenia and other psychoses.