DSIP: Sleep Regulation & Mitochondrial Protection

DSIP (delta sleep-inducing peptide) is a naturally-occurring nonapeptide (9 amino acids long) that can be found in numerous bodily tissues in both free or bound form. DSIP promotes sleep by targeting various areas of the brain. The peptide is easily absorbed from the gut and is not denatured by enzymes. It crosses the blood-brain barrier easily. DSIP influences the circadian rhythm in humans. Low concentrations of the peptide are observed in patients with schizophrenia and depression.

Delta sleep-inducing peptide: a still unresolved riddle

Delta sleep-inducing peptide, a nonapeptide with a unique amino-acid sequence (Table 1), was isolated from the cerebral venous blood of rabbits subjected to low-frequency (‘hypnogenic’) electrical stimulation of the intralaminar thalamic nuclei (the so-called ‘trophotropic zone’; Hess W. R. (1944, see: Monnier and Schoenenberger, 1983, for reference) by Schoenenberger-Monnier group from Basel in 1977 (see Monnier and Schoenenberger, 1983; Schoenenberger, 1984, for reference). In the following three decades, extensive studies carried out in a number of laboratories (the total DSIP bibliography could be estimated at not less than 1500 references; Myers 1994) have demonstrated that some structurally closely related peptide(s), is present in both free and bound forms in some cerebral structures, primarily the hypothalamus and limbic system, as well as pituitary and different peripheral organs, tissues and body fluids, where it co-localizes with several peptide and non-peptide mediators. Hence, we suggest that the simultaneous registration of the physiological effects of DSIP/dermorphin and the detection of its binding sites in the same experiments might be more successful in the search for the mechanism of action of DSIP. Finally, as follows from the proposed conclusions, the definitive solution to both the problems of DSIP natural occurrence and its physiological activity needs new and extensive investigations. We feel that despite the objectively skeptical view on the questions discussed, there is enough background and motivation to be encouraged to perform the studies leading to the definitive answer.[1]

To resolve the paradoxical problem of the natural occurrence and biological activity of DSIP, we proposed the existence of some as yet unknown peptide of which the entire amino-acid sequence is similar although not identical to that of Delta sleep-inducing peptide. This molecule could be responsible (at least partly) for the binding with both anti-DSIP antiserum and Delta sleep-inducing peptide putative receptor(s). This idea was supported by the discovery of a dermorphin-like decapeptide). In these in vitro experiments, the authors used a recombinant vaccine virus expressed in mammalian cells, the cDNA coding for preprodermorphin precursor that processed further to prodermorphin. After its enzymatic digesting, a new peptide was liberated. The authors noted some similarity of this new decapeptide to bradykinin and luteinizing hormone, but were not concerned with its similarity to DSIP. Using the peptide bank EROP-Moscow (Zamyatnin 1991a,b) we discovered the close similarity of this peptide to DSIP, which was especially evident in the C-terminal site of the molecule. The dermorphin-decapeptide molecule has three aromatic hydrophobic amino acid residues separated from each other by linear non-polar radicals. These structural features suggest a high potency of the peptide for binding with membrane receptors and activating intracellular processes; therefore, high biological activity of the analogue 1 could be anticipated.

Delta sleep inducing peptide: effect on respiration activity

For some years, we have conducted investigations on chemical and biological aspects of DSIP and its analogs. In the course of these studies, we clarify that unique stress-protective and adaptive properties of this neuropeptide and its derivatives are the most important and intriguing in their biological profile. DSIP was shown to substantially increase the resistance of animals to various experimental stressful manipulations and mitigate stress-induced pathological metabolic deviations from the normality. DSIP also exhibited strong antioxidant properties and considerably inhibited stress-induced elevation of the intensity of lipid peroxidation and the content of free radicals in brain and other tissues. The antioxidant action is indirect and can be assigned partly to activation of protective antioxidant enzymes. In this work, we attempted to evaluate the putative DSIP influence on rat brain mitochondria in vitro. Utilization of oxygen by mitochondria occurs through the respiratory chain that localized in the inner mitochondrial membrane. The respiratory chain, a special enzyme system, takes part in electron transport and synthesis of ATP. The coupling of these processes provides the normal operation of the enzymatic energetic system. Modulating action of DSIP on the main parameters of oxidative phosphorylation in rat brain mitochondria was studied in this work.[2]

There are substantial evidences of mitochondrial alterations in ischemic organs . Mitochondria isolated from ischemic hearts and brains exhibited reduced respiratory activity derived from the damage of affected complexes 1 and 111. ANT and ATPase were also found inhibited under hypoxia. In experiments with mitochondria prepared from the brain of rats after short-term hypoxia, we observed a significant hypoxia-induced decrease of the rate of phosphorylated respiration V3 (20%) and the rate of ADP phosphorylation ADP/t (31%). DSIP completely prevented these alterations when it was preliminary administered in rats in the small dose of 120 μg/kg and totally protected mitochondria. The exact mechanism of such action is not known. A decrease in complex 1 and ANT activity was suggested to be mainly responsible for functional mitochondrial disturbances under ischemic conditions and DSIP appeared to be involved in modulation of oxidative phosphorylation, thus, allowing preservation of ATP production and ischemia-induced damage. Reported anti-ischemic and neuroprotective properties of DSIP are consistent with modulating effects of the peptide on oxidative phosphorylation. We believe that these data concerning DSIP activating action on oxidative phosphorylation and preventive action of the peptide under hypoxia found in vitro experiments on rat brain mitochondrial preparations can help to understand numerous known experimental and clinical evidences of DSIP stress-protective activity.

References

[1]Kovalzon, Vladimir M, and Tatyana V Strekalova. “Delta sleep-inducing peptide (DSIP): a still unresolved riddle.” Journal of neurochemistry vol. 97,2 (2006): 303-9. doi:10.1111/j.1471-4159.2006.03693.x

[2]Khvatova, Elena M et al. “Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia.” Peptides vol. 24,2 (2003): 307-11. doi:10.1016/s0196-9781(03)00040-8

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