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NEUROENDOCRINOLOGY LETTERS
including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology
and Human Ethology, ISSN 0172–780X

NEL Vol.23 No.5/6, Oct-Dec 2002

ORIGINAL ARTICLE

Epitalon influences pineal secretion
(Short title)

2002; 23: 452454
pii: NEL235602A10
PMID: 12500171

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Epitalon influences pineal secretion in stress-exposed rats in the daytime

by Dmitry A. Sibarov, Rimma I. Kovalenko, Vladimir V. Malinin &
Vladimir Kh. Khavinson

Submitted: July 23, 2002 Accepted: August 19, 2002

Key words:
pinealocytes, Epitalon, c-Fos, oncogenes, osmotic stress


Abstract

Objectives. The content of C-Fos protein was tested in rat pinealocytes in the norm and stress and in case of intranasal administration of Epitalon (Ala-Glu-Asp-Gly), which regulated pineal secretion processes, presumably, via protooncogenes.

SETTING. Intact and osmotic-stress-exposed rats were used for the immunohistochemical detection of C-Fos protein. All animals were intranasally administered with Epitalon, the last infusion made in two hours before the biopsy. Simultaneously, light microscopy of the pineal parenchyma was performed in all groups of animals.

RESULTS. A slight but significant C-Fos increase was observed only in stress-exposed pinealocytes of rats after intranasal Epitalon infusions. C-Fos was irregularly distributed throughout pineal cells. In stress, the clusters of 5–10 cells containing C-Fos in their cytoplasm were detected. The dilation of capillaries and pericapillary space induced by an osmotic stress was partially reduced by the intranasal infusions of Epitalon.

CONCLUSIONS. Tetrapeptide Epitalon is synthesised on the basis of the amino acid composition of pineal peptide extract Epithalamin. Epitalon modulates pineal secretion only under a stress impact but never in the norm. It prevents osmotic-stress-induced pathologic changes in the pineal parenchyma structure. Besides, the physiological activity of Epitalon seems to be mediated by the activation of protooncogenes in pinealocytes.

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Introduction

Both the pineal gland and the hypothalamus-hypophysis complex take part in the formation of general adaptation syndrome [1, 2]. Stress causes the pineal gland to increase the secretion of melatonin and peptide substances [2, 11], which are known to reduce the damaging effect of oxygenic, osmotic, psychic and other stresses. The peak of pineal melatonin secretion occurs only at night, while in the daytime pinealocytes secrete other substances, peptides in particular. Yet, the works dedicated to pineal peptides are disproportionally few as compared to available publications on melatonin.
The pineal gland belongs to circumventricular organs having no blood-brain barrier. Consequently, this organ is highly sensitive to macromolecular biologically active substances circulating with the cerebral blood flow and, especially, to peptides. The unique location of the olfactory system, its chemical links both to the environment and the central nervous system turn it to a convenient pathway for the non-invasive delivery of substances to the cerebral blood flow and circumventricular organs. This pathway bases on the anatomic connection of the nasal submucosa to the subarachnoid space surrounding olfactory nerves as they penetrate the cribriform plate of the skull and enter the brain [6]. The cribriform region has no significant barrier to cerebrospinal fluid drainage [3, 8]. This is the possible way for metals, dyes, viruses, peptides [14, 15], proteins and narcotics to enter the brain via nasal cavity avoiding the blood-brain barrier [4]. Previously we have shown that intranasally infused epiphyseal peptides reach the pineal gland and specifically regulate its electric activity and pinealocytic ultrastructure. Furthermore, these effects have been observed only in stress, but not in the norm [20]. An important role in intracellular pineal synthesis activation, for example, in stress, belongs to heterodimer AP-1 formed of C-Fos and C-Jun transcription factors [10, 13]. C-Fos protein exists longer than its mRNA. The peak of its content in the cytoplasm is usually observed in two hours after, for instance, a stress impact. Some authors [12] have suggested cytomedins to influence the cells through C-Fos synthesis activation. To prove the hypothesis on the participation of oncogenes in the pineal humoral self-regulation, we have performed an immunohistochemical detection of C-Fos protein in the pinealocytes of stress-exposed rats subjected to the intranasal infusions of Epitalon.

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