The Involvement of Pineal Gland and Melatonin in Immunity and Aging: II. Thyrotropin-Releasing Hormone and Melatonin Forestall Involution and Promote Reconstitution of the Thymus in Anterior Hypothalamic Area (Aha)-Lesioned Mice

Lesnikov, Vladimir; Корнева, Е. А.; Dall'Ara, A; Pierpaoli, Walter

doi:10.3109/00207459108999767

Cited by 19 publications

(23 citation statements)

References 20 publications

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“…TRH and melatonin can block steroid-or stressrelated thymic involution (9,16,34,35) and restore immunocompetence in nude (athymic) mice (16). TRH and melatonin have receptors in the preoptic hypothalamic areas of the brain important to thyroid and thymus regulation (22,24,34,35).…”

mentioning

confidence: 99%

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Pierpaoli¹,

Regelson²

1994

Proc. Natl. Acad. Sci. U.S.A.

266

189

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The pineal hormone melatonin is secreted in all mammals during the dark phase of the circadian cycle (1), but, even more importantly, there are indications that it is a key regulator of aging and senescence (2, 3). The role of melatonin in controlling sexual maturity, sexual cycling, cancer, stress, and the immune response makes it likely that the pineal may be a factor in the syndrome of aging (4)(5)(6). With this in mind, we have administered exogenous melatonin in the drinking water of mice during a fixed circadian dark cycle-i.e., when melatonin is normally produced-in order to ascertain its influence on patterns of survival. In addition, as the pineal gland is the prime source of melatonin, we transplanted the pineal gland from young to syngeneic histocompatible older recipients. We have utilized the thymus as the graft recipient site inasmuch as the thymus and the pineal gland share a common adrenergic innervation via the superior cervical ganglion (7,8). This common innervation is of importance as melatonin synthesis is inhibited by pharmacologic sympathetic blockade, which also modulates the immune response (9). Moreover, the pineal morphologically contains lymphocytes and it has been likened in its embryologic developmental origin to the thymus (10).In our studies, exogenous nocturnal circadian administration of melatonin or engraftment of young homologous (3-4 months) pineals to old (18-22 months) syngeneic mice adjacent to the thymus, leaving the recipient's pineal in situ, resulted in a significant enhancement of survival independent of significant weight loss. These results suggest that the pineal may act as an endogenous clock governing aging.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. MATERIALS AND METHODSMelatonin Administration. Mice were fed ad libitum using NAFAG pellets (Gossau, Switzerland) and housed 4-10 to a cage in air-conditioned quarters at 22°C. Light exposure was controlled by a fixed timer that governs a standard fluorescent fixture (Philips TLD 36W/84). Melatonin, solubilized in ethanol, was given in the drinking water during a fixed darkness cycle from 6 p.m. to 8:30 a.m. (10 pg/ml of tap water, 0.01% ethanol). The control (only ethanol) and melatonin-containing water bottles were removed from 8:30 a.m. to 6 p.m. No drinking water was given during that period. The mice were individually weighed at intervals to determine whether the effects seen were related to dietary intake.Pineal Grafting. In young-to-old, pineal-to-thymus grafting, the "young" pineals were obtained from 3-to 4-monthold, postpubertal mice. Syngeneic recipients were groups of "aging" mice. The recipient mice were uniform as to sex and age, housed 3-7 per cage. They were prepared for surgery and studied in groups, as indicated in Tables 1 and 2. Weight changes of control and pineal-transplanted animals were recorded monthly. Donor mice were killed by ...

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mentioning

confidence: 99%

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Pierpaoli¹,

Regelson²

1994

Proc. Natl. Acad. Sci. U.S.A.

266

189

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“…In fact, the multiplicity of functions of those key hypothalamic areas is so large that a lesion may also affect pineal function to the extent that we may be able to observe an ageing-promoting and/or delaying activity. For this reason groups of mice of the C57BL/6 inbred strain were operated or sham-operated with the technique already de scribed in other reports [12,13]. The results are illustrated in figures 1 and 2.…”

Section: Hypothalamic Lesions As Preliminary Experimental Evidence Fomentioning

confidence: 81%

“…C57BL/6, 2.5-month-old female mice were used. Bilateral electrolytic lesions were produced in the anterior (AHA) or in the posteri or hypothalamic area (PHA) and confirmed histologically as previously described [12,13]. Body weights and the life span of the operated mice were recorded, n = Number of mice per group.…”

Section: A Ge In G P Ostponing Effects Of Melatonin and Pineal Graftingmentioning

confidence: 99%

Theoretical Considerations on the Nature of the Pineal ‘Ageing Clock’

Pierpaoli¹,

Lesnikov²

1997

Gerontology

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The models developed in our laboratory demonstrate that ageing initiates and progresses in the pineal gland. However, the ageing postponing effects of pineal grafting into older recipients cannot be explained by a simple maintenance and/or normalization of the night melatonin synthesis and release. We propose here that the pineal gland monitors and regulates, via its control of neuroendocrine function, the maintenance of ‘self-identity’ and the capacity of the immune system to recognize and react against any noxious, endogenous or exogenous agent. Senescence is characterized by the extinction of this central pineal function. The progressive decline of the self-recognition capacity distinguishes the typical diseases of ageing expressed as emergence of peripheral desynchronization and autoimmune, anaplastic, neoplastic and degenerative processes. Our approaches aim at a prevention and/or restoration of central pineal functions.

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“…One possible role is growth control since TRH has been reported to increase thymocyte cell proliferation in rats [43]. Similarly, Lesnikov et al [44] made the interesting observation that a stereotactic electrolytic lesion of the anterior hypothalamic area in mice produced a rapid involution of the thymus and a reduction of lymphocytes in the peripheral blood, an effect that was prevented by postoperational administration of TRH or melatonin and which seemed to reflect a direct activity of TRH on thymic targets or binding sites on lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb

Matre

Høvring

Fjeldheim

et al. 2003

Biochemical Journal

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Thyrotropin-releasing hormone (TRH) receptor (TRHR) is a G-protein-coupled receptor playing a crucial role in the anterior pituitary where it controls the synthesis and secretion of thyroidstimulating hormone and prolactin. Its widespread presence not only in the central nervous system, but also in peripheral tissues, including thymus, indicates other important, but unknown, functions. One hypothesis is that the neuropeptide TRH could play a role in the immune system. We report here that the human TRHR promoter contains 11 putative response elements for the haematopoietic transcription factor c-Myb and is highly Mybresponsive in transfection assays. Analysis of Myb binding to putative response elements revealed one preferred binding site in intron 1 of the receptor gene. Transfection studies of promoter deletions confirmed that this high-affinity element is necessary for efficient Myb-dependent transactivation of reporter plasmids in CV-1 cells. The Myb-dependent activation of the TRHR promoter was strongly suppressed by expression of a dominant negative Myb-Engrailed fusion. In line with these observations, reverse transcriptase PCR analysis of rat tissues showed that the TRHR gene is expressed both in thymocytes and bone marrow. Furthermore, specific, high-affinity TRH agonist binding to cell-surface receptors was demonstrated in thymocytes and a haematopoietic cell line. Our findings imply a novel functional link between the neuroendocrine and the immune systems at the level of promoter regulation.

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The Involvement of Pineal Gland and Melatonin in Immunity and Aging: II. Thyrotropin-Releasing Hormone and Melatonin Forestall Involution and Promote Reconstitution of the Thymus in Anterior Hypothalamic Area (Aha)-Lesioned Mice

Cited by 19 publications

References 20 publications

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Theoretical Considerations on the Nature of the Pineal ‘Ageing Clock’

The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb

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