Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Alba, Maria; Fintini, Danilo; Sagazio, Alessia; Lawrence, Betty; Castaigne, Jean Paul; Frohman, Lawrence A.; Salvatori, Roberto

doi:10.1152/ajpendo.00201.2006

Cited by 12 publications

(14 citation statements)

References 15 publications

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“…Because M 3 mAChRs are expressed in the hypothalamus at relatively high density (17,18), we speculated that hypothalamic M 3 receptor activity might be required for the proper function of GHRH neurons, resulting in the observed hypoplasia of the anterior pituitary and reduced longitudinal growth of Br-M3-KO mice. Consistent with this notion, we found that treatment of Br-M3-KO mice with CJC-1295, a synthetic GHRH analog (19)(20)(21), restored normal pituitary size and serum GH and IGF-1 levels, and normal longitudinal growth. The ability of CJC-1295 to rescue the various hormonal and morphological deficits of Br-M3-KO mice supports the concept that the primary defect underlying the dwarf phenotype of these mutant mice does not reside in the pituitary gland itself but most likely involves impaired function of hypothalamic GHRH neurons.…”

Section: Discussionsupporting

confidence: 80%

“…Specifically, we examined whether chronic administration of CJC-1295, a synthetic GHRH analog (19)(20)(21), was able to prevent the various hormonal and morphological deficits characteristic of Br-M3-KO mice. CJC-1295 selectively and covalently binds to endogenous albumin after injection, thereby extending its half-life and duration of action.…”

Section: Cjc-1295 Rescue Experimentsmentioning

confidence: 99%

“…Strikingly, Br-M3-KO mice showed a dwarf phenotype, associated with a dramatic reduction in the size of the anterior pituitary gland, a marked decrease in pituitary GH and prolactin levels, and significantly reduced serum GH, insulin-like growth factor-1 (IGF-1), and prolactin levels. Remarkably, treatment of Br-M3-KO mice with CJC-1295, a synthetic GHRH analog (19)(20)(21), restored normal pituitary size, serum GH and IGF-1 levels, and longitudinal growth. These data reveal an unexpected and critical role for central M 3 receptors in promoting longitudinal growth.…”

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confidence: 97%

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Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Gautam

Jeon²,

Starost³

et al. 2009

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

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The molecular pathways that promote the proliferation and maintenance of pituitary somatotrophs and other cell types of the anterior pituitary gland are not well understood at present. However, such knowledge is likely to lead to the development of novel drugs useful for the treatment of various human growth disorders. Although muscarinic cholinergic pathways have been implicated in regulating somatotroph function, the physiological relevance of this effect and the localization and nature of the receptor subtypes involved in this activity remain unclear. We report the surprising observation that mutant mice that selectively lack the M3 muscarinic acetylcholine receptor subtype in the brain (neurons and glial cells; Br-M3-KO mice) showed a dwarf phenotype associated with a pronounced hypoplasia of the anterior pituitary gland and a marked decrease in pituitary and serum growth hormone (GH) and prolactin. anterior pituitary gland ͉ dwarfism ͉ knockout mice V arious neurotransmitter systems have been implicated in regulating somatotroph function and growth hormone (GH) secretion, either by acting on the anterior pituitary gland directly or by modulating the release of GH-releasing hormone (GHRH) or somatostatin from the hypothalamus (for a comprehensive review, see ref. 1). However, the physiological relevance of the individual pathways and the identity and localization of the receptor subtypes involved in mediating these effects are not well understood in most cases.Pharmacological studies suggest that central muscarinic cholinergic pathways play a role in stimulating GH release in experimental animals and humans (1-9). The identification of the molecular pathways and the specific muscarinic ACh receptor (mAChR) subtypes involved in mediating these responses should be of considerable potential therapeutic interest. However, work in this area has been complicated by the existence of 5 molecularly distinct mAChR subtypes (M 1 -M 5 ) that are difficult to distinguish by classical pharmacological tools (10, 11). Moreover, virtually all brain regions express multiple mAChRs in a complex, overlapping pattern (12-15).The M 3 mAChR subtype is expressed at relatively high levels in the hypothalamus but is also found in many other brain regions (16-18). At present, little is known about the physiological relevance of these neuronal M 3 mAChRs. To shed light on this issue, we used Cre/loxP technology to generate a set of mutant mice, referred to as Br-M3-KO mice, that selectively lacked the M 3 mAChR subtype in the brain (neurons and glial cells). Strikingly, Br-M3-KO mice showed a dwarf phenotype, associated with a dramatic reduction in the size of the anterior pituitary gland, a marked decrease in pituitary GH and prolactin levels, and significantly reduced serum GH, insulin-like growth factor-1 (IGF-1), and prolactin levels. Remarkably, treatment of Br-M3-KO mice with CJC-1295, a synthetic GHRH analog (19-21), restored normal pituitary size, serum GH and IGF-1 levels, and longitudinal growth. These data reveal an unexpect...

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Section: Discussionsupporting

confidence: 80%

Section: Cjc-1295 Rescue Experimentsmentioning

confidence: 99%

mentioning

confidence: 97%

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Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Gautam

Jeon²,

Starost³

et al. 2009

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

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“…In this context, GHS could be more appropriate to restoring GH secretion in aged individuals than GHRH with its major limitation of a short half-life. Recent studies with CJC-1295, a long-lasting human GHRH analog, have shown that once-daily administration of the GHRH analog normalizes growth in the GHRH knockout mouse (1). In humans, prolonged stimulation of GH and IGF-I has been shown with a single subcutaneous administration of CJC-1295 in normal subjects (58).…”

Section: Discussionmentioning

confidence: 99%

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Frutos¹,

Cacicedo²,

Fernández³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P Ͻ 0.01 and P Ͻ 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P Ͻ 0.001) and SS mRNA (P Ͻ 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P Ͻ 0.01 and P Ͻ 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment. growth hormone; ghrelin; growth hormone-releasing peptide-6; growth hormone secretagogue; aging; growth hormone decline GROWTH HORMONE (GH) secretion in humans and rats declines progressively with aging (17, 41) and results in lower serum insulin-like growth factor-I (IGF-I) levels.Early studies in elderly humans showed an age-associated attenuation of GH pulse amplitude and GH secretion in response to several stimuli, including insulin-induced hypoglycemia and arginine administration (32,43). Subsequent studies revealed a decrease in plasma IGF-I parallel to the decline in GH pulses (51). The studies in humans have been confirmed in experimental animals, and it is now evident that the decline in high-amplitude pulsatile GH release and plasma IGF-I concentrations is one of the best characterized events that occur with aging in humans and rats (61). Thus the aging rat is a model of relative or partial GH deficiency and consequently is suitable for studying the mechanisms of this alteration.GH has a broad range of actions and therefore its diminished secretion rate has clinical significance and may be responsible for the generalized catabolic state, functional alterations, cognitive impairment, and decreased neuroprotection associated with normal aging. In elderly adults, with or without GH defect, GH increases IGF-I, the lean-to-fat ratio, muscle strength, and skin thickness and reduces total body fat cont...

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“…GHRH-KO mice have also served to characterize a potent GHRH analog (i.e., CJC-1295) that exhibits a longer halflife and duration of action than the natural peptide because of its selective and covalent binding to endogenous albumin. 1 This analog has been successfully used in clinical trials, which highlights its potential utility as a therapeutic agent. 33 Indeed, since the discovery of the sequences crucial for GHRH somatotrophic activity, much effort has been invested in generating synthetic analogs with extended half-life and duration of action.…”

Section: Pathophysiological Implicationsmentioning

confidence: 99%

GHRH

Malagón¹,

Vázquez-Martı́nez²,

Martínez-Fuentes³

et al. 2013

Handbook of Biologically Active Peptides

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Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Cited by 12 publications

References 15 publications

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

GHRH

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Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Cited by 12 publications

References 15 publications

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

GHRH

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Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth