Growth Hormone Hyperresponsiveness to Dopaminergic Stimulation in Huntington’s Chorea

Müller, E. E.; Parati, Eugenio; Panerai, A; Caraceni, T.

doi:10.1159/000122878

Cited by 18 publications

(3 citation statements)

References 12 publications

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“…This may be due to differences in the methodology employed in collecting plasma samples and measuring IGF-1 levels in the two studies, and additional studies are necessary to resolve this discrepancy. Indeed, further indirect evidence in support of this is provided by early studies examining growth hormone (GH) responses in HD, where more prompt and increased GH release was observed in HD patients following stimulation compared with control (36)(37)(38)(39)(40)(41)(42)(43). As IGF-1 Figure 3.…”

Section: Body Weight Changes In Hd Patientsmentioning

confidence: 94%

Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

Pouladi

Xie

Skotte

et al. 2010

Human Molecular Genetics

101

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Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.

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Section: Body Weight Changes In Hd Patientsmentioning

confidence: 94%

Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

Pouladi

Xie

Skotte

et al. 2010

Human Molecular Genetics

101

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“…It is thus likely that APO acts directly (via pituitary DRD 2 ) or indirectly (via hypothalamic DRD 2 and GHRH release) on GH secretion. APO has widely been used to assess dopaminergic sensitivity by measuring plasma GH concentration in healthy subjects and in patients with various disorders [6][7][8][9][10][11][12][13][14][15][16][17][18]. In these APO challenge studies, the APO doses range from 2 to 20 lg/kg, the highest dose which could be responsible for the occurrence of adverse effects such as nausea and vomiting.…”

mentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects

Aymard

Berlin

Brettes

et al. 2003

Fundamemntal Clinical Pharma

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Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.

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“…Initial observations of increased levels of growth hormone (GH), which is released upon dopaminergic stimulation from the hypothalamus, supported this theory [23][24][25] . Follow-up studies found increased basal levels or increased release of GH after stimulation by dopaminergic agonists in HD patients [26][27][28][29][30] . Since dopamine stimulation inhibits prolactin release, the notion of increased dopaminergic activity gained further support from reports of reduced prolactin levels, which would be expected if the dopaminergic tone was high in the hypothalamus [31] .…”

Section: Introductionmentioning

confidence: 99%

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

Petersén¹,

Hult²,

Kirik³

2009

Neurodegener Dis

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although it is characterized by progressive motor impairments, cognitive changes and psychiatric disturbances are major components of the disease. In addition, recent studies have shown that other non-motor symptoms such as alterations in sleep pattern, disruption of the circadian rhythm and increased energy metabolism are common and occur early. Emerging evidence suggests that the latter symptoms are likely results of disturbed functions of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Whereas clinical data are essential to define key pathological features of HD, animal models that can recapitulate the neurobiological and behavioral features of the disorder are critical tools to elucidate the underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine alterations as well as in highlighting novel potential disease pathways. This review summarizes the current state of knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical relevance and points to future implications for this emerging field.

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Growth Hormone Hyperresponsiveness to Dopaminergic Stimulation in Huntington’s Chorea

Cited by 18 publications

References 12 publications

Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

Pharmacokinetic–pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

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