Forced Exercise-Induced Flushing of Tail Skin in Ovariectomized Mice, as a New Experimental Model of Menopausal Hot Flushes

Shuto, Hideki; Yamauchi, Atsushi; Ikeda, Munehiko; Sohda, Yoshio; Koga, Ayako; Tominaga, Kohji; Egawa, Takashi; Kataoka, Yasufumi

doi:10.1254/jphs.sc0050046

Cited by 10 publications

(4 citation statements)

References 16 publications

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“…Experiments on OVX rats make use of various triggers. Previous studies have found that OVX rats increased TST by the induction of stress with physical exercise [27]. Numerous studies have also reported that yohimbine administration causes hot flashes [28,29].…”

Section: Discussionmentioning

confidence: 94%

Effects of Herbal Mixture Extract on Menopausal Hot Flashes and Pharmacokinetics in Ovariectomized Rat Models

Lee¹,

Kim²,

Kang³

et al. 2018

JFNR

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This study was conducted to evaluate the effects of Cynanchum wilfordii Hemsley, Phlomis umbrosa Turcz., and Angelica gigas Nakai extract (CPAE) on the reduction of tail skin temperature (TST) in ovariectomized (OVX) rats. To evaluate TST reduction in ovariectomized rats, 125, 250, and 1000 mg/kg CPAE was administered to rats for 1 week. The measurement of TST after the induction of artificial stress revealed a significant temperature reduction effect in the CPAE administration group (p<0.05). The TST induced by the injection of yohimbine, to induce hot flashes, was found to decrease as the administered dose of CPAE increased from 10 min to 20min (125 and 250 mg/kg/day, p<0.05; 1000 mg/kg/day, p<0.01). In addition, in a drug interaction test between tamoxifen, an anti-estrogen drug, and CPAE, no significant difference was found between the pharmacokinetic (PK) profiles after the administration of tamoxifen only and the combination of tamoxifen and CPAE. We also found that CPAE did not affect CYP2d4 and CYP3a2, which affect tamoxifen metabolism, in a subsequent experiment on liver tissues extracted during the drug interaction test. In this study, we found that CPAE inhibited temperature increase on the tail skin of OVX rats, and therefore is effective in the improvement of hot flashes. CPAE may be potentially used for the improvement of hot flashes induced by the administration of tamoxifen.

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Section: Discussionmentioning

confidence: 94%

Effects of Herbal Mixture Extract on Menopausal Hot Flashes and Pharmacokinetics in Ovariectomized Rat Models

Lee¹,

Kim²,

Kang³

et al. 2018

JFNR

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“…Animal models of hot flushes have proved difficult to develop, but measurements of tail skin temperature in ovariectomized mice is an attractive model since it mirrors the peripheral vascular events seen in hot flushes (vasodilation in the skin leading to an increased temperature) and these effects can be blocked by estrogen supplementation (Kobayashi et al, 2000; Shuto et al, 2005). The model used in this study relies on flush-like events triggered by exercise on a treadmill.…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacological tools are available; antagonists toward CGRP-receptors have been developed and tested in human phase II and phase III studies, mainly for treatment of migraine (Villalon and Olesen, 2009; Bell et al, 2010; Hirsch et al, 2013) and MK-8825, a non-peptide CGRP receptor antagonist administered orally, has been shown to be active in rodents migraine (Villalon and Olesen, 2009). In order to find out if CGRP plays a causal role in hot flushes and if CGRP antagonism has therapeutic potential for this indication, we used the CGRP receptor antagonist MK-8825 in a previously reported mouse model of menopausal hot flushes (Shuto et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

CGRP Is Critical for Hot Flushes in Ovariectomized Mice

et al. 2019

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Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, p < 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking αCGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.

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“…Ovariectomized, morphine-dependent rats exhibit rises in tail temperature during antagonist induced opiate withdrawal (44). Additionally, ovariectomized mice forced to exercise exhibit similar changes (45). Temperature effects in both models are dependent on ovariectomy and are tempered by exogenous estrogen.…”

Section: Discussionmentioning

confidence: 99%

A novel animal model to study hot flashes

Albertson¹,

Skinner²

2009

Menopause

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Menopausal hot flushes compromise the quality of life for the majority of women. The physiological mechanisms underlying hot flushes remain poorly understood and the absence of an animal model to investigate hot flushes hinders investigations in this field. We have developed the sheep as a model to study peripheral skin temperature changes. Subjecting sheep to fever-inducing treatments with lipopolysaccharide, a significant (P<0.01) change in ear skin temperature was observed. As a strong correlation between luteinizing hormone pulses and hot flushes has previously been reported, we then determined whether intravenous gonadotropin-releasing hormone (GnRH), at doses sufficient to elevate CSF GnRH concentrations, could modulate ear skin temperature. No effect was observed, suggesting that GnRH per se dose not play a role in the etiology of hot flashes.

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Forced Exercise-Induced Flushing of Tail Skin in Ovariectomized Mice, as a New Experimental Model of Menopausal Hot Flushes

Cited by 10 publications

References 16 publications

Effects of Herbal Mixture Extract on Menopausal Hot Flashes and Pharmacokinetics in Ovariectomized Rat Models

Effects of Herbal Mixture Extract on Menopausal Hot Flashes and Pharmacokinetics in Ovariectomized Rat Models

CGRP Is Critical for Hot Flushes in Ovariectomized Mice

A novel animal model to study hot flashes

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