Effects of neurokinin 3 receptor antagonist fezolinetant on hot flash-like symptoms in ovariectomized rats
| Autor: | Atsuo Tahara, Seiji Kaku, Akiyoshi Ohtake, Hajime Takamatsu, Keiko Tanaka-Amino |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Injections Subcutaneous Ovariectomy Administration Oral Heterocyclic Compounds 2-Ring Body Temperature 03 medical and health sciences 0302 clinical medicine Hot flash Internal medicine Thiadiazoles Medicine Animals Testosterone Rats Wistar Median preoptic nucleus Progesterone Pharmacology Estradiol business.industry Antagonist Receptors Neurokinin-3 Luteinizing Hormone medicine.disease Preoptic Area Menopause Disease Models Animal 030104 developmental biology Endocrinology Hypothalamus Hot Flashes Ovariectomized rat Female medicine.symptom Follicle Stimulating Hormone business Luteinizing hormone Skin Temperature 030217 neurology & neurosurgery Hormone |
| Zdroj: | European journal of pharmacology. 905 |
| ISSN: | 1879-0712 |
| Popis: | The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1–10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause. |
| Databáze: | OpenAIRE |
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