Envolvimento do sistema noradrenérgico e de neurônios hipotalâmicos nos efeitos termorregulatórios do estrógeno em modelo animal de ondas de calor da menopausa

Abstract

Hot flashes consist of episodic activation of heat dissipation mechanisms and are effectively treated by estrogen replacement. Estrogen has pronounced effects on thermoregulation, but the anatomic sites of integration between the reproductive and thermoregulatory axes are unknown as are the physiological mechanisms. In this work, the interrelationship between noradrenergic neurons and hypothalamic nuclei in the vasomotor effect of 17 -estradiol (E2) was evaluated, in particular the role of kisspeptin-producing neurons (Kp) of the arcuate nucleus (ARC). Adult female rats were ovariectomized and implanted with subcutaneous capsules containing oil (OVX) or E2 (OVX + E2), as an animal model of vasomotor effects of E2. The temperature of the tail (TC) was measured for 1 to 4 hours at different times after surgery. Animals were perfused in the morning and the brains were processed for immunohistochemistry. Neuronal activity was evaluated by counting the number of cells stained for Fos in hypothalamus and brain stem nuclei. The TC was increased in OVX rats compared to OVX + E2 after 7 and 14 days after ovariectomy. On day 14, an increased expression of Fos was detected in noradrenergic neurons of A1, A2 and locus coeruleus (LC), as well as nuclei of the preoptic area (APO) and the paraventricular nucleus of the hypothalamus (PVN) OVX rats compared to OVX + E2. OVX rats also showed a higher number of neurons Kp co-located with Fos in the ARC. Furthermore, there was a positive correlation between CT and Fos expression in the MPO (medial preoptic nucleus), AVPV (anteroventral periventricular nucleus), PVN, ARC, A1 and A2 and LC. In a second experiment, we evaluated the effect of reducing the central release of noradrenaline (NA) on TC and the expression of thegene in Kiss1 in the AVPV and ARC. For that, OVX and OVX + E2 rats received intracerebroventricular injections (ICV) daily of 2-adrenergic clonidine agonist (OVX + CLO; 10 g / 3 L / rat) or saline (OVX + V; OVX + E2 + V) on days 12, 13 and 14 after ovariectomy. OVX + V rats showed higher TC than OVX + E2 + V rats, and this response was restored in OVX + CLO group whose TC was similar to OVX + E2 + V group. The mRNA expression Kiss1 the ARC was higher in OVX group than in OVX + E2, and this increase was also reversed the OVX + CLO rats, demonstrating a strong correlation with TC levels. On the other hand, clonidine significantly increased Kiss1 expression in AVPV compared to control groups (OVX + V and OVX + E2 + V). This response was associated with an increased secretion of luteinizing hormone (LH) in OVX + CLO rats. In conclusion, the results of this study show that the increase in TC caused by the absence of E2 is associated with an increased activity of noradrenergic and hypothalamic nuclei and seems to depend on activation of ARC neurons by the central Kp. These findings contribute to a better understanding of the mechanisms involved in the menopausal hot flashes.