RESUMO
Patients with Parkinson's disease (PD) have a high prevalence of glucose metabolism abnormalities. However, the mechanism underlying these symptoms remains unclear. The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine axis that regulates homeostasis in mammals, including glucose metabolism. Corticotrophin releasing hormone (CRH), which is synthesized in the paraventricular nucleus (PVN) of the hypothalamus, plays an important role in the regulation of blood glucose levels via the HPA axis. Our previous studies have reported that PVN neurons express numerous dopamine receptors (DRs) and accept direct projections from the substantia nigra (SN). We hypothesize that damage to dopaminergic neurons in the SN might influence the blood glucose level through the HPA system. Rats with bilateral SN lesions induced by 6-hydroxydopamine (6-OHDA) (referred to as 6-OHDA rats) were used to investigate alterations in the levels of blood glucose, CRH, and factors related to the HPA axis and to explore possible mechanisms. Blood glucose levels were detected at different time points after the glucose solution was intraperitoneally administered. CRH and DRs in the PVN were evaluated by immunofluorescence and western blot analysis. Adrenocorticotropic hormone (ACTH) in the pituitary and plasma corticosterone (CORT) was evaluated by radioimmunoassay (RIA). The results showed that 6-OHDA rats exhibited significantly decreased tyrosine hydroxylase (TH) in the SN and decreased glucose tolerance at 6 weeks, but not at 4 weeks. In the PVN, dopamine receptor 2 (D2) was expressed on CRH-positive neurons, and D2-positive neurons were surrounded by TH-positive fibers. Additionally, the expression of CRH was upregulated, whereas the expression of D2 and TH were downregulated in 6-OHDA rats compared with control rats. In D2 knock-out mice, the significantly enhanced expression of CRH and reduced expression of D2 were detected in the PVN. Furthermore, RIA revealed increased ACTH in the pituitary and elevated CORT in the blood. In summary, the present study suggests that the dopaminergic neurons in the SN are involved in the regulation of body glucose metabolism through CRH neurons that express D2 in the hypothalamic PVN. SN lesions decrease glucose tolerance mainly by downregulating D2 and upregulating CRH in the PVN through the HPA neuroendocrine system.
RESUMO
Most Parkinson's Disease (PD) patients experience gastrointestinal (GI) dysfunction especially the gastroparesis, but its underlying mechanism is not clear. We have previously demonstrated that the neurons in the substantia nigra (SN) project to the lateral hypothalamic nucleus (LH) and the dorsal motor nucleus of vagus (DMV) receives the neural projection from LH by the means of anterograde and retrograde neural tracing technology. Orexin A (OXA) is predominately expressed in the LH. It has been reported that OXA can alter the gastric motility through the orexin receptor 1 (OX1R) in DMV. We speculated that this SN-LH-DMV pathway could modulate the motility of stomach because of the important role of LH and DMV in the regulation of gastric motility. However, the distribution and expression of dopamine receptors (DR) in the LH is unknown. In the present study, using a double-labeling immunofluorescence technique combined with confocal microscopy, we significantly extend our understanding of the SN-LH-DMV pathway by showing that (1) a considerable quantity of dopamine receptor 1 and 2 (D1 and D2) was expressed in the LH as well as the OX1R was expressed in the DMV; (2) Nearly all of the D1-immuoreactve (IR) neurons were also OXA-positive while only a few neurons express both D2 and OXA in the LH, and the DR-positive neurons were surrounded by the dopaminergic neural fibers; In the DMV, OX1R were colocalized with choline acetyltransferase (ChAT)-labeled motor neurons; (3) When the gastroparesis was induced by the destruction of dopaminergic neurons in the SN, the decreased expression of D1 and OXA was observed in the LH as well as the reduced OX1R and ChAT expression in the DMV. These findings suggest that SN might regulate the function of OXA-positive neurons via D1 receptor, which then affect the motor neurons in the DMV through OX1R. If the SN is damaged the vagal pathway would be affected, which may lead to gastric dysfunction. The present study raises the possibility that the SN-LH-DMV pathway can regulate the movement of stomach.