RESUMEN
The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain ß-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aßin vitro, reducing its ability to aggregate in fibrillar Aß. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of ß-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Demencia Vascular/tratamiento farmacológico , Ghrelina/farmacología , Oligopéptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Citocinas/inmunología , Demencia Vascular/inmunología , Demencia Vascular/metabolismo , Ghrelina/uso terapéutico , Humanos , Oligopéptidos/uso terapéutico , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Estructura Terciaria de Proteína/efectos de los fármacos , Conejos , Receptores de Ghrelina/metabolismoRESUMEN
The hypothalamic-pituitary-adrenal (HPA) axis is a major integrated system that maintains body homeostasis by regulating the neuroendocrine and sympathetic nervous systems and modulating immune function. It is well established that the central nervous system (CNS) integrates responses to different stimuli secreting a specific corticotropin-releasing hormone (CRH) and vasopressin (AVP). In turn, they stimulate the release of ACTH, which induces steroidogenesis in the adrenal gland. The HPA axis is regulated by diurnal rhythms and negative feedback by corticosteroids. Many neurotransmitters and neuropeptides are responsible for the modulation of CRH and AVP neurons. In addition to synthetic glucocorticoids that inhibit the HPA axis, GABA agonists, opioid peptides and endocannabinoids can inhibit cortisol secretion. On the contrary, serotonin, norepinephrine, dopamine, acetylcholine, ghrelin, angiotensin II and different cytokines can stimulate it. It follows that a number of neuroactive drugs, acting as agonists or antagonists on several brain neurotransmitter or neuropeptide receptors, can influence ACTH/cortisol secretion thereby interfering with clinical testing of the functionality of the HPA axis.
Asunto(s)
Fármacos del Sistema Nervioso Central/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Acetilcolina/metabolismo , Acetilcolina/farmacología , Catecolaminas/metabolismo , Catecolaminas/farmacología , Glucocorticoides/farmacología , Histamina/metabolismo , Histamina/farmacología , Humanos , Neuropéptidos/metabolismo , Neuropéptidos/farmacología , Serotonina/metabolismo , Serotonina/farmacología , Serotoninérgicos/farmacología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Data from Alzheimer's disease (AD) patients and AD animal models demonstrate the accumulation of inflammatory microglia at sites of insoluble fibrillar beta-amyloid protein (fAbeta) deposition. It is known that fAbeta binds to CD36, a type B scavenger receptor also involved in internalization of oxidized low-density lipoprotein (LDL), and initiate a signaling cascade that regulates microglial recruitment, activation, and secretion of inflammatory mediators leading to neuronal dysfunction and death. The recent demonstration of a binding site for the growth hormone secretagogues (GHS) on CD36 prompted us to ascertain whether ghrelin and synthetic GHS could modulate the synthesis of inflammatory cytokines in fAbeta-activated microglia cells. We demonstrate that N9 microglia cells express the CD36 and are a suitable model to study the activation of inflammatory cytokines synthesis. In fact, in N9 cells exposed to fAbeta(25-35) for 24 hr, the expression of interleukin (IL)-1beta and IL-6 mRNA significantly increased. Interestingly, 10(-7) M desacyl-ghrelin, hexarelin, and EP80317 in the nanomolar range effectively counteracted fAbeta(25-35) stimulation of IL-6 mRNA levels, whereas ghrelin was ineffective. Similarly, the effects of fAbeta(25-35) on IL-1beta mRNA levels were attenuated by desacyl-ghrelin, hexarelin, and EP80317, but not ghrelin. Because we have observed that the specific GHS receptor GHS-R1a is not expressed in N9 cells, the actions of GHS should be mediated by different receptors. Reportedly, hexarelin and EP80317 are capable of binding the CD36 in mouse macrophages and reducing atherosclerotic plaque deposition in mice. We conclude that desacyl-ghrelin, hexarelin, and EP80317 might interfere with fAbeta activation of CD36 in microglia cells.