RESUMO
The sympathetic arm of the inflammatory reflex is the efferent pathway through which the central nervous system (CNS) can control peripheral immune responses. Diminazene aceturate (DIZE) is an antiparasitic drug that has been reported to exert protective effects on various experimental models of inflammation. However, the pathways by which DIZE promotes a protective immunomodulatory effects still need to be well established, and no studies demonstrate the capacity of DIZE to modulate a neural reflex to control inflammation. C57BL/6 male mice received intraperitoneal administration of DIZE (2 mg/Kg) followed by lipopolysaccharide (LPS, 5 mg/Kg, i.p.). Endotoxemic animals showed hyperresponsiveness to inflammatory signals, while those treated with DIZE promoted the activation of the inflammatory reflex to attenuate the inflammatory response during endotoxemia. The unilateral cervical vagotomy did not affect the anti-inflammatory effect of DIZE in the spleen and serum. At the same time, splenic denervation attenuated tumor necrosis factor (TNF) synthesis in the spleen and serum. Using broad-spectrum antibiotics for two weeks showed that LPS modulated the microbiota to induce a pro-inflammatory profile in the intestine and reduced the serum concentration of tryptophan and serotonin (5-HT), while DIZE restored serum tryptophan and increased the hypothalamic 5-HT levels. Furthermore, the treatment with 4-Chloro-DL-phenylalanine (pcpa, an inhibitor of 5-HT synthesis) abolished the anti-inflammatory effects of the DIZE in the spleen. Our results indicate that DIZE promotes microbiota modulation to increase central 5-HT levels and activates the efferent sympathetic arm of the inflammatory reflex to control splenic TNF production in endotoxemic mice.
Assuntos
Diminazena , Endotoxemia , Microbioma Gastrointestinal , Inflamação , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Serotonina , Baço , Sistema Nervoso Simpático , Animais , Masculino , Camundongos , Baço/metabolismo , Baço/efeitos dos fármacos , Diminazena/análogos & derivados , Diminazena/farmacologia , Lipopolissacarídeos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/metabolismo , Serotonina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Endotoxemia/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Eixo Encéfalo-Intestino/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Levodopa-induced dyskinesia (LID) is a common complication of Parkinson's disease (PD) therapy. Nitric oxide in the central nervous system may have a role in its pathophysiology. The present work investigates plasma and CSF levels of nitric oxide metabolites nitrite and nitrate in patients with PD, LID, and healthy control. We measured plasma and CSF nitrite and nitrate levels in patients with PD with and without LID and in healthy controls. The levels of plasma and CSF nitrite and nitrate were measured by ozone-based chemiluminescence. Sixty-seven participants were enrolled. CSF nitrite levels in patients with PD and LID were higher than in patients with PD without LID and healthy controls. CSF/plasma ratio of nitrite was higher in patients with PD and LID than in patients with PD without LID. The CSF/plasma ratio of nitrite in patients with PD and LID was higher than 1, indicating an intrathecal production of NO in patients with this motor complication. There was an increase in nitrate levels of CSF and CSF/plasma ratio of nitrate in patients with PD and LID compared to the healthy controls. Sex, age at evaluation, disease duration, and levodopa equivalent daily doses, as well as processing and storage time, did not critically influence these results. The present study demonstrated an increase in nitrite and nitrate levels in the central nervous system of patients with PD and LID. This finding strengthens the role of NO on LID pathophysiology.
Assuntos
Discinesias , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Humanos , Levodopa/efeitos adversos , Óxido NítricoRESUMO
Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.