RESUMEN
The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.
Asunto(s)
Angiotensina I , Enzima Convertidora de Angiotensina 2 , Enfermedad de Huntington , Fragmentos de Péptidos , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina , Angiotensina I/genética , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedad de Huntington/genética , Ratones , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologíaRESUMEN
INTRODUCTION: The ultimate cause of neuronal death in Huntington's disease (HD) is still uncertain. Apart from impairment in systems handling abnormal proteins, other mechanisms might contribute to neurodegeneration and progression of HD. Decreased cerebral blood flow (CBF) has been described in other neurodegenerative disorders and may play a role in HD. OBJECTIVES: To investigate CBF changes in HD gene carriers. METHODS: A group of 39 HD gene carriers (18 premanifest and 21 manifest HD) and 16 controls underwent a comprehensive clinical evaluation and a brain magnetic resonance imaging protocol that included pseudo-continuous arterial spin labeling to quantify CBF. Regions of interest (ROI) analyses were performed to compare CBF in controls vs premanifest HD vs manifest HD. Correlation analyses were performed to ascertain the relationship between CBF and clinical and biomarkers data. RESULTS: We found a decrease in CBF in bilateral caudate and putamen of patients with manifest HD in comparison with controls. CBF of premanifest HD carriers in the same ROIs was midway between controls and the HD patients, with differences not reaching statistical significance. Lower CBF in caudate and putamen was associated with worse motor symptoms, functionality, and cognitive performance. CBF was also associated with markers of neurodegeneration: higher CBF in caudate and putamen significantly correlated to higher volumes in the same ROI and to lower levels of neurofilament light chain. CONCLUSION: As CBF changes in caudate and putamen nuclei were associated with markers of neurodegeneration and with clinical outcomes, decreased CBF and oxygen supply could emerge as a relevant mechanism contributing to degeneration in HD.
Asunto(s)
Enfermedad de Huntington , Biomarcadores , Circulación Cerebrovascular , Humanos , Enfermedad de Huntington/genética , Imagen por Resonancia Magnética/métodos , OxígenoRESUMEN
OBJECTIVE: To define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease. METHODS: This is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes. RESULTS: Individuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity. CONCLUSIONS: Altogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression.
Asunto(s)
Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/fisiopatología , Microglía/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Enfermedad de Huntington/genética , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Cultivo Primario de Células , Putamen/metabolismo , Receptores de GABA/genéticaAsunto(s)
Anfetaminas/efectos adversos , Anestesia/efectos adversos , Anestésicos por Inhalación/efectos adversos , Cannabis/efectos adversos , Hipotensión/inducido químicamente , Paroxetina/efectos adversos , Adolescente , Anfetaminas/orina , Anestesia/métodos , Anestésicos por Inhalación/administración & dosificación , Depresión/tratamiento farmacológico , Interacciones Farmacológicas , Femenino , Humanos , Fumar Marihuana/efectos adversos , Fumar Marihuana/orina , Dolor Postoperatorio/prevención & control , Paroxetina/administración & dosificación , Fusión Vertebral/efectos adversos , Detección de Abuso de SustanciasRESUMEN
A 4-year-old female developed hypotension, tachycardia, hypoxemia, and diffuse erythema after induction of anesthesia with ketamine, fentanyl, and cisatracurium. Treatment consisted of repeated doses of epinephrine, diphenhydramine, corticosteroids, and IV fluids. Skin prick testing performed 4 weeks after the incident confirmed an immunoglobulin E-mediated anaphylaxis to cisatracurium. She had 8 previous exposures to cisatracurium without incident. She had experienced hypotension on the ninth exposure to cisatracurium but the decrease in arterial blood pressure was attributed to propofol. On the tenth exposure to cisatracurium, the patient developed evidence of anaphylactic shock that led to the diagnosis.