Caracterización de la neuroinflamación en modelos animales y en pacientes con encefalopatía hepática. Implicaciones terapéuticas

Varios millones de personas afectadas por enfermedades hepáticas crónicas (cirrosis, hepatitis) muestran alteraciones neurológicas, denominadas encefalopatía hepática (HE) con alteraciones cognitivas y motoras que deterioran la calidad de vida y reducen la esperanza de vida. La carga económica de la encefalopatía hepática es sustancial, con un costo estimado entre mil y siete mil millones de dólares por año en los EE.UU. La patogénesis de la encefalopatía hepática y los mecanismos que conducen a las alteraciones neurológicas aún no se entienden completamente. Algunos estudios sugieren la presencia de neuroinflamación en pacientes con cirrosis hepática o hepatitis C. Estudios en modelos animales demuestran que la neuroinflamación juega un papel principal en las alteraciones cognitivas y motoras en HE. Los objetivos principales de la tesis son: 1. Caracterizar la neuroinflamación y las alteraciones estructurales en ratas con HE y en pacientes en diferentes estadios de enfermedad hepática crónica. Para llevar a cabo este objetivo se han analizado la activación de las células gliales y los marcadores inflamatorios por inmunohistoquímica en ratas con anastomosis porto-cava (PCS) y en secciones post-mortem de pacientes con distintos grados de enfermedades hepáticas. 2. Evaluar si reduciendo la inflamación periférica en ratas PCS mediante la administración periférica de anti-TNFα, el infliximab, se previene la neuroinflamación y el deterioro cognitivo y motor. Las ratas PCS muestran inflamación periférica, activación de astrocitos y microglía y niveles aumentados de TNF-α e IL-1β en el cerebelo e hipocampo. Estos cambios conducen al deterioro de la coordinación motora y de la capacidad de aprendizaje. El tratamiento con infliximab reduce la inflamación periférica previniendo la activación de microglía y astrocitos y la neuroinflamación y normalizando la coordinación motora y la capacidad de aprendizaje. En muestras de pacientes se ha visto que la neuroinflamación y la pérdida neuronal en cerebelo comienzan desde los primeros estadios de la enfermedad hepática. El análisis con marcadores de linfocitos T, sugiere que la infiltración de las células del sistema inmune en cerebelo podría desencadenar la respuesta neuro-inflamatoria. En conclusión, estos datos representan un nuevo punto de vista sobre cómo los cambios periféricos afectan el SNC, lo que conduce a deterioro cognitivo y motor en HE. Además, elucidar el curso temporal de alteraciones en diferentes áreas cerebrales, permitirá diseñar mejores tratamientos para prevenir las alteraciones neurológicas en las enfermedades hepáticas y mejorar la calidad de vida de los pacientes

Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors

Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

血液脳関門開放術による遺伝子治療法の開発 --身体を傷つけない脳疾患の治療を目指して--. 京都大学プレスリリース. 2023-04-20.Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders

Rifaximin Prevents T-Lymphocytes and Macrophages Infiltration in Cerebellum and Restores Motor Incoordination in Rats with Mild Liver Damage

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCl4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis

Strain of the genus Bacteroides for use in the treatment and/or prevention of eating disorders

[ES] La presente invención se refiere a la cepa B. uniformis CECT 7771, para uso en la prevención o reducción del nesgo y en el tratamiento de formas sub-clínicas o clínicas de trastornos del comportamiento alimentario, tales como la hiperfagia, el trastorno por atracón, la ingesta adictiva o selectiva de alimentos, la bulimia nerviosa, la anorexia nerviosa, la ansiedad asociada a alteraciones de la conducta alimentaria y la megarexia. La presente invención también se refiere a una composición que comprende dicha cepa para el mismo uso.[EN] The present invention relates to a strain of the genus Bacteroides, preferably to the strain B. unifomis CECT 7771, for use in the prevention or reduction of risk and in the treatment of sub-clinical or clinical forms of eating disorders, such as hyperphagia, binge eating disorder, addictive or selective food intake, bulimia nervosa, anorexia nervosa, anxiety associated with eating disorders and megarexia. The present invention also relates to a composition comprising said strain for the same use.NoConsejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Principe FelipeB2 Patente con examen previ

Strain of the bacteroides genus for use in the treatment and/or prevention of eating disorders

La presente invención se refiere a una cepa del género Bacteroides, preferiblemente a la cepa B. uniformis CECT 7771, para uso en la prevención o reducción del riesgo y en el tratamiento de formas sub-clínicas o clínicas de trastornos del comportamiento alimentario, tales como hiperfagia, el trastorno por atracón, la ingesta adictiva o selectiva de alimentos, la bulimia nerviosa, la anorexia nerviosa, la ansiedad asociada a alteraciones de la conducta alimentaria y la megarexia. La presente invención también se refiere a una composición que comprende dicha cepa para el mismo uso. [ES]The present invention relates to a strain of the Bacteroides genus, preferably the B.uniformis CECT 7771 strain, for use in the prevention of or reduction in the risk of, and in the treatment of, subclinical or clinical forms of eating behaviour disorders such as hyperphagia, binge-eating disorder, addictive or selective consumption of food, bulimia nervosa, anorexia nervosa, the anxiety associated with disturbances in eating behaviour, and megarexia. The present invention also relates to a composition comprising said strain for the above use. [EN]Peer reviewedConsejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Príncipe FelipeA1 Solicitud de patente con informe sobre el estado de la técnic

Cepa del género Bacteroides para su uso en el tratamiento y/o prevención de trastornos alimenticios

La presente invención se refiere a la cepa B. uniformis CECT 7771, para uso en la prevención o reducción del nesgo y en el tratamiento de formas sub-clínicas o clínicas de trastornos del comportamiento alimentario, tales como la hiperfagia, el trastorno por atracón, la ingesta adictiva o selectiva de alimentos, la bulimia nerviosa, la anorexia nerviosa, la ansiedad asociada a alteraciones de la conducta alimentaria y la megarexia. La presente invención también se refiere a una composición que comprende dicha cepa para el mismo uso.Peer reviewedConsejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Príncipe FelipeA1 Solicitud de patente con informe sobre el estado de la técnic

Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment