RESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which patients lose motor functions due to progressive loss of motor neurons in the cortex, brainstem, and spinal cord. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytes play an important role in maintaining ion homeostasis in the extracellular milieu and regulate multiple brain functions by altering their extracellular concentrations. In this study, we have investigated the ability of astrocytes to maintain K+ homeostasis in the brain via direct measurement of the astrocytic K+ clearance rate in the motor and somatosensory cortices of an ALS mouse model (SOD1G93A ). Using electrophysiological recordings from acute brain slices, we show region-specific alterations in the K+ clearance rate, which was significantly reduced in the primary motor cortex but not the somatosensory cortex. This decrease was accompanied by significant changes in astrocytic morphology, impaired conductivity via Kir4.1 channels and low coupling ratio in astrocytic networks in the motor cortex, which affected their ability to form the K+ gradient needed to disperse K+ through the astrocytic syncytium. These findings indicate that the supportive function astrocytes typically provide to motoneurons is diminished during disease progression and provides a potential explanation for the increased vulnerability of motoneurons in ALS.
Assuntos
Esclerose Lateral Amiotrófica , Camundongos , Animais , Astrócitos , Superóxido Dismutase-1 , Neurônios Motores/fisiologia , Medula Espinal , Modelos Animais de Doenças , Progressão da Doença , Camundongos Transgênicos , Superóxido DismutaseRESUMO
Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2-3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Animais , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Humanos , Deficiência Intelectual/complicações , Camundongos , Neurônios , Transdução de Sinais/genéticaRESUMO
Neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function, posing a tremendous burden on health systems worldwide. Although the underlying pathological mechanisms for various neurodegenerative diseases are still unclear, a common pathological hallmark is the abundance of neuroinflammatory processes, which affect both disease onset and progression. In this review, we explore the pathways and role of neuroinflammation in various neurodegenerative diseases and further assess the potential use of curcumin, a natural spice with antioxidant and anti-inflammatory properties that has been extensively used worldwide as a traditional medicine and potential therapeutic agent. Following the examination of preclinical and clinical studies that assessed curcumin as a potential therapeutic agent, we highlight the bioavailability of curcumin in the body and discuss both the challenges and benefits of using curcumin as a therapeutic compound for treating neurodegeneration. Although elucidating the involvement of curcumin in aging and neurodegeneration has great potential for developing future CNS-related therapeutic targets, further research is required to elucidate the mechanisms by which Curcumin affects brain physiology, especially BBB integrity, under both physiological and disease conditions.
Assuntos
Curcumina , Doenças Neurodegenerativas , Curcumina/uso terapêutico , Curcumina/farmacologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Animais , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/farmacologiaRESUMO
Neuronal signalling is a key element in neuronal communication and is essential for the proper functioning of the CNS. Astrocytes, the most prominent glia in the brain play a key role in modulating neuronal signalling at the molecular, synaptic, cellular, and network levels. Over the past few decades, our knowledge about astrocytes and their functioning has evolved from considering them as merely a brain glue that provides structural support to neurons, to key communication elements. Astrocytes can regulate the activity of neurons by controlling the concentrations of ions and neurotransmitters in the extracellular milieu, as well as releasing chemicals and gliotransmitters that modulate neuronal activity. The aim of this review is to summarise the main processes through which astrocytes are modulating brain function. We will systematically distinguish between direct and indirect pathways in which astrocytes affect neuronal signalling at all levels. Lastly, we will summarize pathological conditions that arise once these signalling pathways are impaired focusing on neurodegeneration.