Astrocytes and their Phenomenal Possibilities in the Treatment of Various Neurodegenerative Disorders: An Overview (original) (raw)

Role of astrocytes in major neurological disorders: The evidence and implications

IUBMB Life, 2013

Given the huge amount and great complexity of astrocyte functions in the maintenance of brain homeostasis, it is easily understood how alterations in their physiology may be involved in the pathogenesis of many, if not all, neurological disorders. This assumption is strongly supported by accumulated evidence produced in humans and in experimental models of pathology. Based on these considerations, it is reasonable to encourage studies aimed at improving the knowledge about the implicated mechanisms, and astroglial cells can be considered as the innovative target for new, and possibly more effective, drug therapies.

Targeting astrocytes in CNS injury and disease: A translational research approach

Progress in neurobiology, 2016

Astrocytes are a major constituent of the central nervous system. These glia play a major role in regulating blood-brain barrier function, the formation and maintenance of synapses, glutamate uptake, and trophic support for surrounding neurons and glia. Therefore, maintaining the proper functioning of these cells is crucial to survival. Astrocyte defects are associated with a wide variety of neuropathological insults, ranging from neurodegenerative diseases to gliomas. Additionally, injury to the CNS causes drastic changes to astrocytes, often leading to a phenomenon known as reactive astrogliosis. This process is important for protecting the surrounding healthy tissue from the spread of injury, while it also inhibits axonal regeneration and plasticity. Here, we discuss the important roles of astrocytes after injury and in disease, as well as potential therapeutic approaches to restore proper astrocyte functioning.

Targeting reactive astrogliosis by novel biotechnological strategies

Biotechnology Advances

Neuroglial cells are fundamental for control of brain homeostasis and synaptic plasticity. Decades of pathological and physiological studies have focused on neurons in neurodegenerative disorders, but it is becoming increasingly evident that glial cells play an irreplaceable part in brain homeostasis and synaptic plasticity. Animal models of brain injury and neurodegenerative diseases have largely contributed to current understanding of astrocyte-specific mechanisms participating in brain function and neurodegeneration. Specifically, gliotransmission (presence of glial neurotransmitters, and their receptors and active transporters), trophic support (release, maturation and degradation of neurotrophins) and metabolism (production of lactate and GSH components) are relevant aspects of astrocyte function in neuronal metabolism, synaptic plasticity and neuroprotection. Morphofunctional changes of astrocytes and microglial cells after traumatic or toxic insults to the central nervous system (namely, reactive gliosis) disrupt the complex neuro-glial networks underlying homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as gliodegenerative processes, in which profound alterations of glial activation have a clear impact on progression and outcomes of neuropathological processes. This review provides an overview of current knowledge of astrocyte functions in the brain and how targeting glial-specific pathways might ultimately impact the development of therapies for clinical management of neurodegenerative disorders.

Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

Physiological Reviews, 2014

Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment st...

Chemical inhibition of pathological reactive astrocytes promotes neural protection

bioRxiv (Cold Spring Harbor Laboratory), 2021

Disease, injury, and aging induce reactive astrocyte states with pathological functions 1-4. In neurodegenerative diseases, inflammatory reactive astrocytes are abundant and contribute to progressive cell loss. Modulating the state or function of these reactive astrocytes thereby represents an attractive therapeutic goal 5,6. Leveraging a cellular phenotypic screening platform, we show that chemical inhibitors of HDAC3 effectively block pathological astrocyte reactivity. Inhibition of HDAC3 reduces molecular and functional features of reactive astrocytes in vitro including inflammatory gene expression, cytokine secretion, and antigen presentation. Transcriptional and chromatin mapping studies show that HDAC3 inhibition mediates a switch between pro-inflammatory and anti-inflammatory states, which disarms the pathological functions of reactive astrocytes. Systemic administration of a blood-brain barrier penetrant chemical inhibitor of HDAC3, RGFP966, blocks reactive astrocyte formation and promotes axonal protection in vivo. Collectively, these results establish a platform for discovering chemical modulators of reactive astrocyte states, inform the mechanisms controlling astrocyte reactivity, and demonstrate the therapeutic potential of modulating astrocyte reactivity for neurodegenerative diseases. Main Astrocytes in the central nervous system (CNS) play important homeostatic roles that include trophic support of neurons, promotion of functional synapse formation, and formation and maintenance of the blood-brain barrier 7-9. In the context of disease, injury, or normal aging, astrocytes become reactive and can adopt a pathological state that kills neurons and oligodendrocytes 6. These pathogenic reactive astrocytes are found in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral. CC-BY-NC-ND 4.

Neuroprotective potential of astroglia

Journal of Neuroscience Research

Astroglia are the homoeostatic cells of the central nervous system, which participate in all essential functions of the brain. Astrocytes support neuronal networks by handling water and ion fluxes, transmitter clearance, provision of antioxidants, and metabolic precursors and growth factors. The critical dependence of neurons on constant support from the astrocytes confers astrocytes with intrinsic neuroprotective properties. On the other hand, loss of astrocytic support or their pathological transformation compromises neuronal functionality and viability. Manipulating neuroprotective functions of astrocytes is thus an important strategy to enhance neuronal survival and improve outcomes in disease states.