Targeting reactive astrogliosis by novel biotechnological strategies (original) (raw)
Related papers
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.
Gliotoxicity and Glioprotection: the Dual Role of Glial Cells
Molecular Neurobiology
Glial cells (astrocytes, oligodendrocytes and microglia) are critical for the central nervous system (CNS) in both physiological and pathological conditions. With this in mind, several studies have indicated that glial cells play key roles in the development and progression of CNS diseases. In this sense, gliotoxicity can be referred as the cellular, molecular, and neurochemical changes that can mediate toxic effects or ultimately lead to impairment of the ability of glial cells to protect neurons and/ or other glial cells. On the other hand, glioprotection is associated with specific responses of glial cells, by which they can protect themselves as well as neurons, resulting in an overall improvement of the CNS functioning. In addition, gliotoxic events, including metabolic stresses, inflammation, excitotoxicity, and oxidative stress, as well as their related mechanisms, are strongly associated with the pathogenesis of neurological, psychiatric and infectious diseases. However, glioprotective molecules can prevent or improve these glial dysfunctions, representing glial cells-targeting therapies. Therefore, this review will provide a brief summary of types and functions of glial cells and point out cellular and molecular mechanisms associated with gliotoxicity and glioprotection, potential glioprotective molecules and their mechanisms, as well as gliotherapy. In summary, we expect to address the relevance of gliotoxicity and glioprotection in the CNS homeostasis and diseases.
Journal of Pharmaceutical Research International, 2021
At present, research in the field of the brain does not cease to surprise us with new facts and discoveries that no one could have suspected about 30 years ago. But it was at the time when it became clear that the cerebral neurons are not the only cells that can respond to changes in the external environment. A real scientific boom began to study a heterogeneous group called glia. And scientists are paying close attention to the largest of them – astrocytes. Understanding the importance of astrocytes in the mechanisms of repair and damage to brain cells in various forms of CNS pathology determines the possibility of targeted search for drugs that affect the rate of development of reactive astrogliosis in response to various brain injuries. At the same time, pharmacological modulation of activated astrocytes and other components of glia can be an integral part of the therapy of neurological diseases.
Neurobiology of Disease, 2011
Reactive gliosis has been implicated in both inflammatory and neurodegenerative diseases. However, mechanisms by which astrocytic activation affects synaptic efficacy have been poorly elucidated. We have used the spared nerve injury (SNI) of the sciatic nerve to induce reactive astrocytosis in the lumbar spinal cord and investigate its potential role in disrupting the neuro-glial circuitry. Analysis of spinal cord sections revealed that SNI was associated with an increase of microglial (Iba1) and astrocytic (GFAP) markers. These changes, indicative of reactive gliosis, were paralleled by (i) a decrease of glial amino acid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. Besides the increase of Glutamate/ GABA ratio, indicative of the perturbation of synaptic circuitry homeostasis, the boost of glutamate also compromised glial function in neuroprotection by up-regulating the xCT subunit of the glutamate-cystine antiport system and reducing glutathione (GSH) production. Finally, this study also shows that all these structural changes were linked to an alteration of endogenous NGF metabolism, as demonstrated by the decrease of endogenous NGF expression levels and increased activity of the NGF-degrading metalloproteinases. All the changes displayed by SNI-animals were reversed by a 7-days i.t. administration of NGF or GM6001, a generic metalloproteinase inhibitor, as compared to vehicle (ACSF)-treated animals. All together, these data strongly support the correlation between reactive astrogliosis and mechanisms underlying the perturbation of the synaptic circuitry in the SNI model of peripheral nerve injury, and the essential role of NGF in restoring both synaptic homeostasis and the neuroprotective function of glia.
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...
Increased microglial activation and astrogliosis 2004
Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, intranasal administration of kainic acid (KA), an analogue of the excitotoxin glutamate, results in hippocampal cell death and provides a wellcharacterized model for studies of human neurodegenerative diseases. In this study, we describe neurodegeneration and gliosis following intranasal administration of KA in C57BL/6 mice. By using Nissl's staining, neurodegeneration was found in area CA3 of hippocampus, and neuronal apoptosis was demonstrated by enhanced FAS(CD95/APO-1) expression detected by immunohistochemistry and Western blotting. Astrogliosis was ex-hibited by increased glial fibrillary acidic protein (GFAP) expression in the hippocampus and cortex. We also studied the profile of molecular expression on microglia in C57BL/6 mice. One and 3 days after KA administration, CD45, F4/80, CD86, MHCII, iNOS but not CD40 expression was enhanced or induced on microglia. In summary, KA administration results in an early microglial activation and a prolonged astrogliosis in C57BL/6 mice.
Astroglia as a cellular target for neuroprotection and treatment of neuro-psychiatric disorders
Glia
Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem-cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocytespecific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2-ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.
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.
Glia in the pathogenesis of neurodegenerative diseases
Biochemical Society Transactions, 2014
Exclusively neuron-centric approaches to neuropathological mechanisms have not resulted in major new breakthroughs in the prevention and therapy of neurodegenerative diseases. In the present paper, we review the role of glia in neurodegeneration in an attempt to identify novel targets that could be used to develop much-needed strategies for the containment and cure of neurodegenerative disorders. We discuss this in the context of glial roles in the homoeostasis and defence of the brain. We consider the mounting evidence supporting a change away from the perception of reactive glial responses merely as secondary detrimental processes that exacerbate the course of neurological disorders, in favour of an emerging contemporary view of glial pathological responses as complex and multistaged defensive processes that also have the potential for dysfunction.