Such scar, which represents the hallmark of reactive astrogliosis, is due to astrocyte interaction with different cell types of the brain tissue and is characterized by phenomena of necrosis, tumors, chronic neurodegeneration, infection, or inflammatory infiltration [ 15 , 21 ]. These structural changes are not reversible and persist also after the resolution of the triggering insult [ 15 ]. More important, mature glial scars act as barriers to inflammatory cells to protect surrounding healthy tissue from nearby areas of intense inflammation.
Reactive astrocytes can also protect CNS cells and tissue by up-taking excitotoxic glutamate, producing glutathione against oxidative stress, degrading amyloid-beta peptides, regulating extracellular space volume and ion balance, facilitating blood-brain barrier repair, and regulating CNS inflammation.
Nevertheless, growing evidence also shows that reactive astrocytes can contribute to or be the primary source of CNS physiopathology. Reactive astrocytes from glial scars can indeed synthesize collagen and sulfate proteoglycans, which prevent axon regeneration [ 17 ]. Traditionally, astrocytes have been studied as a homogeneous group of cells, even if the peculiar morphology of mature mammalian astrocytes was observed since thanks to the studies on mouse brain by Otto Deiters [ 22 ].
- Document - Astrocytes: Pharmacology and Function
A detailed morphological study of glial cells came from Camillo Golgi and Ramon y Cajal in who, independently, by means of the black staining reaction, observed two different types of astrocytes: the protoplasmic and the fibrous astrocytes. However, for a long time, astrocytes received little or no consideration as target for neurological studies because the neurocentric paradigm dominated.
New and recent findings demonstrated that astrocytes are positioned to promote both the regeneration of the damaged neurons and to protect existing neurons from degeneration. For this reason, astrocytes represent an important focus in the development of new therapeutic tools for neurodegenerative disorder that have been historically viewed as purely neuronal in their pathology. Within the past 5 years, important progress has been made deriving astrocytes from induced pluripotent stem cells IPSC.
Once healthy astrocytes have been obtained and characterized, they can be used to replace dying astrocytes or to promote the survival of existing neurons. This kind of application has not yet been tested in humans; however, there is a growing body of in vitro and in vivo evidence that indicates that these therapies would be beneficial for many neuronal diseases [ 23 ].
Indeed, in an amyotrophic lateral sclerosis ALS mouse model, researchers have shown that the direct transplantation of human h iPSC-derived neural progenitor cells prolonged the lifespan of the animal [ 24 ]. In these experiments, NPCs differentiated into astrocytes and exhibited an upregulation of vascular endothelial growth factor VEGF , which induces the activation of the AKT-dependent intracellular signaling, which has previously been shown to be important for cell survival and proliferation in ALS [ 25 ].
The authors also hypothesized that the introduction of progenitor-derived astrocytes with normal expression of glucose transporters could restore glucose homeostasis in this model [ 26 ]. Moreover, these versatile human astrocytes could be used alone or in co-culture with neurons in both target-based and phenotypic high-throughput drug-screening research studies, promoting the discovery of novel therapeutics tools useful in the treatment of neurodegenerative disorders.
For decades, therapeutic development for neurodegenerative disorders has focused only on diseased neurons.
Due to the crucial role of astrocytes in physiology of the central nervous system and in the pathogenesis of several neurodegenerative diseases, it is not surprising that the traditional drug development strategy which follows the neurocentric paradigm has not produced effective therapies. Developing new drugs that complement and combine therapies which target both neuronal and astrocytic degeneration could provide a new direction to increase the success of therapeutic development for neurodegenerative diseases in the future. The shift from a neurocentric view to one that incorporates astrocytes in disease models for drug discovery is a critical step in renewing drug development strategies to treat neurodegenerative diseases.
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Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes
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Nitric oxide signalling in astrocytes Xuewei Wang. Current technical approaches to brain energy metabolism. References Publications referenced by this paper. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes.
Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. Richard M. Henson , Adam C. Newton G. Castro , Edson X.
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