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Neurotherapeutics. Author manuscript; available in PMC 2011 Oct 1.
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PMCID: PMC2952540

Reactive astrocytes as therapeutic targets for CNS disorders


Reactive astrogliosis has long been recognized as a ubiquitous feature of central nervous system (CNS) pathologies. Although its roles in CNS pathologies are only beginning to be defined, genetic tools are enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. It is now clear that reactive astrogliosis is not simply an all-or-none phenomenon but, rather, is a finely gradated continuum of molecular, cellular and functional changes ranging from subtle alterations in gene expression to scar formation. These changes can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Dysfunction of either astrocytes or the process of reactive astrogliosis is emerging as an important source of potential mechanisms that might contribute to, or play primary roles in, a host of CNS disorders via loss of normal or gain of abnormal astrocyte activities. The rapidly growing understanding of the mechanisms underlying astrocyte signaling and reactive astrogliosis has the potential to open doors to identifying many molecules that might serve as novel therapeutic targets for a wide range of neurological disorders. This article considers general principles and examines selected examples regarding the potential of targeting specific molecular aspects of reactive astrogliosis for therapeutic manipulations including the regulation of glutamate, reactive oxygen species, and cytokines.

I. Introduction

Astrocytes are specialized glial cells that are ubiquitous throughout all regions of the central nervous system (CNS). Astrocytes outnumber neurons by over five fold and contiguously tile the entire CNS in an essentially uninterrupted manner. Although neurons have long been the focus of attention as mediators of CNS functions, an ever growing body of evidence indicates that astrocytes and other glia play primary roles in neural processing in both health and disease. Astrocytes play essential roles in normal, continually ongoing CNS functions including regulation of blood flow, provision of energy metabolites to neurons, participation in synaptic function and plasticity, and maintenance of the extracellular balance of ions, fluid balance and transmitters, as reviewed in detail elsewhere 15. In addition, astrocytes respond to all forms of CNS insults such as infection, trauma, ischemia and neurodegenerative disease by a process commonly referred to as reactive astrogliosis, which involves changes in astrocyte molecular expression and in severe cases results in scar formation, as reviewed in detail elsewhere 6, 7. Reactive astrogliosis is not merely a marker of neuropathology, but plays essential roles in orchestrating the injury response as well as in regulating inflammation and repair in a manner that markedly impacts functional and clinical outcomes 5, 7, 8. Enormous progress has been made in characterizing molecular mechanisms underlying astrocyte and reactive astrocyte functions. As such, a vast molecular arsenal at the disposal of astrocytes and reactive astrocytes is being defined. Accordingly, astrocytes and reactive astrocytes are increasingly recognized as potential targets for novel therapeutic strategies for a variety of CNS conditions 7, 911. This article will review recent findings and consider general principles regarding the potential of targeting reactive astrogliosis for therapeutic manipulations, with a focus on a number of specific molecular mechanisms as examples.

II. General approach to reactive astrocytes as therapeutic targets

When considering the potential for reactive astrocytes as therapeutic targets, it is useful first to examine their characteristics, functions and molecular mechanisms. Concepts about the functions and effects of reactive astrogliosis have long been dominated by the 100-year-old recognition that scars formed by reactive astrocytes inhibit axon regeneration and by the interpretation that this scar was the main impediment to functional recovery after CNS injury or disease. These observations have sometimes led to the simplistic notion that reactive astrogliosis is an all or none maladaptive process synonymous with scar formation and that the total inhibition of reactive astrogliosis could be regarded as a therapeutic strategy. This absolutely negative view of reactive astrogliosis is no longer tenable, and it is clear from a growing body of experimental evidence that there is a normal, adaptive process of reactive astrogliosis, including scar formation, which exerts essential beneficial functions 5, 7, 8. These studies have shown that reactive astrogliosis is not a simple, all-or-none phenomenon, nor is it ubiquitously synonymous with scar formation. Instead, reactive astrogliosis is a finely gradated continuum of changes that occur in response to all CNS insults in a context-dependent manner regulated by specific signaling events 7. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure after mild insults to long lasting scar formation with permanent rearrangement of tissue structure after severe insults 5, 7, 8. The changes undergone during reactive astrogliosis have the potential to alter astrocyte activities both through gain and loss of functions that can impact surrounding neural and non-neural cells both beneficially and detrimentally 5, 7, 8. Because astrocytes and reactive astrocytes have the potential to influence essentially all aspects of neural function through the regulation of blood flow, provision of energy substrates, or by influencing synaptic function and plasticity, it is perhaps not surprising that dysfunction of the processes underlying reactive astrogliosis and scar formation have the potential to contribute to, or even be the primary cause of, CNS disease mechanisms either through loss of normal functions or through gain of detrimental effects 5, 7.

Numerous studies using transgenic and experimental animal models provide compelling evidence that reactive astrocytes protect CNS cells and tissue in multiple ways that involve a variety of different molecular mechanisms, including (i) uptake of potentially excitotoxic glutamate 1214, (ii) protection from oxidative stress via glutathione production 1418, (iii) neuroprotection via adenosine release 19, (iv) protection from NH4+ toxicity 20, (v) neuroprotection by degradation of amyloid-beta peptides, 21 (vi) facilitation of blood brain barrier repair 13, (vii) reduction of vasogenic edema after trauma, stroke or obstructive hydrocephalus 13, 22, (viii) stabilization of extracellular fluid and ion balance thereby reducing seizure threshold 22, and (ix) limiting the spread of inflammatory cells or infectious agents from areas of tissue damage or disease into healthy CNS parenchyma 13, 2329. Nevertheless, it is also clear that reactive astrocytes may also play harmful roles during injury or disease through gain of abnormal effects such as over production of reactive oxygen species (ROS) or certain inflammatory cytokines 5, 7, 14. Thus, overall, reactive astrocytes have the potential to influence injury/disease outcomes both positively and negatively, as determined by specific signaling events and molecular effector mechanisms 5, 7, 8.

Taken together, observations from experimental animal studies indicate that the global inhibition or ablation of reactive astrogliosis is not likely to be a useful therapeutic approach and has the potential to do more harm than good in most situations 5, 7, 8. Instead, therapeutic strategies should be directed at more specific astrocyte functions or specific aspects of reactive astrogliosis by targeting astrocyte-related molecular mechanisms. Considerable progress has been made in identifying molecular mechanisms that regulate specific aspects of reactive astrogliosis or that are involved in mediating its functions and effects 5, 7. Some of these molecules will be common to many cells (e.g. cytokines, ROS) while other molecules will be selective to astrocytes and may be targetable selectively (e.g., astrocyte glutamate transporters, SOD1). In the following sections, we consider a number of molecules related to astrocytes and reactive astrogliosis and discuss their potential, and in some cases on-going development, as therapeutic targets for specific CNS disorders. Space constraints limit consideration to a cross-section of representative potential molecules.

III. Specific potential molecular therapeutic targets related to astrocytes and reactive astrogliosis

A. Glutamate transmission and excitotoxicity

Astrocyte processes that envelope synapses express high levels of transporters for the amino acid neurotransmitter glutamate. These transporters clear the glutamate from the synaptic space, and after uptake into astrocytes, the glutamate is converted by glutamine synthetase into glutamine and recycled back to synapses for reconversion to the active transmitter, glutamate 30, 31. Through these transporters, astrocytes play essential roles in regulating extracellular levels of glutamate, which puts astrocytes in a position to reduce the potential for excitotoxicity. Indeed, genetic animal models have shown that loss of astrocytes or attenuation of astrocyte glutamate transporters such as EAAT1 and EAAT2 can lead to excitotoxic neurodegeneration 12, 13. The expression or activity of astrocyte glutamate transporters is subject to a high degree of regulation both transcriptionally and post-transcriptionally 3033. Glutamate transporter activity is reduced in various neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) 34. Thus, modulation of EAAT1 and EAAT2 represent pharmacological targets that may modify neuronal function or protect neurons by manipulating glutamate levels 9, 30. For example, augmenting the function of the astrocyte glutamate transporter EAAT2 with parawexin 1, a molecule isolated from spider venom, has been shown to protect retinal neurons from ischemic degeneration by enhancing glutamate uptake and thereby reducing the potential for glutamate excitotoxicity 35, 36. A high-throughput screen of small molecules has identified that certain β-lactam antibiotics can enhance astrocyte-mediated glutamate uptake sufficiently to provide neuroprotection in models of stroke and ALS by stimulating the expression of astrocyte glutamate transporters and thereby reducing excitotoxicity 37. The β-lactam antibiotic, Ceftriaxone, is currently (2010) in stage 3 clinical trials to determine efficacy in reducing excitotoxicity and neurodegeneration in ALS. Finally, a non-competitive blocker of the AMPA glutamate receptor, talampanel, is also in clinical trials for ALS and has just completed Phase II 38.

An additional potential target for manipulating astrocyte influences on glutamatergic synaptic transmission is astrocyte calcium signaling. Astrocytes exhibit transient elevations of cytosolic calcium levels in respond to activation of a number of different membrane receptors and these calcium transients are regarded as a form of astrocyte excitability 3941. Although the precise roles and mechanisms of astrocyte calcium signaling are incompletely understood, calcium transients in astrocytes have been shown to affect neuronal excitatory transmission including network properties such as the ability to induce long term potentiation 42, 43. In this regard, it is particularly interesting that receptor selectivity has been noted such that calcium transients triggered in astrocytes by activation of PAR-1 receptors led to the appearance of NMDA receptor-mediated slow inward currents (SICs) in hippocampal pyramidal neurons, whereas calcium transients triggered in astrocytes by activation of P2Y1 receptors did not 44.

B. Enzymes and scavengers related to oxidative stress


Nitric oxide synthase-2 (iNOS or NOS-2) is the inducible and calcium-independent isoform of nitric oxide synthase, the enzyme responsible for the production of the free radical nitric oxide (NO). Whereas under normal physiological conditions NOS-2 is not expressed, it is induced due to injury or inflammation by a variety of stimuli including IL-1 β, LPS and TNFα in both astrocytes and microglia 4549. In several rodent models, there is evidence that NOS-2 expression/activity contributes to neurological injury/disease 5056. For example, inhibition of NOS-2 activity 57 or genetic deletion of NOS-2 in mice subjected to a middle cerebral artery occlusion 53 have reduced infarct volumes compared to wildtype control. Further, transgenic mice modeling Alzheimer’s disease (i.e., hAPP-hPS1-double transgenic mice) were found to have reduced Alzheimer’s disease-associated pathology when crossed with mice lacking NOS-2 58. These mice exhibited reduced amyloid beta plaque formation, attenuated gliosis and notably had an increased lifespan compared to that bred with NOS-2+/+ mice 58. Other evidence, however, suggests that NOS-2 induction may be beneficial in certain instances 59 60 61, 62 including expression of astrocyte-specific NOS-2 61, 62. In this regard it is interesting that although one study found NOS-2 to contribute to Alzheimer’s pathology in hAPP-hPS1-double transgenic mice 58, different results were obtained when using a different transgenic mouse model of Alzheimer’s disease [the Swedish familial double mutation APP (i.e., APPsw)]. When APPsw mice were crossed onto a NOS2−/− background, the offspring exhibited increased Alzheimer’s disease-associated pathology including hyperphosphorylation of tau, increased levels of insoluble beta-amyloid along with an increase in neuronal degeneration compared to APPsw mice on a NOS+/+ background 63. These observations suggest that NOS-2 may have positive and negative consequences in Alzheimer’s disease depending on the nature of the pathological etiologies.

While the specific molecular mechanisms underlying the outcomes of NOS-2 induction in vivo remain largely elusive, several mechanisms have been established in vitro. It has been well-documented in a host of cells throughout the body that NOS-2-derived NO can contribute to cell death through the depletion of cellular energy sources by causing DNA strand breaks and via inhibiting mitochondrial respiration, among other mechanisms 64, 65. Given the close apposition of astrocytes to the neuronal synapse, one putative role for an astrocyte-mediated effect of NOS-2-derived NO is in the modulation of neuronal glutamate activity. In support, astrocyte-specific NOS-2-derived NO has been shown to enhance NMDA-dependent neuronal cell death through synaptic glutamate-release 46, 66, 67. However, at higher concentrations of NO, astrocytic NOS-2-derived NO may play a role in preventing excitotoxic cell death. In support, in astrocyte neuronal co-cultures addition of NO donors that released high concentrations of NO resulted in protection of NMDA-dependent excitotoxicity, an effect that was paralleled by a concentration-dependent reduction in NMDA channel activity 61, 62. Given the intimate association of astrocyte endfeet with the vasculature and the known role of NO as a potent vasodialator 68, astrocytic NOS-2-derived NO might be instrumental in increasing blood flow in times of need, for example, by increasing oxygen extraction and in providing the proper energy sources needed during cellular repair. Overall, evidence suggests that astrocyte-specific NOS-2 may be an important target for designing therapies for neurological diseases/disorders. Since NOS-2 can also be induced in microglia, it is critical that studies continue to elucidate the cell-type-specific regulation of NOS-2.

Cu/Zn superoxide dismutase (SOD)

Mutations in Cu/Zn2 superoxide dismutase (SOD) are the primary cause of familial ALS. Although, the precise mechanisms contributing to the disease are still unclear, numerous mechanisms, including oxidative stress and excitotoxicity, are thought to contribute to this disease 69, 70. A large body of evidence suggests that astrocytes play an important role in the disease process. In a mouse model of ALS, reduced expression of dominantly inherited mutant SOD (G37R mutation) selectively in astrocytes of the brain through Cre-lox technology resulted in delayed microglial activation and slowed late disease progression resulting in increased lifespan 71. Notably, this implicated a sole molecule in astrocytes as mediating non-cell-autonomous neuropathology. Although the mechanisms as to how the decrease in astrocyte mutant SOD affects microglial reactivity and increases the survival of these mice is unknown, a robust reduction in astrocyte glutamate transporter GLT-1 expression was evident in both the motor cortex and spinal cord of ALS patients 72 as well as in transgenic SOD-1 mutant mouse models 73. Thus, devising therapies aimed at targeting mutant SOD in astrocytes may hold therapeutic promise for patients with inherited ALS. Along these lines, a transplantation-based replacement of astrocytes is reported to be neuroprotective in a mutant SOD1 transgenic mouse model of ALS 74. Overall, these studies highlight the potential benefits that targeting astrocytes for therapeutic purposes, especially in ALS, may provide.


The therapeutic potential, as well as preventative potential, of non-steroidal antiinflammatory inhibitory drugs (NSAIDS) in neurological diseases/disorders has been reviewed in great detail 75. NSAIDS act to inhibit cyclooxygenases 1 and 2 (COX-1 and COX-2), enzymes that have various critical functions, through prostaglandin production, in regulating blood flow as well as inflammatory pathways. However, NSAIDS are now known to have alternate targets including NFκB, AP-1 and NOS among others (for review see 75, 76). Treatment with NSAIDS in mouse models leads to diminished reactive astrogliosis as evidenced following administration of ibuprofen in a transgenic model of Alzheimer’s disease (APPV717I) 77 and celecoxib in a transgenic model of ALS 78, but it is not clear if these are direct effects on astrocytes or indirect effects on other mechanisms that may in turn be responsible for astrocyte reactivity. In vitro studies have demonstrated that the NSAID Aspirin abrogates both NFκB activity and the upregulation GFAP induced by hypoxia in a human astroglial cell line 79. Whether any of the beneficial effects of NSAIDs in vivo work directly through astrocytes, however, remains unclear and requires further investigation.


Astrocytes are the predominant source of glutathione (GSH) in the CNS 80 and astrocyte-derived GSH plays important roles in protecting neurons from oxidative stress 14, 15. Astrocyte GSH levels are influenced by cytokine signaling pathways associated with regulating specific aspects of astrogliosis, for example disruption of STAT3 signaling in astrocytes markedly attenuates GSH levels and increases oxidative stress 18. S-nitrosoglutathione (GSNO) has been identified as a molecule produced by enteric astroglia that has mucosal barrier inducing functions 81, 82. The roles of astroglial-derived GSNO in the CNS have not yet been adequately explored. Modulating GSH production by reactive astrocytes is an interesting potential target for neuronal protection from oxidative stress in both acute and chronic CNS disorders 9, 10.

C. Cytokine and growth factor signaling

Astrocytes can both secrete and respond to a number of important cytokines affecting the cellular state of both surrounding cells such as microglia and neurons as well as astrocytes themselves. For example, cytokines such as interleuking-1β (IL-1β), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) can act to up- or down-regulate other pro- and anti-inflammatory genes including nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) 45, 8387. Astrocytes also play a important role in the secretion of trophic factors such as glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and basic fibroblast growth factor (bFGF). Through the secretion of various growth factors, astrocytes can promote neuronal and oligodendrocyte survival 8892 as well as promote myelination in mature oligodendrocytes 93. Thus, targeting the astrocyte in a way to promote growth factor release or modulate cytokine release (up or down) is very much an important area of study. In this section, we will focus on some of the better characterized signaling pathways with respect to astrocytes and neurological disease/disorder.

Transforming growth factor-β1 (TGF-β1) and SMAD3 Signaling

Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine normally expressed at low to undetectable levels in the brain, but is strongly upregulated under neuropathological conditions in a plethora of neurological diseases/disorders 94110. TGF-β1 signals by binding to TGFβRII which then heterodimerizes and transphosphorylates the TGFβ signaling receptor TGFβRI, either activin-like kinase 5 or 1 (ALK5, ALK1), initiating an intracellular serine/threonine kinase signaling cascade 111. Whereas ALK1 phosphorylates SMAD1/5/8, ALK5 phosphorylates SMAD2/3, each resulting in nuclear translocation of distinct signaling complexes producing disparate changes in gene expression 111.

The effects of TGF-β1 in the brain are widespread and appear to be context-dependent with respect to the disease/disorder examined. Extensive literature has clearly demonstrated a neuroprotective role of TGF-β1 in a variety of in vivo (i.e., MCAO) and in vitro (i.e., excitotoxic) models of cerebral ischemia 112117. Other studies, however, show a proinflammatory and neuropathological role for TGF-β1, which has been especially well-documented in the case of Alzheimer’s disease in both in vivo and in vitro rodent models 118124.

Whether any of the roles of TGF-β1 in neuroprotection or neuropathology rely on TGF-β1 signaling through astrocytes remains elusive. However, TGF-β1 is known to have several effects on astrocytes including effects on gene expression such as the upregulation of amyloid precursor protein (APP) 121, 123, 125, the modulation of the astrocyte response to pro-inflammatory mediators 45, 83, and the regulation of astrogliosis via increasing GFAP expression, eliciting hypertrophy and facilitating glial scar formation through the upregulation of extracellular matrix (ECM) molecules (i.e., CSPGs, fibronectin, laminin). Consistent with the effects of TGF-β1 on ECM formation, mice that lack Smad3, the downstream effector of TGF-β1 signaling through ALK5, exhibit a faster rate of wound closure after stab injury to the brain compared to control mice 126.

Since all brain parenchymal cells are capable of secreting 127 and responding 108, 128130 to TGF-β1, it is interesting to note that neurons and endothelial cells are known to signal through both the ALK1 and ALK5 TGFβRI receptors 131, 132. However, to date, astrocytes and microglia are only known to express and signal through the ALK5 TGFβRI 133, 134. This difference in expression alone could prove to be fortuitous, but, in addition, microglia and astrocytes have, at least in part, divergent responses to the cytokine. For example, when NOS-2 is induced in cultured astrocytes upon pro-inflammatory stimulation, expression of NOS-2 and its resultant NO production are attenuated in microglia but contrastingly enhanced in astrocytes by TGF-β1 48, 83. Although progress has been made in understanding the differential cell-type response to TGF-β1 in the brain, future elucidation of regulatory molecules in this pathway should prove to be fruitful.

NFκB signaling

The transcriptional induction of various inflammatory mediators such as IL-6 135 and NOS-2 requires that the transcription factor NFκB is activated, translocated into the nucleus and bound to its cognate NFκB consensus element. NFκB can be activated by several proinflammatory mediators including lipopolysaccharide (LPS), TNFα and IL-1β. The classical endogenous activator, IL-1β, is a cytokine that has been implicated in the pathogenesis of numerous neurological disorders/diseases/injuries [for review see 136]. For review of the global IL-1β-mediated changes in astrocytes and the IL-1β specific signaling cascades in astrocytes, please see 137. Since NFκB is not specific to astrocytes, identification of astrocyte-specific regulation is warranted. Inhibition of NFκB selectively in astrocytes is reported to ameliorate inflammation and improve the rate of recovery after spinal cord injury 138. Evidence suggests that chromatin remodeling may play a critical role in determining whether NFκB binds to a particular promoter in a given cell type 139143. Given the cell-type specific nature of epigenetic signatures, elucidation of the epigenetic modifications present in astrocytes will be important in understanding the transcriptional regulation of NFκB-dependent genes in astrocytes.

IL-6 and STAT3 signaling

IL-6 is a cytokine that can be produced by both glia and neurons of the CNS and can be induced by inflammatory mediators including IL-1β, TNFa and LPS 144. IL-6 signals through the gp130 receptor, which elicits activation of the JAK/Stat pathway and elicits changes in gene expression mainly through the activation of STAT3 145. IL-6 signaling through STAT3 is a known trigger of reactive astrogliosis 7. The role of IL-6 can be beneficial or detrimental depending on the rodent model (e.g., IL-6 over-expresser or IL-6 conditional over-expresser) utilized and disease model studied 146150.

With regard to astrocytes, STAT3 is an early trigger of astrogliosis 151. Indeed, in a mouse model of MPTP-induced striatal degeneration, gp130-related cytokines (i.e., IL-6, CNTF) were upregulated prior to STAT3 activation in astrocytes [i.e., phosphorylated STAT3 (pSTAT3)] and nuclear translocation, events that preceded the upregulation of GFAP mRNA and protein expression 151. Given that the Gfap promoter has STAT3 consensus binding sites known to be required for proper induction of GFAP 152, 153, the notion of IL-6 signaling through STAT3 as a trigger of astrogliosis, which is hallmarked by an upregulation in GFAP expression, is not surprising. However, not only is STAT3 a trigger of astrogliosis, but it seems to be required for proper astrogliosis to occur, at least in the case of spinal cord injury 154. More specifically, astrocyte-specific Stat3 conditional knockout mice have attenuated GFAP expression, diminished astrocyte hypertrophy and a lack of proper glial scar formation compared to Stat3+/+ mice. This genetic deletion of Stat3 selectively in astrocytes also resulted in cell non-autonomous effects including increased microgliosis and inflammatory cell infiltrate which corresponded to an increase in lesion size following spinal cord injury and resulted in a diminution in motor function recovery 154.

A recently published study found that the triptolide, an active ingredient in the traditional Chinese herb Tripterygium wilfordii Hook F, was found to reduce astrogliosis in vitro and in vivo 155. In both cases, in an astrocyte culture scratch injury model and after spinal cord injury in rat, pSTAT3 levels were reduced in parallel with a decrease in GFAP immunoreactivity. In culture, a decreased number of proliferative cells were present whereas in vivo a marked reduction in glial scar formation as assessed 4 wks post-injury was observed. In addition, animals treated with triptolide have improved locomotion function as compared to control spinal cord injured mice 155 However, given that triptolide can affect other cells in an anti-inflammatory fashion including microglia 156, whether the in vivo phenotype of diminished astrogliosis is directly or indirectly mediated by the herb remains unknown. Overall, further study of IL-6 and STAT3 signaling pathways should prove beneficial in the long-term.

Other cytokines and growth factors

Astrocytes can express receptors and respond to a large variety of other growth factors and cytokines, including, but by no means limited to TNFα, EGF, FGF, endothelins and various interleukins (for reviews see 7, 157). These factors can induce the expression of molecules associated with reactive astrogliosis, such as GFAP, or have been implicated in astrocyte proliferation 158, 159. Space constraints limit their detailed consideration here, but some of these factors may come to represent interesting potential therapeutic targets.

E. Nucleotides & their receptors

In addition to their many essential intracellular functions, the nucleotides ATP, ADP and adenosine have functions as extracellular signaling molecules that act through specific plasma membrane receptors, the purinoreceptors P2X and P2Y and the adenosine receptor (A), all of which have multiple family members 160. ATP signaling triggers elevations in cytosolic calcium in astrocytes 44, 161, 162 and leads to gene expression changes associated with reactive astrogliosis after trauma-induced cell injury in vitro 163165. The molecular pharmacology of P2X, P2Y and adenosine receptors provides a number of inhibitors and activators, and some of these are being studied for effects on reactive astrogliosis and CNS injury and repair after traumatic injuries such as spinal cord injury 166, 167. This is a promising area for future exploration.

F. Epigenetic regulators

Epigenetic regulation of gene expression and its role in neurological disease/disorders is a growing field of potential therapeutic importance. See 168 for a thorough and recent review of the epigenetic regulation in relation to neurological diseases/disorders. Two putative targets of regulation have been widely studied in recent years, namely histone deacetylases (HDACs) and histone acetyltransferases (HATs). HATs and HDACs have opposing roles in the acetylation and deacetylation of histones, a dynamic process that can robustly and globally affect gene expression patterns in a cell. HATs and HDACs not only affect histone acetylation patterns, but can modulate transcription factors through acetylation. Moreover, the patterns of genes affected by this process are varied between cell type and are context-dependent. Thus, modulation of HAT and HDAC function through pharmacological manipulation could broadly influence astrocyte responses to other signaling molecules and could powerfully modulate astrocyte functions in health and disease.

HDAC inhibitors

Pharmacological inhibition of HDACs results in an increase in histone acetylation as well as decreased neuropathology and neurological deficits in a variety of animal models of neurological diseases/disorders including experimental autoimmune encephalomyelitis (EAE) 169 and ischemia 170172. Although the exact cellular and molecular targets underlying such beneficial effects of HDACis remain unknown, in vivo and in vitro evidence suggests that astrocytes may be important targets 173. Astrocytes express various HDACs and treatment of rodent astrocytes in vitro with HDACi including valproic acid and TSA results in global and specific histone residue hyperacetylation 174 and thus changes in gene expression profiles. In astrocytes, several genes have already been shown to be affected by various HDACis including the reduction in levels of various pro-inflammatory-related genes 175, the upregulation of the glutamate transporter GLT-1 176, 177 and the enhancement of growth factor secretion (i.e., GDNF and BDNF) 173. Currently, the HDAC inhibitor, valproic acid is currently used in treating epilepsy 178 and is also being tested for cancer 179. For further review on the potential of HDACs as therapies in neurological disease/disorders please see 180, 181.

The HAT inhibitor curcumin

Curcumin, a major curcumanoid in the spice turmeric, is an inhibitor of the histone acetyltransferase (HAT) p300 182, 183 and is currently being investigated in rodent models of neurological disease as a prospective future therapeutic option. The effects of curcumin have been generally described as having anti-inflammatory and anti-oxidant properties. Consistent with that, evidence suggests that curcumin reduces the clinical severity and/or improves neurological function of several neurological diseases/disorders and injuries including experimental allergic encephalomyelitis (EAE) 184 and traumatic brain injury (TBI) 185 in mice and spinal cord injury in rat 186. Pathologically, curcumin-treated animals subjected to contusional brain injury exhibit reduced edema correlating with a reduction in IL-1β and AQP4 levels compared to control 185. Although it is unclear what underlies the beneficial effect of curcumin in these instances, it is clear that curcumin affects astrocytes. In mouse models of EAE 184, spinal cord injury 186 and traumatic brain injury 185, curcumin-treated animals display reduced astrogliosis as evidenced by an attenuation in the upregulation of GFAP expression, an effect that appears to be cell autonomous as curcumin also reduces GFAP expression in purified astrocyte cultures 186. Treatment of mouse cortical astrocytes with curcumin in vitro also reduces the IL-1β-mediated activation of the classical inflammatory mediator NFκB 185. Future studies delineating the roles of curcumin under neuropathological conditions and the regulation of signaling pathways and gene expression profiles in astrocytes should be worthwhile.

G. Other astrocyte specific molecules/regulators

Aquaporin 4

Aquaporin 4 (AQP4) is a water channel responsible for bi-directionally transporting water to and from the blood and the brain, and is normally localized on astrocyte endfeet. The expression levels and localization of AQP4 in astrocytes are subject to much regulation. During inflammatory conditions, for example, AQP4 is subject to upregulation by cytokines such as 1L-1β185. Dysregulation of AQP4 expression or function can lead to brain edema 187, 188. Mice lacking Aqp4 exhibit decreased brain edema that corresponds to a decrease in astrocyte endfeet swelling following cerebral ischemia or acute water intoxication 187. AQP4 expression is elevated in animal models of hydrocephalus, an effect that seems productive, as edema clearance as well as survival is decreased in mice that lack Aqp4 189. Given the large number of known regulators for AQP4, including AVP, which can activate AQP4-mediated radial water transport across the astrocyte syncytium 190, it will be important to continue to study the regulation of AQP4 and test whether manipulation of this channel proves useful in the treatment of various diseases involving brain edema. For review of AQP4 function in astrocytes in more detail, please see 191, 192

It is also important to note that AQP4 is now established as the target antigen in the CNS autoimmune demyelinating inflammatory disorder, neuromyelitis optic (NMO) 193, 194. Neuropathological evaluations in NMO are consistent with a mechanism whereby autoimmune destruction of astrocytes triggered by binding of AQP4 autoantibodies leads to inflammatory cell invasion and destruction of neural parenchyma 195197. These neuropathological findings are in line with and are supported by a large body of work in experimental animals showing that astrocytes are essential regulators that restrict inflammatory cell infiltration into CNS parechyma and protect neural tissue during both innate and adaptive immune inflammation 7, 13, 23, 197, 198. Interventions that reduce autoimmune recognition of AQP4 and consequent astrocyte dysfunction and damage represent important therapeutic targets.

Connexin gap junctions

Astrocytes are highly connected to one another by homologous connexin (Cx) 43 gap junctional coupling, forming what is known as the glial syncytium, in which inter-glial communication (e.g., Ca2+ waves) can occur 199202. This glial network afforded by Cx43 gap junctions is important not only in supporting neuronal activity by sustaining proper energy sources, but also in orchestrating the activity of neuronal network through the release of gliotransmitters such as L-glutamate in an apposing glial syncytium 203. Under neuropathological conditions, changes in Cx43 expression and/or in cellular localization shift and glial communication through the syncytium is stunted 204. This change in astrocyte coupling can be beneficial or detrimental, an effect that is likely disease- and context-dependent. Nevertheless, astrocyte Cx43 will likely be a good target to consider modulating for ameliorating the neuropathology in specific instances/contexts of neurological diseases/disorders. For a extensive review on this subject matter, please see 203, 205.

Potassium channels

The role of astrocyte inwardly rectifying K+ channels (Kir channels) with regard to brain function has been nicely and thoroughly reviewed 206. In brief, Kir channels are localized to astrocyte endfeet and are responsible for maintaining the resting membrane potential of astrocytes and needed for proper K+ buffering 206. Given the fact that the predominant astrocyte Kir channel Kir4.1 is highly regulated, and that its expression and/or activity decreases upon injury/inflammation/disease, it would seem reasonable to attempt to enhance its activity or expression as a potential therapeutic target.

Arundic Acid

While the precise molecular target(s) of arundic acid (i.e., ONO-2506) remain elusive, it is reported to target changes in astrocyte gene expression while also ameliorating several neurological diseases/disorders in rodent models. Notably, in vitro, the neuroprotective effect of arundic acid on neurons in culture required the presence of astrocytes. In vivo, astrogliosis as measured via GFAP immunoreactivity is reduced by arundic acid in a mouse model of Alzheimer’s disease (APPsw transgenic mice) 207 as well as in mice subjected to MPTP- mediated neurotoxicity 208. Notably, treatment with arundic acid resulted in amelioration of the pathology associated with the aforementioned mouse models 207, 208 and in mice subjected to a permanent focal ischemia 209. Although the mechanism(s) for these beneficial effects remain unknown, studies have speculated that they may involve astrocyte-specific functions including modulation of glutamate transporter (increased) and S100B (decreased) expression. Altogether, more studies will be necessary to fully elucidate whether this compound does target astrocytes and, if so, what molecular mechanisms might be involved.

IV Cell delivery

It deserves brief mention that transplantation strategies involving astrocytes are also under investigation. For example, grafts of stem or progenitor cells that mature into healthy astrocytes cells are reported to improve outcome in a mouse model of ALS in which host astrocytes are abnormal and express a mutant SOD 210. A different strategy employs grafts of astrocytes that are genetically modified to produce specific molecules, such as growth factors, as therapeutic pumps to deliver those molecules in specific locations 211, 212. Such grafts of genetically modified astrocytes may be able to provide long term locally restricted delivery of therapeutic molecules via cells that integrate into the neural parenchyma both structurally and functionally.

V Concluding remarks

Reactive astrogliosis is emerging as a complex and multifaceted process that can range from subtle and reversible alterations in gene expression and morphology to the pronounced and long-lasting changes associated with scar formation. The responses of reactive astrocytes to CNS insults are controlled in a context-dependent manner by specific signaling mechanisms that mediate numerous essential beneficial functions, but under certain circumstances can lead to harmful effects. The simplistic but widely held notions that reactive astrogliosis and scar formation are maladaptive responses and that complete blockade of reactive astrogliosis per se will be beneficial, are no longer tenable. Big-picture functions of reactive astrogliosis and scar formation include protecting neural cells, tissue and function, and restricting the spread of inflammation and infection. Dysfunctions of reactive astrogliosis and scar formation have the potential to contribute to, or be primary causes of, CNS disease mechanisms either through loss of normal functions or through gain of detrimental effects. Accordingly, therapeutic strategies will need to be directed at specific aspects of reactive astrogliosis and specific molecular mechanisms that may be augmented or attenuated for specific purposes. In this regard, it will be important to elucidate the many potential biological functions of specific molecules, including potential cross-talk between different cellular signaling and other pathways. Even well-thought out therapeutic targets could have unexpected ill-effects, highlighting the need to further unravel the basic science underlying potential therapeutic targets.


The authors’ work is supported by NIH NINDS NS057624 (M.V.S.), NIH T32-MH19925 to M.E.H. through the Cousins Center for Psychoneuroimmunology at UCLA, the Wing’s for Life Charitable Foundation (M.V.S.), and the National Multiple Sclerosis Society (M.V.S.).


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