Astrocytic β2-adrenergic receptors: From physiology to pathology

Progress in Neurobiology 91 (2010) 189–199

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Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Astrocytic b2-adrenergic receptors: From physiology to pathology Guy Laureys b,1, Ralph Clinckers b,1, Sarah Gerlo d, Anneleen Spooren d, Nadine Wilczak c, Ron Kooijman b, Ilse Smolders b, Yvette Michotte b, Jacques De Keyser a,c,* a

Department of Neurology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Belgium c Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands d Department of Physiology, Gent University, Gent, Belgium b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 August 2009 Received in revised form 7 December 2009 Accepted 27 January 2010

Evidence accumulates for a key role of the b2-adrenergic receptors in the many homeostatic and neuroprotective functions of astrocytes, including glycogen metabolism, regulation of immune responses, release of neurotrophic factors, and the astrogliosis that occurs in response to neuronal injury. A dysregulation of the astrocytic b2-adrenergic-pathway is suspected to contribute to the physiopathology of a number of prevalent and devastating neurological conditions such as multiple sclerosis, Alzheimer’s disease, human immunodeficiency virus encephalitis, stroke and hepatic encephalopathy. In this review we focus on the physiological functions of astrocytic b2-adrenergic receptors, and their possible impact in disease states. ß 2010 Elsevier Ltd. All rights reserved.

Keywords: Astrocytes Beta-adrenergic receptors Alzheimer Stroke Multiple sclerosis Hepatic encephalopathy HIV encephalitis

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiological functions of astrocytic b2-adrenergic receptors . . . . . 2.1. Regulation of immune-inflammatory responses . . . . . . . . . . 2.1.1. Modulation of transcription factor-activity . . . . . . 2.1.2. Regulating expression of inflammatory molecules. 2.2. Glycogen synthesis and breakdown . . . . . . . . . . . . . . . . . . . . 2.3. Trophic support and neuroprotection . . . . . . . . . . . . . . . . . . 2.4. Astrocyte proliferation, maturation and differentiation . . . . Astrocytic b-adrenergic receptors in neurological disorders . . . . . . 3.1. Multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. HIV-encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Hepatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AP-1, activator protein-1; APP, amyloid precursor protein; APC’s, antigen presenting cells; BDNF, brain-derived neurotrophic factor; C5aR, C5a-receptor; CREB, cAMP-responsive element binding protein; CDV, canine distemper-virus; C/EBP, CCAAT/enhancer binding protein; CNS, central nervous system; CSF, cerebrospinal fluid; MCP-1, chemokine monocyte chemoattractant protein-1; C5L2, complement 5a-like receptor; cAMP, cyclic adenosine-50 -30 -monophosphate; Epac, exchange protein activated by cAMP; EAE, experimental autoimmune encephalomyelitis; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL, interleukin; IFN-g, interferon-g; GPCR, G protein-coupled receptor; iNOS, inducible nitric oxide synthase; ICAM-1, intercellular adhesion molecule-1; LPS, lipolysaccharide; LC, locus coeruleus; MHC-II, major histocompatibility complex class II molecules; MMP’s, matrix metalloproteinases; MS, multiple sclerosis; NGF, nerve growth factor; NE, norepinephrine; NAWM, normal appearing white matter; NFkB, nuclear factor-kappa B; PPAR-g, peroxisome proliferator-activated receptor gamma; PKA, proteine kinase A; SUMO, small ubiquitin like modifier; TNF-a, tumor necrosis factor-a; VCAM-1, vascular cell adhesion molecule-1; VIP, vaso-intestinal peptide. * Corresponding author at: Department of Neurology, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel.: +32 (02) 477 60 12. E-mail address: [email protected] (J. De Keyser). 1 Both authors contributed equally to this work. 0301-0082/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2010.01.011

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Astrocytes, once regarded as silent elements lacking transmitter receptors and expressing a limited set of ion channels, have emerged as sophisticated cells playing crucial roles in a large and diverse variety of functions critical for normal brain development, adult physiology and pathology (De Keyser et al., 2008a; Nimmerjahn, 2009; Volterra and Meldolesi, 2005). Astrocytes express almost the same repertoire of receptors as neurons, although to a variable extent depending on the cell type and in anticipation of their surrounding microenvironment (Deschepper, 1998; Kimelberg, 1995; Porter and McCarthy, 1997). They contain receptors for neurotransmitters, peptides, hormones and cytokines, which regulate their functional activities. Astrocytes dynamically regulate synaptic transmission via an intriguing bidirectional communication with neurons. In response to neurotransmitters present in the synaptic cleft, astrocytes can release neuroactive substances (gliotransmitters) that can feed back onto synaptic terminals or directly stimulate postsynaptic receptors (Newman, 2003). Astrocytes are the main cellular target of norepinephrine (NE) terminals in the brain (Cohen et al., 1997). Therefore NE is considered as one of the main players in the neuronal control of glial activation (Carnevale et al., 2007). In the present review we focus on the role of astrocytic b2-adrenergic receptors in function and dysfunction of astrocytes. Immunohistochemical and radioligand binding studies have shown that astrocytes in both animal and human gray and white matter express b-adrenergic receptors (Liu et al., 1992; Mantyh et al., 1995; Salm and McCarthy, 1992; Shao and Sutin, 1992; Zeinstra et al., 2000). b2-adrenergic receptors are proportionally more expressed than b1-adrenergic receptors on astrocytes from gray matter of different rat brain regions, whereas human and rodent white matter astrocytes only express b2adrenergic receptors (Aoki, 1992; Sutin and Shao, 1992). Aoki (1992) demonstrated that astrocytic b2 receptors are present near adrenergic nerve terminals, which arise form neurons originating in the locus coeruleus (LC) (Aston-Jones et al., 1992; Cohen et al., 1997; Paspalas and Papadopoulos, 1996). b-adrenoreceptors are Gsprotein coupled receptors that stimulate adenylyl cyclase, leading to an increase in the formation of cyclic adenosine-50 -30 -monophosphate (cAMP), an activator of proteine kinase A (PKA). More recently it was shown that both b1 and b2 receptors, in addition to PKA, can also activate the exchange protein activated by cAMP (Epac), resulting in Rap1 activation (Ouyang et al., 2008; Rangarajan et al., 2003). Interestingly, this latter pathway was shown to be implicated in memory-retrieval. Whether the Epac signalling cascade is activated downstream to b-adrenergic receptors in astrocytes remains to be established. In addition to the conventional synaptic structures, NE-ergic terminals show atypical varicosities that are thought to release NE extra-synaptically (Carnevale et al., 2007). In situ astrocytic b2-adrenergic receptor immunoreactivity has been detected apposed to glutamatergic synapses where it influences glutamatergic transmission (Aoki, 1992; Hansson and Ronnback, 1992). It is important to note that in situ astrocytic badrenergic receptor expression may differ significantly from in vivo conditions as astrocytes increase their expression levels in the absence of neuronal activity (Aoki et al., 1994), once again showing that the expression level of astrocytic receptors is highly tuned by the environment. In a first section we review the available literature on the protective and supportive roles of astrocytic b2-adrenergic

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receptors. In recent years a vast body of evidence has put forward the hypothesis that astrocyte dysfunction or impairment may play a key role in the pathogenesis of various neurological diseases (De Keyser et al., 2008a; Seifert et al., 2006). For most conditions it remains unclear whether the astrocytic changes are causative of the disease or merely represent an accompanying phenomenon. In the second section of this review we will focus on the possible role of astrocytic b2-adrenergic signalling in multiple sclerosis, Alzheimer’s disease, HIV-encephalitis, hepatic encephalopathy, and stroke. 2. Physiological functions of astrocytic b2-adrenergic receptors 2.1. Regulation of immune-inflammatory responses Astrocytes have a complex dual role in the regulation of cerebral innate immune reactivity (for review see: Farina et al., 2007). In response to activation of pattern-recognition receptors, astrocytes release different mediators that activate both inflammatory and immunosuppressive pathways that are fundamental for controlled reactions to central nervous system (CNS) injury. Dysregulation of this delicate balance is considered to result into pathogenic chronic neuroinflammation and neurodegeneration. Stimulation of astrocytic b2-adrenergic receptors controls brain inflammatory processes by modulation of the transcription of proinflammatory and neuroprotective genes in astrocytes, resulting in altered expression of inflammatory and neuroprotective regulators (see Fig. 1 for overview). 2.1.1. Modulation of transcription factor-activity The underlying mechanism of NE-induced immune regulation seems to be a shift away from the ‘pro-inflammatory’ nuclear factor-kappa B (NFkB)-dependent pathway towards the ‘antiinflammatory’ peroxisome proliferator-activated receptor gamma (PPARg)-pathway. In astrocytes, NFkB-activation induces apoptosis (Takuma et al., 2004), cell proliferation and differentiation (Denis-Donini et al.,

Fig. 1. Anti-inflammatory and neuroprotective effects of astrocytic beta-adrenergic receptors: activation of b-adrenergic receptors shifts transcription factor activity from NF-kB to PPAR-g (1), initiating anti-inflammatory effects: downregulation of cytokine (2), MHC-II/B7-1 and 2 (3), adhesion molecule (4) and iNOS expression (5), whilst neuroprotective factors are upregulated (6).

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2005), and the expression of inducible type nitric oxide synthase (iNOS) and a variety of cytokines and chemokines (Nomura, 2001). The NFkB pathway in astrocytes has been demonstrated to play a key role in the capacities of astrocytes to regulate neuroinflammation. Brambilla et al. (2005) demonstrated that transgenic mice, in which the astrocytic NFkB pathway was selectively inactivated, showed improved functional recovery and reduced lesion volume after spinal cord injury. Similarly, blockade of the same pathway in neuroectodermal cells of the CNS decreased proinflammatory gene expression during experimental autoimmune encephalomyelitis (EAE) and clinical–pathological amelioration (van Loo et al., 2006). NFkB is regulated by several distinct signaling pathways and by multiple ligands and heterologous cell–cell interactions (Fraser, 2008). G protein-coupled receptor (GPCR) agonists that enhance intracellular cAMP levels and activate PKA have been demonstrated to inhibit NFkB function in peripheral immune cells (Delgado and Ganea, 2001; Fraser, 2008; Ollivier et al., 1996; Serezani et al., 2008; Takahashi et al., 2002). In contrast, some reports describe a stimulatory effect of PKA activation on NFkB function (Gao et al., 2008; Zhong et al., 1997). NFkB is sequestered in an inactive form in the cytoplasm by its natural inhibitor, IkB-a. IkB-a phosphorylation and degradation induces the nuclear translocation of NFkB and the binding of the protein to specific responding elements in the promoter regions of inflammatory genes (Baeuerle and Baltimore, 1988). A study by Farmer and Pugin (2000) showed that b-adrenergic receptor agonists inhibit tumor necrosis factora (TNF-a) and interleukin-8 (IL-8) production in human acute monocytic leukemia cells (THP-1 cells) predominantly via the b2adrenergic receptor. The addition of the non-selective b-adrenergic agonist isoproterenol inhibited the lipopolysaccharide (LPS)induced activation of NFkB and increased cytosolic IkB-a levels and half-life. A noradrenergic control of IkB-a levels was confirmed in vivo as depletion of central NE levels by lesioning of the LC was found to reduce IkB-a levels in the frontal cortex of rats (Gavrilyuk et al., 2002). These findings suggest that the antiinflammatory effects of NE are, at least in part, mediated by inhibition of NFkB. The complete signal transduction cascade mediating these anti-inflammatory effects awaits further elucidation. Another key mechanism of NE-mediated anti-inflammation is the positive regulation of PPARg. PPARg belongs to a group of nuclear hormone receptors mediating anti-inflammatory actions of non-steroidal anti-inflammatory drugs and thiazolidinediones (Desvergne and Wahli, 1999; Szanto and Nagy, 2008; Wahli et al., 1995). The activation of PPARg reduces the expression of proinflammatory cytokines and iNOS in macrophages (Combs et al., 2000; Ricote et al., 1998), monocytes (Jiang et al., 1998), microglial cells (Bernardo et al., 2000), and neurons (Heneka et al., 2000), suggesting a role of PPARg in inflammatory events. Incubation of astrocytes and neurons with NE resulted in an increase of PPARg mRNA and protein levels in both cell types. These effects were blocked by the non-selective b-adrenergic antagonist propranolol, but not by the a-adrenergic antagonist phentolamine, showing that b-adrenergic receptors are driving the noradrenergic effect on PPARg expression (Klotz et al., 2003). This group of transcription factors is also under the control of intracellular cAMP (Klotz et al., 2003; Michael et al., 1997). Additionally, PKA represents a potential key position in the signal transduction cascade initiated by NE that eventually leads to PPARg activation (Lazennec et al., 2000). PKA mediates the phosphorylation of PPARg in the DNA-binding domain as well as the stabilization of the ligand-activated PPARg to DNA. NE induces the expression of CCAAT/enhancer binding protein beta and delta (C/EBP) family of transcription factors in rat cortical astrocytes (Cardinaux and Magistretti, 1996). This pathway is identified as a key player in the synthesis of glycogen (see Section

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2.2) (Cardinaux and Magistretti, 1996), nerve growth factor (NGF) (Colangelo et al., 1998) and iNOS in astrocytes (Gavrilyuk et al., 2001). The activity of C/EBP family members, like many transcription factors and co-factors, is regulated by the protein Small Ubiquitin like Modifier (SUMO) (Berberich-Siebelt et al., 2006; Eaton and Sealy, 2003; Kim et al., 2002). Akar and Feinstein (2009) showed that SUMO-1 and SUMO related genes are present in astrocytes, and that SUMOylation in astrocytes contributes to the anti-inflammatory effects mediated by NE. It is noteworthy that there is a well documented ‘cross-talk’ between transcription factors (Vlaeminck-Guillem et al., 2003). Cross-coupling of members of the NFkB and members of the C/EBP family has been demonstrated. NFkB functionally synergizes with C/EBP alpha, beta and delta (Stein et al., 1993). This cross-coupling results in the inhibition of promoters with kappa B enhancer motifs and in the synergistic stimulation of promoters with C/EBP binding sites. Additionally, PPAR’s have been shown to negatively regulate the inflammatory gene response by negative cross-talk with transcription factors NFkB and the activator protein 1 (AP-1) (Delerive et al., 1999). 2.1.2. Regulating expression of inflammatory molecules Astrocytes may contribute to the immunocompetence of the CNS via their expression of class II major histocompatibility complex (MHC-II) antigens. In normal conditions astrocytes do not express MHC-II molecules. NE inhibits, in a dose-dependent way, the ability of interferon-gamma (IFN-g) to induce MHC-II expression on astrocytes (Frohman et al., 1988b), via b2adrenergic receptors and cAMP signalling (Frohman et al., 1988a). A reduction in intracellular cAMP levels may transform astrocytes into antigen-presenting cells (APC’s), enabling these cells to initiate immune-mediated responses. This concept is supported by the finding that cAMP-elevating agents, such as isoproterenol, also reduce LPS-and IFN-g-induced astrocytic expression of B7-1 and B7-2 (Menendez Iglesias et al., 1997; Zeinstra et al., 2006), which are important costimulatory molecules for T-cell activation. Cytokines are small secreted (glyco)proteins mediating immunity, inflammation, and haematopoiesis. Substantial evidence indicates that the suppressive effects of NE on the release of inflammatory molecules by astrocytes is mediated by activation of astrocytic b2-adrenergic receptors and intracellular elevation of cAMP (Galea and Feinstein, 1999; Hu et al., 1991; Pahan et al., 1997; Willis and Nisen, 1995; Farmer and Pugin, 2000; Pahan et al., 1997; Szabo et al., 1997). Loss of a noradrenergic input to astrocytes has been put forward as one of the mechanisms underlying their activation and their increased production of cytokines (Frohman et al., 1988b). The prototypical pro-inflammatory cytokines that are NFkBregulated are TNF-a, IL1-b and IL-6. NE blocks the synthesis of TNF-a (Nakamura et al., 1998) and IL-1b (Willis and Nisen, 1995) in astrocytes via b2-adrenergic receptor activation. On the contrary, NE induces both IL-6 mRNA and protein-expression in primary neonatal rat astrocytes through the activation of b2adrenergic receptors (Maimone et al., 1993; Norris and Benveniste, 1993). These studies contradict the finding of Nakamura et al. (1998) who demonstrated that isoproterenol suppressed LPSinduced TNF-a and IL-6 promoter activities, mRNA accumulation, and protein levels in astrocytes. Results from in vivo studies regarding modulation of IL-6 expression by b-adrenergic stimuli are also confusing. In line with Nakamura’s findings is the observation that chemically-induced LC-destruction induces elevated astrocytic IL-6 expression (Heneka et al., 2002). However the fact that propranolol treatment reduces IL1-b-induced IL-6 levels in rat CSF might argue against an anti-inflammatory function of b-adrenergic receptors (Woiciechowsky et al., 2004). However,

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in the latter paper, the origin of the IL-6 detected in CSF was not addressed. Because one of the functions of IL-6 is the promotion of immunoglobulin synthesis, it is thought that IL-6 expression may exacerbate autoimmune disease of the CNS, which is marked by local immunoglobulin production (Norris and Benveniste, 1993). On the other hand, neuroprotective effects of IL-6, such as inhibition of NMDA-mediated excitotoxicity (Wang et al., 2009), protection against hypoxia and chemical induced-seizures by upregulation of adenosine-receptors (Biber et al., 2008), and protection against neuroglial degeneration induced by niacin antagonists (Penkowa et al., 2003) have also been described. A possible explanation is that IL-6 overexpression leads to neurodegeneration in basal conditions, whereas IL-6 overexpression in combination with brain injury exerts protective effects, such as reduction of oxidative stress and cell death (Penkowa et al., 2003). Importantly, IL-6 was recently identified as a key player in the generation of Th17 cells (reviewed in Korn et al., 2009), which have since been shown to play a central role in EAE and multiple sclerosis (MS) (reviewed in Aranami and Yamamura, 2008). Interestingly, IL17 was not only detected in CNS-infiltrating T cells, but also in astrocytes in the active areas of MS lesions in patients (Tzartos et al., 2008). Taken together these data demand for further research on the effect of b-adrenergic receptors on the expression of IL-6 and its putative neurotoxic or neuroprotective effects. Noradrenergic activation of astrocytes also controls the release of iNOS, an important mediator of inflammatory neurodegeneration (Brown, 2007; Feinstein et al., 1993; Feinstein, 1998). Additionally, the uptake L-arginine, which is a precursor of NO, is inhibited by stimulation of b-adrenergic receptors (Feinstein and Rozelman, 1997). Single reports have been published demonstrating that the astrocytic expression of DST11, matrix metalloproteinases (MMP’s) and some adhesion molecules are under noradrenergic control (Ballestas and Benveniste, 1997; Gavrilyuk et al., 2005; Maolood et al., 2008; Sheng et al., 2004). Total gene expression analysis, used to screen rat astrocytederived mRNA expression induced by NE, demonstrated increased expression of DST11 (Gavrilyuk et al., 2005). DST11 is a cDNA clone coding for an isoform of the complement C5a receptor (C5aR) with 56% identity to a human C5aR variant, and hence termed complement 5a-like receptor (C5L2). Neutralisation of DST11 by antisense oligonucleotides induced NFkB reporter gene and iNOS expression, suggesting that NOS and NFkB suppression by NE is, at least partly, mediated by DST11. Both in vivo and in vitro, the biological activity of C5a is enhanced by a targeted deletion of C5L2 in mice. C5L2 thus appears to limit the pro-inflammatory response to the anaphylatoxin C5a (Gerard et al., 2005). Astrocytes synthesize and secrete MMP’s (Muir et al., 2002; Wells et al., 1996), which play a pivotal role in degradation and remodelling of the extracellular matrix (for review see: Shapiro, 1998; Yong et al., 1998). Several studies have focused attention on the potential role of MMP’s in the neuroplasticity and neuropathology of the brain (reviewed by Mun-Bryce and Rosenberg, 1998; Wright and Harding, 2004; Yong et al., 2001). MMP’s, and particularly MMP-9, are implicated in excitotoxic neuronal damage and subsequent neuro-inflammatory processes (Jourquin et al., 2003). MMP-2 and MMP-9 are expressed in neurons and astrocytes of rat hippocampus and mouse supraoptic nucleus (Maolood et al., 2008; Szklarczyk et al., 2002). These enzymes are activated following noradrenergic stimulation of astrocytes (Maolood et al., 2008) and have been demonstrated to contribute to the degradation and clearance of extracellular amyloid-b peptide (Yin et al., 2006) and the modulation of rat hippocampal synaptic plasticity during learning and memory (Nagy et al., 2006). The activation by NE of MMP-9 is mediated via b-adrenoreceptor activation (Lee et al., 2008).

Cell–cell adhesions underpin axon-axon contacts, link neurons with supporting glial cells and oligodendrocytes, regulate cellmigration, determine brain morphology, synapse formation and coordinate highly complex brain functions such as memory and learning (Sakisaka and Takai, 2005). Different cAMP inducers/ mimetics, including NE, do not influence adhesion molecule expression in primary rat astrocytes (Ballestas and Benveniste, 1995, 1997). However, enhancing cAMP levels with the same agents in rat astrocytes suppresses IL-1/b- and TNF-a-induced intercellular adhesion molecule-1 (ICAM-1) and circulating vascular cell adhesion molecule-1 (VCAM-1) expression by this cell type. Taken together, these results suggest that IL-1/b- and TNF-a-induced adhesion molecule expression is antagonized by PKA-mediated signaling pathways. The inhibition of adhesion molecule gene expression in astrocytes by elevating intracellular cAMP levels may either result from an alteration of transcription factors required for cytokine-mediated ICAM-l/VCAM-1 gene expression (i.e., NF-kB, IRF-1, C/EBP, AP-2) or the activation of a repressor of adhesion molecule transcription (Collins et al., 1995; van de Stolpe and van der Saag, 1996). 2.2. Glycogen synthesis and breakdown Because of their tight organization around the microvasculature, astrocytes are ideally poised to provide nurturing environments for neurons (Abbott et al., 2006). Astrocytes express GLUT1 glucose transporters on their endfeet facing blood vessels (for review see Vannucci et al., 1997). It was originally thought that astrocytes take up glucose from the blood, making it available to neurons as predominant energy source to support their function. The past two decades glycogen and lactate (although controversial, see Wang and Bordey, 2008) have emerged as two additional substrates by which astrocytes can regulate neuronal metabolic responses to activity. Fig. 2 illustrates how this metabolic process is influenced by beta-adrenergic stimulation. The brain glycogen resides in astrocytes (Cataldo and Broadwell, 1986; Fillenz et al., 1999; Wender et al., 2000). Astrocytes convert glycogen to lactate, which is released in the extracellular space. Axons take up lactate and metabolize it aerobically to energy. This mechanism not only protects axons against injury during glucose deprivation (Wender et al., 2000), but it also provides axons with energy during physiological conditions

Fig. 2. Astrocytes take up glucose from the blood stream by GLUT-1 transporters expressed on their endfeet (1). b-Adrenergic activation stimulates glycogen synthesis, the major energy reserve in astrocytes (2). At the same time the receptor stimulates lactate production by means of glycogenolysis and stimulation of the glycogen shunt (3). Lactate provides in a major energy source for neurones (4) and their white-matter axons (5).

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(Ransom and Fern, 1997). Brain glycogen may also serve as a major energy reserve for neurons and axons that can be mobilized in response to stressful events such as hypoglycaemia or intense neural activity (Brown and Ransom, 2007; Fillenz et al., 1999). Glycogen is continuously broken down in the CNS, indicating that these local carbohydrate reserves are vital even under steady-state conditions, and CNS activity correlates with an increased turnover of glycogen (Swanson, 1992). The effect of noradrenergic stimulation on astrocytic glycogenolysis was first described by Cummins et al. (1983). In cultured astrocytes they demonstrated that NE and isoproterenol treatment resulted in the conversion of phosphorylase b to phosphorylase a, leading to glycogenolysis. This effect is likely mediated by intracellular cAMP elevations because it can be reproduced by cAMP analogues (Sorg and Magistretti, 1991). It has been demonstrated that stimulation of astrocytic glycogenolysis by NE is mediated by astrocytic b2-adrenergic receptors (Fillenz et al., 1999; Sorg and Magistretti, 1991; Subbarao and Hertz, 1990). Neuropeptides seem to have important modulatory effects on this process (Rougon et al., 1983), including stimulation by somatostatin and substance P and inhibition by enkephalin. Both NE and VIP induce synthesis of glycogen synthetase, leading to increased total glycogen content in astrocytes (Allaman et al., 2000; Sorg and Magistretti, 1992), this effect seems to be mediated by cAMPdependent protein synthesis. It is evident that glycogen metabolism is important also in the presence of glucose (Brown et al., 2003, 2005; Dienel et al., 2007; Swanson et al., 1992). Metabolism of glucose via glycogen, i.e. glycogen shunt activity, has been shown to play a significant role in astrocytic energy metabolism with NE as a modulating factor (Walls et al., 2009). In summary, we can conclude that NE has an important impact on astocytic glycogen metabolism by its complex impact on glycogenolysis, glycogen synthesis and the glycogen shunt activity. 2.3. Trophic support and neuroprotection The neuronal soma, except at synaptic contacts, is entirely covered by astrocytic membranes. This close anatomical relationship suggests a functional significance of membrane apposition between these two cell types, such as to compartmentalize neuroprotective mediators released by astrocytes. Astrocytes produce a large variety of neuroprotective molecules, and an astrocyte–neuron dyad is well established in neuroprotective networks (Fernandez et al., 2007a). Neurotrophins are vital growth factors in survival and maintenance of different neuronal cell-types, adult CNS homeostasis and in the response to brain tissue damage, they are implicated in the pathogenesis of various neurodegenerative diseases (Allen and Dawbarn, 2006; Kernie and Parada, 2000). Brain-derived neurotrophic factor (BDNF) and NGF are two important representatives of this class of molecules. For BDNF, astrocytic expression is under the influence of all three monoamine neurotransmitters: NE, dopamine and serotonin (Juric et al., 2006; Schwartz et al., 1994). The most potent effect, however, seems to be elicited by NE. Stimulation of BDNF expression by NE was also demonstrated in Mu¨ller-cells, the predominant glial cell of the retina (Seki et al., 2005), BDNF and NGF stimulation in astrocytes was demonstrated to be mediated by activation of b2-adrenergic receptors using clenbuterol (Culmsee et al., 1999a,b; Follesa and Mocchetti, 1993). The stimulatory effect on astrocytic NGF was identified as underlying mechanism for the in vitro and in vivo neuroprotective effects of clenbuterol (Culmsee et al., 1999a; Fukumoto et al., 1994; Hayes et al., 1995; Semkova et al., 1996). NGF mediates neuroprotective effects on different cell types, including oligodendrocytes, for review see (Sofroniew et al., 2001).

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The insulin-like growth factors, IGF-1 and IGF-2, the type 1 and type 2 IGF receptors, and the six known IGF binding proteins IGFBPs 1–6, comprise a complex system of peptide hormones, cell surface receptors and circulating factors involved in the regulation of growth, survival and differentiation in a vast number of tissues (Chesik et al., 2007; Firth and Baxter, 2002; Rajaram et al., 1997). In the CNS, IGF-1 is an essential factor for proper development, neuronal differentiation and survival (Anlar et al., 1999; Russo et al., 2005). It exerts neurotrophic and neuroprotective effects, thereby participating in CNS maintenance (Trejo et al., 2004). A major role of IGF-1 on adult astrocytes is the modulation of their response to tissue damage (for review see Fernandez et al., 2007b). Among the many actions reported for IGF-1 on astrocytes, one may distinguish between those primarily affecting astrocyte function per se, such as proliferation (Torres-Aleman et al., 1990), from those that utilize astrocytes as intermediaries in neuroprotective actions of IGF-1 through modification of astrocyte behaviour, such as regulation of glucose or glutamate uptake by astrocytes (Masters et al., 1991; Suzuki et al., 2001). The anti-inflammatory actions of IGF-1 on astrocytes constitute an example of the intermediary role of these cells in the neuroprotective mechanisms of IGF-1. When astrocytes are activated by pro-inflammatory stimuli such as TNFa, they actively contribute to the deleterious inflammatory cascade that damages neighbouring neurons. But in the presence of IGF-1, reactive astrocytes turn into anti-inflammatory cells. Astrocyte-derived pro-inflammatory molecules are no longer produced, and at the same time neuroprotective mediators are released. This IGF-1 controlled mechanism ultimately dictates the outcome of the inflammatory insult (Fernandez et al., 2007b). IGF-1 has the potential to regulate cAMP levels in astrocytes in b2-adrenergic receptors-dependent manner via a thus far unknown route (Chesik et al., 2006, 2008). It has been hypothesized that IGF-1 can catalyze the phosphorylation of b2adrenergic receptors, which results in their desensitisation (Baltensperger et al., 1996; Hadcock et al., 1992; Karoor and Malbon, 1996). Astrocytes produce various other trophic factors under badrenergic control such as fibroblast growth factor (FGF)-1 and -2 (Follesa and Mocchetti, 1993; Riva et al., 1996, 1998), neuregulin (Tokita et al., 2001) and taurine (Shain et al., 1986). Glutamate functions as an intercellular messenger in the bidirectional communication between neurons and astrocytes. In the glutamatergic system, astrocytes secrete glutamate in response to activation, modulate glutamate receptor expression, and keep the extracellular glutamate concentrations in the non-toxic range by glutamate transporters GLT-1 and GLAST (Dabir et al., 2006). Dysregulation of this delicate process may lead to glutamate excitotoxicity and neuronal death (Schousboe and Waagepetersen, 2005; Stout et al., 1998). Several lines of evidence suggest that glutamate household by astrocytes is under NE control. Glutamate uptake into astrocytes is stimulated by NE, an effect mainly mediated by a1-adrenergic receptors (Fahrig, 1993; Hansson, 1989). These in vitro results were confirmed in vivo by means of microdialysis in rats (Alexander et al., 1997). Additionally, NE was reported to induce the synthesis and activity of glutamine synthetase in astroglial cells, but only when co-administrated with glucocorticoids (Hansson, 1989). The author hypothesized that NE increases glutamine synthetase activity through an increased glutamate uptake into the cells with a direct effect on the activity of the enzyme converting glutamate to glutamine. By combining the modulation of the glutamate uptake and the interaction with glucocorticoid transducing systems, the intracellular metabolism of the amino acid might be regulated. Later, NE was demonstrated to stimulate the rates of glutamine uptake, glutamate synthesis, and CO2 production from glutamine in primary cultures of mouse astrocytes (Huang and Hertz, 1995).

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The neuroprotective effects of NE against glutamate excitotoxicity were recently attributed, at least partly, to the astrocytic release of the neuroprotective chemokine monocyte chemoattractant protein (MCP)-1/CCR2, which is neuroprotective against excitotoxic-dependent damage (Madrigal et al., 2009). MCP-1 reduces the receptivity of neuronal NMDA receptors, thereby reducing glutamate release and neuronal damage (Bruno et al., 2000; Madrigal et al., 2009). Consistent with this, MCP-1 inhibits NMDA-induced increases in extracellular glutamate (Eugenin et al., 2003) and increases the ability of astrocytes to uptake glutamate through xc() system transporters (Gochenauer and Robinson, 2001). The ability of NE to induce MCP-1 involves b2adrenergic receptors and its downstream messenger is cAMP as the effects can be replicated by cAMP analogues (Tawfik et al., 2006) and be blocked by a selective b2-adrenergic receptor antagonist (Madrigal et al., 2009). 2.4. Astrocyte proliferation, maturation and differentiation Astrocytes play a major role in the process of astrogliosis, the physiological reaction to brain injury. The key element in this process is the formation of reactive astrocytes, which play a pivotal role in the coordinate response to brain damage. Whether astrogliosis is favorable or deleterious for the outcome after a brain-insult is still a matter of debate (Rolls et al., 2009). b-Adrenergic agonists applied to primary cultures of astrocytes produce a cAMP-mediated increase in phosphorylated GFAP and accelerate differentiation and stellation of astrocytes (Abe and Saito, 1997; Le Prince et al., 1991; McCarthy et al., 1985; Shain et al., 1987). In vivo depletion of noradrenergic axons clearly diminishes the degree of reactive astrocyte formation to injury (Griffith and Sutin, 1996), experimental data from injured rabbit optic nerves show that propranolol inhibits astrocytosis, whilst isoproterenol clearly induces astrocyte proliferation and hypertrophy when applied to healthy optic nerves (Hodges-Savola et al., 1996). These findings are in line with studies in a rat model for spinal cord injury where propranolol has been shown to potently suppress astrocytic hypertrophy and glial-scar formation (Sutin and Griffith, 1993). In vivo experiments in rats further suggest that propranolol mediates this effect by inhibition of IL-6 secretion, an inducer of astrogliosis (Woiciechowsky et al., 2004). Neurotransmitters are well known to act as trophic factors controlling nervous system development (Kobayashi et al., 1995; Lauder, 1985; Mohanakumar et al., 1995; Whitaker-Azmitia, 1991). Without noradrenergic influence, neurones and glial cells do not proliferate normally as shown in studies of cerebellar development in rats (Podkletnova and Alho, 1998). Supplementary evidence for the adrenergic role in normal astrocyte maturation comes from studies showing that thyroid-hormone-induced differentiation and maturation of astrocytes is mediated by the b-adrenergic pathway (Gharami and Das, 2000; Ghosh and Das, 2007). On the other hand a role for NE as an inhibitor of glial cell proliferation was first suggested by Bendek and Hahn (1979). NE potently blocks glial cell proliferation in cultured rat astrocytes (Feinstein and Rozelman, 1997). NE mediates this effect by cAMPmediated inhibition of the cell cycle (Gagelin et al., 1999), probably by means of the b2-adrenergic receptor since astrocytes derived from b2-adrenergic receptor knockout mice demonstrated higher proliferation rates (Chesik et al., 2006). 3. Astrocytic b-adrenergic receptors in neurological disorders 3.1. Multiple sclerosis MS is a neuroinflammatory and neurodegenerative disorder, traditionally attributed to T-cell-mediated autoimmune demye-

lination in the CNS, developing in genetically susceptible individuals probably as a consequence of environmental factors (Noseworthy et al., 2000). In most cases (about 85%) patients with MS experience an initial relapsing-remitting disease course followed, at a later stage, by a slow and progressive accumulation of disability (secondary progression). Some patients have a primary progressive form, characterized by the absence of prior relapses. There is now substantial evidence that the progressive disease course of MS is due to a widespread axonal degeneration. Epidemiological data, treatment studies and histological findings indicate that inflammation alone is not the sole cause of this diffuse axonopathy (Wilkins and Scolding, 2008). b2-Adrenergic receptors on astrocytes usually upregulate in areas of CNS or optic nerve injury (Mantyh et al., 1995). However, astrocytes in MS-plaques and ‘‘normal appearing white matter’’ (NAWM) in MS-patients were found to be severely deficient in b2adrenergic receptors (De Keyser et al., 1999). Neuronal b2adrenergic expression in this same tissue was not affected. The mechanism by which these receptors are downregulated remains a subject for ongoing research. No association was found between polymorphisms of the b2-adrenergic receptor gene and the occurrence of MS (Niino et al., 2002). The question has been raised whether a virus could be implicated. Canine distemper (CD) virus, a paramyxovirus mainly affecting astrocytes, causes a chronic inflammatory demyelinating disease in dogs that closely resembles MS (Mutinelli et al., 1989). In dogs with CD encephalitis, b2-adrenergic receptors were present on neurons, but were no longer detectable on astrocytes in both demyelinated lesions and normal-appearing white matter (De Keyser et al., 2001). As b2adrenergic receptors on astrocytes play an important role in a wide range of anti-inflammatory and neuroprotective functions it is tempting to suggest that this abnormality could play a role in the inflammatory aspect of MS, as well as the axonopathy which is hypothesized to be caused by an impairment of glycogen metabolism (De Keyser et al., 2004). Astrocytes contact vascular networks and have a major influence on the microcirculation by increasing intracellular calcium to induce vasodilatation (Takano et al., 2006). Data from perfusion magnetic resonance imaging indicate that in MS perfusion of the white matter is decreased. The reason is unclear, but it is possibly secondary to astrocytic dysfunction, related to a downregulation of b-adrenergic receptors (De Keyser et al., 2008b), thus a second mechanism by which astrocytic b-adrenergic deficiency could play a role in axonopathy is by perturbing the microcirculation in the brain. A recent proofof-concept study showed fluoxetine to reduce formation of new enhancing lesions (Mostert et al., 2008a) and possible neuroprotective effects against axonal degeneration (Sijens et al., 2008). The underlying mechanism of action of fluoxetine has been attributed to possible down-stream compensation of factors influenced by astrocytic b2-adrenergic deficiency. Indeed fluoxetine has been shown to stimulate the cAMP-responsive element binding protein (CREB) (Schwaninger et al., 1995), increase the production of BDNF (Mercier et al., 2004) and enhance glycogenolysis in astrocytes (Kong et al., 2002) (for further reference see Mostert et al., 2008b). 3.2. Alzheimer’s disease Alzheimer’s disease is the most frequent cause of dementia and abnormal deposition of amyloid b-42 protein plays a prominent pathophysiological role (Van Broeck et al., 2007). Degeneration of LC-neurons is a well-known feature of Alzheimer pathology. Decreased LC neuronal counts are significantly correlated with the burden of amyloid b-plaques, neurofibrillary tangles, and the severity of dementia in Alzheimer’s disease (Bondareff et al., 1987). Selective destruction of LC neurons in rats with subsequent cortical injection of amyloid b-protein provoked more marked inflamma-

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tion than in control rats with a normal LC (Heneka et al., 2002). This effect was associated with higher IL1-b, iNOS and IL-6 expression in both microglia and astrocytes. Moreover, the effect of LCdestruction on IL1-b and iNOS expression was attenuated by coadministration of NE or isoproterenol. LC destruction also correlated with more pronounced Alzheimer pathology in the amyloid precursor protein (APP)-23 transgenic Alzheimer mouse model (Heneka et al., 2006). Studies with the water-maze test in rats showed that co-administration of propranolol and chlorophenylalanine (causing a depletion of serotonin) provoked impairment not seen after administration of the individual molecules (Kenton et al., 2008). Recently, it was demonstrated that amyloid b-induced inhibition of long-term potentiation was prevented by b2-adrenergic receptor activation in adult rats (Wang et al., 2008). b-Adrenergic antagonists can also block the cAMPmediated induction of apolipoprotein-E after amyloid b-exposure, thereby reducing amyloid b cytotoxicity (Igbavboa et al., 2006). Conversely, in a few studies negative effects of b-adrenergic receptor signalling on Alzheimer’s disease parameters have also been described. For instance, it has been shown that in vitro treatment of rat astrocytes with NE or isoproterenol increased both APP mRNA and protein levels, and that these increases were blocked by propranolol (Lee et al., 1997). Also it was demonstrated that upon intra-hippocampal injection of isoproterenol, Alzheimer-like tau hyperphosphorylation, associated with impaired memory, became apparent in rats (Sun et al., 2005). Furthermore, chronic treatment with b2-adrenergic agonists increased plaque formation in an Alzheimer disease mouse model (Ni et al., 2006). Finally, activation of b2-adrenergic receptors was shown to contribute to Ab-42 deposition, by activating g-secretase, one of the enzymes responsible for cleavage of APP to Ab-42. The effects mediated by b-adrenergic receptors on astrocytes thus seem to have both deleterious (amyloid plaque formation) and protective effects (inhibition of inflammation). The global net effect needs to be further elucidated. A significant protective effect of beta-blockers on functional decline in Alzheimer patients gives us a possible hint (Rosenberg et al., 2008) although the mechanism of the protective effect was not addressed in this paper. 3.3. HIV-encephalitis HIV-dementia and its minor form ‘mild cognitive motor disorder’, remain a debilitating complication of HIV infection (Nath et al., 2008). The pathogenesis of this disease is largely unknown (Gonzalez-Scarano and Martin-Garcia, 2005). Coatproteins of the virus have been implicated in the mechanism of this disease. The gp-120 glycoprotein (responsible for HIV-binding to CD4+ receptors of lymphocytes) has been shown to cause a depression of the b-adrenergic response in both astrocytes and microglia. Experiments in cultured rat astrocytes (Bernardo et al., 1994; Levi et al., 1993), showed decreased cAMP levels in response to isoproterenol after pre-treatment with gp-120. Functional repercussion on astrocytic protein phosphorylation and TNF-a expression was demonstrated, suggesting that by interfering with brain b-adrenergic receptors, the HIV envelope protein gp120 may contribute to the pathogenesis of HIV-encephalitis by altering astroglial reactivity and disturbing the cytokine network responsible for the defence against viral as well as opportunistic infections. 3.4. Hepatic encephalopathy Hepatic encephalopathy is characterized by neuropsychiatric manifestations that can range in severity from a mild alteration in mental state to coma. Substantial evidence indicates that astrocytes, specifically the protoplasmatic astrocytes in grey

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matter, play a crucial role in the pathogenesis of this syndrome (Jalan et al., 2003; Lizardi-Cervera et al., 2003; Norenberg, 1987). The damaged liver can no longer remove neurotoxic substances such as ammonia and manganese from the blood. Both ammonia and manganese induce astrocytic mitochondrial dysfunction, leading to changes in multiple neurotransmitter systems that contribute to neuropsychiatric disturbances. Exposure of astrocytes to ammonia also leads to a decreased sensitivity of badrenergic receptors for its neurotransmitter, an abnormality that may contribute to the encephalopathic state (Liskowsky et al., 1986). However, whether this is caused by an effect on the badrenergic receptor itself or on the linkage between the badrenergic receptor and adenylate cyclase has not been further studied. 3.5. Stroke A series of in vitro and in vivo experiments (Culmsee et al., 2007; Junker et al., 2002) suggest that the b-adrenergic receptor may serve as a neuroprotective target for stroke. In an in vitro assay, b1 and b2 receptors were demonstrated to induce activation of astrocytes and neuroprotective effects. In vivo administration of clenbuterol showed marked reduction of infarct size in a mouse model of focal brain ischemia. This effect was abolished by coadministration of propranolol as well as by the b2 antagonist butoxamine. However co-administration of the selective b1antagonist metoprolol showed a reduction in infarct size as compared to treatment with clenbuterol alone. These findings suggest that activation of astrocytes and neuroprotection in vitro can be achieved by stimulation of either b1- or b2-adrenergic receptors, whereas in vivo neuroprotection is preferentially mediated through b2-adrenergic receptors. 4. Conclusion Dysfunction of astrocytic b2-adrenergic receptor signaling is suspected to play a central role in some ill understood neurological disorders, including MS, Alzheimer’s disease, stroke, hepatic encephalopathy and HIV encephalitis. However, many findings on the role of the astrocytic b2-adrenergic receptors are based on in vitro findings, and need confirmation in in vivo conditions. Further elucidation of the role of b2-adrenergic receptor in health and disease may hold promise for innovative therapeutic interventions. References Abbott, N.J., Ronnback, L., Hansson, E., 2006. Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53. Abe, K., Saito, H., 1997. Developmental changes in cyclic AMP-stimulated stellation of cultured rat cortical astrocytes. Jpn. J. Pharmacol. 75, 433–438. Akar, C.A., Feinstein, D.L., 2009. Modulation of inducible nitric oxide synthase expression by sumoylation. J. Neuroinflamm. 6, 12. Alexander, G.M., Grothusen, J.R., Gordon, S.W., Schwartzman, R.J., 1997. Intracerebral microdialysis study of glutamate reuptake in awake, behaving rats. Brain Res. 766, 1–10. Allaman, I., Pellerin, L., Magistretti, P.J., 2000. Protein targeting to glycogen mRNA expression is stimulated by noradrenaline in mouse cortical astrocytes. Glia 30, 382–391. Allen, S.J., Dawbarn, D., 2006. Clinical relevance of the neurotrophins and their receptors. Clin. Sci. (Lond.) 110, 175–191. Anlar, B., Sullivan, K.A., Feldman, E.L., 1999. Insulin-like growth factor-I and central nervous system development. Horm. Metab. Res. 31, 120–125. Aoki, C., 1992. Beta-adrenergic receptors: astrocytic localization in the adult visual cortex and their relation to catecholamine axon terminals as revealed by electron microscopic immunocytochemistry. J. Neurosci. 12, 781–792. Aoki, C., Lubin, M., Fenstemaker, S., 1994. Columnar activity regulates astrocytic beta-adrenergic receptor-like immunoreactivity in V1 of adult monkeys. Vis. Neurosci. 11, 179–187. Aranami, T., Yamamura, T., 2008. Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol. Int. 57, 115–120.

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