Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases

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Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases

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Vladimir Berezin*, Peter S. Walmod*,1, Mikhail Filippov†, Alexander Dityatev†,{,} *Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Symbion, Fruebjergvej 3, Box 39, Copenhagen Ø, Denmark † Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany { Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany } Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany 1 Corresponding author: Tel.: 4551319719, e-mail address: [email protected]

Abstract Extracellular matrix (ECM) molecules, their receptors at the cell surface, and cell adhesion molecules (CAMs) involved in cell–cell or cell–ECM interactions are implicated in processes related to major diseases of the central nervous system including Alzheimer’s disease (AD), epilepsy, schizophrenia, addiction, multiple sclerosis, Parkinson’s disease, and cancer. There are multiple strategies for targeting the ECM molecules and their metabolizing enzymes and receptors with antibodies, peptides, glycosaminoglycans, and other natural and synthetic compounds. ECM-targeting treatments include chondroitinase ABC, heparin/heparan sulfatemimicking oligosaccharides, ECM cross-linking antibodies, and drugs stimulating expression of ECM molecules. The amount or activity of ECM-degrading enzymes like matrix metalloproteinases can be modulated indirectly via the regulation of endogenous inhibitors like TIMPs and RECK or at the transcriptional and translational levels using, e.g., histone deacetylase inhibitors, synthetic inhibitors like Periostat, microRNA-interfering drugs like AC1MMYR2, and natural compounds like flavonoids, epigallocatechin-3-gallate, anacardic acid, and erythropoietin. Among drugs targeting the major ECM receptors, integrins, are the anticancer peptide cilengitide and anti-integrin antibodies, which have a potential for treatment of stroke, multiple sclerosis, and AD. The latter can be also potentially treated with modulators of CAMs, such as peptide mimetics derived from L1-CAM and NCAM1.

Progress in Brain Research, Volume 214, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63486-3.00015-3 © 2014 Elsevier B.V. All rights reserved.

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Keywords Alzheimer’s disease, Cancer, Cell adhesion molecule, Epilepsy, Integrin, Multiple sclerosis, Parkinson’s disease, Proteinase, Proteoglycan, Tenascin

1 INTRODUCTION Neural cells secrete diverse molecules, which accumulate in the extracellular space and form the extracellular matrix (ECM). The most studied is the ECM of Wisteria floribunda agglutinin (WFA)-positive perineuronal nets (PNN) predominantly associated with fast-spiking interneurons in the forebrain and with motoneurons in the spinal cord. However, an increasing number of studies draw attention to perisynaptic ECM on excitatory neurons, ECM coats associated with the axon initial segment and nodes of Ranvier, as well as the ECM of neurogenic niche and neurovascular unit (Dityatev et al., 2010b; Faissner et al., 2010). Interactions between cells and the ECM in developing brains play the crucial role in cell migration and guidance of growing axons, whereas the formation of mature neural ECM in the form of PNNs is believed to restrict certain forms of developmental plasticity (Kwok et al., 2011). On the other hand, major components of PNNs and other ECM molecules support induction of functional plasticity by setting the levels of perisomatic GABAergic inhibition and activity of NMDARs and L-VDCCs (Dityatev et al., 2010a). Also, extracellular proteinases have multiple functions. They can bind to transmembrane molecules and function as signaling ligands or cleave ECM and cell adhesion molecules (CAMs) and thus play a permissive role for changes in synaptic configurations. Finally, proteinases secreted and activated in the extracellular space in response to LTP-inducing stimulation can cleave the ECM and release signaling molecules, which would control trafficking of glutamate receptors, remodeling of the actin cytoskeleton, the formation of new dendritic filopodia, and growth of existing spines (Wlodarczyk et al., 2011).

2 ECM TARGETING IN CNS DISEASES In light of these multiple functions of ECM molecules in developing and mature brains, it is not surprising that they play both the causal and modulatory roles in pathogenesis of various central nervous system (CNS) diseases (Soleman et al., 2013). Mutations in genes encoding ECM molecules, such as LGI1 and collagen type IV, alpha 1, can induce epilepsy and vascular dementia. On the other hand, secondary alterations of ECM accompanying diverse brain insults modulate plasticity and affect regeneration. Injury to the mature mammalian CNS in spinal cord injury, stroke, and traumatic brain injury results in permanent and debilitating consequences, largely due to the failure of neurons to reform lost connections after injury. A number of potent growth inhibitory molecules have been identified in the

2 ECM targeting in CNS diseases

ECM, which restrict this structural plasticity and are either present in the environment or substantially upregulated following CNS injury. Furthermore, studies have shown alterations in ECM expression and composition are linked to other CNS diseases such as Alzheimer’s disease (AD), epilepsy, and schizophrenia (Soleman et al., 2013). A number of strategies to promote anatomical recovery have targeted mechanisms underlying the influence of the ECM.

2.1 REGENERATION AND AFTER STROKE REHABILITATION One of the widely used approaches to target ECM is to degrade inhibitory chondroitin sulfate (CS) chains from the chondroitin sulfate proteoglycan (CSPG) protein core with chondroitinase ABC (ChABC), an enzyme derived from the bacteria Proteus vulgaris. The use of ChABC in vitro first led to evidence that the CS chains represent a major inhibitory component of the CSPGs. It was shown that myelin-free plasma membranes from injured CNS tissue were less inhibitory to neurite outgrowth following ChABC treatment (Bovolenta et al., 1993). By now, this enzyme has been used in multiple studies to stimulate axon regeneration and neural plasticity in the adult CNS after injury (Kwok et al., 2008). But it can be used much broader. For instance, an inspiring example is provided by Hill and colleagues, who showed that infusion of ChABC or heparan sulfate proteoglycan (HSPG) glypican in the periinfarct region after ischemic stroke was able to promote motor recovery and these improvements may be related to the changes in growth factor expression and neuritogenesis (Hill et al., 2012). Plasticity can also be driven by environmental stimulation or rehabilitation. Strikingly, when animals were trained on task-specific rehabilitation for skilled paw function along with ChABC treatment, a synergistic enhancement of skilled motor function and axon sprouting following cervical dorsal funiculus lesions was revealed. ChABC alone was shown to promote anatomical sprouting, but recovery of skilled paw function was only evident in the combination group (Garcia-Alias et al., 2009). This suggests that while ChABC enhances spinal plasticity, the addition of task-specific rehabilitation might strengthen good functional connections and eliminate “incorrect” ones (Soleman et al., 2013). CSs are sulfated at several positions, generating a number of CS subtypes of which CS-E (GlcA-4S and 6SgalNAc) specifically and potently inhibit axon growth (Brown et al., 2012). Genetic suppression of N-acetylgalactosamine 4-sulfate 6-O sulfotransferase 15 (Chst15), the enzyme that generates CS-E via addition of a sulfate group to the 6-O position of GalNAc on CS-A, significantly attenuates the inhibitory activity of CSPGs on axon growth. The inhibitory function of CS-E is implemented via its binding to the transmembrane protein tyrosine phosphatase PTPs. Masking the CS-E motif using a CS-E-specific monoclonal antibody reversed the inhibitory activity of CSPGs and stimulated axonal regeneration in vivo (Brown et al., 2012), suggesting that in the future, more delicate approaches to interfere with specific aspects of ECM-mediated signaling, as compared to digestion of ECM by ChABC, will be applied to promote recovery of neural functions.

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2.2 AGING AND ALZHEIMER’S DISEASE Proteomic analysis revealed that ECM proteins were the only group of proteins that showed a robust and progressive upregulation during aging (Vegh et al., 2014b). Aging affects different regions of the dorsal but not ventral hippocampus (Yamada and Jinno, 2013). Namely, intensity of WFA-labeled PNNs in the dorsal part of old mice declined in the CA1 region, remained unchanged in the CA3 region, but increased in the dentate gyrus. Using analysis of the number of aggrecanexpressing cells in aged rats, another group found a significant increase in aggrecan expression throughout the prefrontal cortex and in the hippocampus compared to young rats (Tanaka and Mizoguchi, 2009). Strikingly, a herbal medicine, yokukansan, which is used in a variety of clinical situations for treating symptoms associated with age-related neurodegenerative disorders, abrogated the age-related upregulation in aggrecan expression and promoted neurogenesis in the dentate gyrus in rats (Tanaka and Mizoguchi, 2009). In an AD model (APP/PS1 mice), an early increase in amyloid-ß (Ab) levels coincides with upregulation of several ECM proteins in hippocampus. This increase in ECM levels occurred before the onset of plaque formation and was paralleled by impairments in hippocampal CA1 long-term potentiation (LTP) and contextual memory in the fear conditioning paradigm. Injection of ChABC into the hippocampus restored both LTP and contextual memory performance (Vegh et al., 2014a). However, since the ECM of PNNs has a neuroprotective value (Suttkus et al., 2014), it would be important to perform a detailed analysis of neurodegeneration of PNN-associated neurons after ChABC treatment. Heparan sulfates (HSs) bind to tau and Ab and affect their aggregation, intracellular internalization, and clearance, suggesting that they may be of therapeutic value for treatment of AD (Cui et al., 2013). Several studies have demonstrated that a lowmolecular-weight (LMW) heparin, neuroparin/C3, may have therapeutic potential for the treatment of AD (Dudas et al., 2008). C3 is composed of 4–10 saccharides and is derived from heparin by gamma irradiation. C3 can penetrate the blood–brain barrier (BBB) and has effects in the CNS. The initial study has shown that oral or subcutaneous administration of C3 prevented Ab25–35-induced appearance of tau-2-immunoreactivity in the hippocampus of rats (Dudas et al., 2002). Further studies found that C3 also effectively reduced cholinergic damage induced by a cholinotoxin, AF64A, in a dose- and time-dependent manner (Rose et al., 2004). Also, injection of LMW heparin (enoxaparin or dalteparin), LMW anionic sulfonate, or sulfate compounds can arrest inflammation associated with amyloid deposits in mice (Kisilevsky et al., 1995; Zhu et al., 2001). Chronic subcutaneous administration of certoparin can prevent Ab25–35-induced abnormal intracellular tau changes and reactive astrogliosis in rats (Walzer et al., 2002). In APP23 transgenic mice, peripheral administration of enoxaparin reduced amyloid plaques and the level of Ab in the brain, as well as decreased the number of activated astrocytes surrounding amyloid deposits and Ab-induced inflammatory response (Bergamaschini et al., 2004). More recent studies demonstrate that administration of enoxaparin can improve cognition

2 ECM targeting in CNS diseases

in APPswe/PS1dE9 mice and influence Ab accumulation at different stages of amyloid plaque formation (Timmer et al., 2010). As heparin has strong anticoagulant properties that preclude its use within a brain, heparin mimetics that do not promote bleeding are more promising therapeutic agents. A recent report demonstrates that such heparin mimetic F6 or treatment with the HS-digesting enzyme, heparinase, blocks neuronal uptake and seeding of tau and a-synuclein fibrils by interfering with their binding to cell surface HSPGs (Holmes et al., 2013). Another attractive compound is PG545, a synthetic, fully sulfated HS mimetic that has recently entered phase I trials for advanced cancer (Ferro et al., 2012). The compound potently inhibits heparanase and HS-binding angiogenic growth factors and shows a long half-life, mild anticoagulant activity, and a high preclinical antitumor and antimetastatic efficacy. As upregulation of heparanase expression impairs inflammatory response and macrophage-mediated clearance of Ab in murine brain (Zhang et al., 2012), it would be promising to investigate the effects of PG545 in AD models as it may target both neuroinflammation and Ab turnover.

2.3 EPILEPSY, SCHIZOPHRENIA, AND ADDICTION A seizure can induce profound reduction in expression of PNN components such as aggrecan, hyaluronan and proteoglycan link protein 1, and hyaluronan synthase 3 (McRae et al., 2012), which may be an important condition for pathological neuroplasticity underlying epileptogenesis. Other studies revealed impaired structure of PNNs in specific brain regions of schizophrenic patients and after intake of addictive drugs (Mauney et al., 2013; Van den Oever et al., 2010). One of few mouse mutants, in which a deficit in PNNs is well described, is the tenascin-R knockout mouse. In cultures from these mice, accumulations of several ECM molecules are mostly associated with somata, whereas dendrites are sparsely covered (Morawski et al., 2014). Excitingly, the formation of dendritic PNNs was fully rescued by polyclonal antibodies to aggrecan and a bivalent, but not monovalent form of WFA. These results suggest that tenascin-R implements its functions by cross-linking and clustering of aggrecan and for the first time demonstrate that genetic defects in an ECM molecule can be pharmacologically compensated by ECM cross-linking reagents (Morawski et al., 2014). These can be potentially converted into therapeutic reagents to stabilize/rescue neural ECM in pathological conditions. Another strategy would be to rely on compounds that may act on signaling pathways upregulating expression of neural ECM molecules. During development, signaling through L-type Ca2+ channels and Ca2+-permeable AMPA receptors is required for the formation of aggrecan-rich PNNs (Dityatev et al., 2007). A recent study (Tsirimonaki et al., 2013) demonstrates that activation with the PKCe-specific activator small peptide ceRACK led sequentially to a prolonged activation of ERK1/2, increased abundance of the early gene products ATF, CREB1, and Fos with concurrent silencing of transcription for Ki67, and increases in mRNA expression for aggrecan. Furthermore, ceRACK induced upregulation of hsa-miR-377 expression,

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coupled with decreases in ADAMTS5 expression, and cleaved aggrecan. Verapamil, a widely prescribed L-type calcium channel blocker, elevates expression of the soluble antagonist of Wnt-signaling FRZB, suppresses Wnt/b-catenin signaling, and upregulates expression of aggrecan and collagens (Takamatsu et al., 2014). Also, antituberculosis drugs stimulate expression of these ECM molecules (Lehmann et al., 2014). Although all these experiments were done using nonneural cells, they stimulate further interest (i) to test the identified drugs for ECM synthesisstimulating activity in neuronal cultures and (ii) to screen FDA-approved drugs to identify therapeutic treatments supporting expression of neural ECM molecules.

3 TARGETING ECM METABOLIZING ENZYMES IN CNS DISEASES Metabolism of the ECM is a central element for the progression of a range of biological phenomena and diseases. In the nervous system, ECM-metabolizing enzymes are implicated in numerous processes including the migration, survival, and differentiation of neurons and neuronal precursor cells, neurite outgrowth, the guidance and stabilization of axons, the dynamics of dendritic spines, synaptogenesis, synaptic plasticity, astrocyte motility, oligodendrocyte maturation, and myelination. Post injury, ECM metabolism is implicated in, e.g., axonal sprouting and regeneration, remyelination, and neural cell precursor mobilization (Rivera et al., 2010). Consequently, ECM-metabolizing enzymes are involved in multiple physiological and pathological phenomena including learning and memory formation, cerebral ischemia and hemorrhage, drug addiction, Down syndrome, epilepsy, bipolar disorder, schizophrenia, and neurodegenerative and inflammatory diseases like MS, AD, and Parkinson’s disease (PD) (Kim and Hwang, 2011; Rivera et al., 2010; Van Hove et al., 2012; Verslegers et al., 2013). Moreover, ECM metabolism is implicated in a range of vascular diseases (Benjamin and Khalil, 2012; Newby, 2012) and cancers, of which gliomas are of particular interest when focusing on the nervous system (Arribas et al., 2006; Bourboulia and Stetler-Stevenson, 2010; Gabriely et al., 2008; Levicar et al., 2003).

3.1 ECM-DEGRADING PROTEASES The ECM proteins is catabolized by a large number of proteases, the majority belonging to the groups of matrix metalloproteinases (MMPs), the “A disintegrin and metalloproteases” (ADAMs), and the “A disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTSs). These three families belong to the metzincin family, which is a subgroup of the zincins (Hooper, 1994; Rivera et al., 2010). Other proteases are also important for degradation of the ECM in the nervous system. These include enzymes of the plasminogen-activating system and brainrelated trypsin and trypsin-like serine proteases. The plasminogen-activating system, traditionally associated with thrombolysis, is believed also to be important for ECM

3 Targeting ECM metabolizing enzymes in CNS diseases

degradation in relation to the development and function of the nervous system, including synaptic plasticity related to learning and memory formation. Plasminogen is a secreted protein that upon cleavage by urokinase plasminogen activator (uPA) or tissue plasminogen activator (tPA) is converted to plasmin, a broad range protease capable of cleaving fibrin and other ECM components. Plasmin is inactivated by, e.g., a2-antiplasmin and a2-macroglobulin (a2M), and the system is also regulated by plasminogen activator inhibitors (PAIs; Ortolano and Spuch, 2013). In addition to cleaving ECM molecules itself, plasmin is also an activator of several MMPs, including MMP-3 and membrane-type MMPs (Rosenberg, 2002). Trypsin-like serine proteases acting on the ECM in the brain include P22, neurosin, neuropsin, and neurotrypsin. These enzymes are related to several diseases including mental retardation, AD, MS, and PD (Wang et al., 2008b). Moreover, e.g., kallikreins, a family of proteases, of which several cleave ECM proteins and myelinassociated proteins, are related to inflammation and demyelination (Sotiropoulou and Pampalakis, 2010).

3.2 ENDOGENOUS MODULATORS OF ECM-DEGRADING PROTEASES The most important endogenous MMP inhibitors (MMPIs) are “tissue inhibitors of metalloproteinases” (TIMPs), which generally are more potent and have a higher degree of specificity than other natural MMPIs (Vargova´ et al., 2012). Importantly, TIMPs do not exclusively inhibit the protease activity of MMPs but also of several ADAMs and ADAMTS proteins (Murphy, 2011). The human genome encodes four TIMPs (TIMP-1 to TIMP-4), which all are expressed in the nervous system including the endothelium of BBB (Hartmann et al., 2009; Rivera et al., 2010). In addition to the TIMPs, MMPs can be inhibited, for instance, by members of the general protease inhibitor a2M family (a2M and ovostatins), the protein “reversion-inducing cysteine-rich protein with kazal motifs”(RECK), serine protease inhibitors (serpins), and tissue factor pathway inhibitor-2 (TFPI-2; Chaudhary et al., 2013; Herman et al., 2001; Swarnakar et al., 2012; Vargova´ et al., 2012). Apart from protein inhibitors, metzincins can also be inhibited by endogenous nonprotein compounds. For instance, long chain fatty acids, preferably unsaturated, inhibit MMP-2 and MMP-9, but not MMP-1, through an interaction with the fibronectin-homology modules of the MMPs (Berton et al., 2001), and the cellular levels of cholesterol modulate the shedding of “low-density lipoprotein receptorrelated protein-1” by affecting the activities of ADAM12 and MMP-14 (Selvais et al., 2011).

3.3 METHODS FOR TARGETING ECM-MODULATING ENZYMES Protease activities can be targeted directly by synthetic or natural inhibitors and indirectly by modulating the levels of endogenous proteases and protease inhibitors. Moreover, recombinant or purified enzymes can be administered. The following sections briefly describe these various strategies.

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3.3.1 Targeting at the Transcriptional and Translational Levels Due to its role as an anticancer target, several studies have focused on the upregulation of RECK expression, which can be induced, e.g., by histone deacetylase (HDAC) inhibitors like valproic acid, trichostatin A, and phenylbutyrate and by anti-inflammatory drugs like the cyclooxygenase inhibitors acetylsalicylic acid or NS-398 (reviewed by Chen and Tseng, 2012). In a pilot study of a new screening system, 34 out of 880 known bioactive compounds were found to activate the RECK promoter including the drug disulfiram (Antabus) (Murai et al., 2010). The expression of RECK can also be increased by the compound tomatidine from tomatoes, which also increases the expression of TIMP-1 (Yan et al., 2013), and by epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea that reduces the methylation state of RECK (Kato et al., 2008). EGCG also downregulates the expression and activities of MMP-2, MMP-9, and MMP-14 (Annabi et al., 2002; Ferreira et al., 2012). The expression of TIMP-1 and TIMP-3 can be increased in brain capillary endothelial cells by treatment with the glucocorticoids dexamethasone and hydrocortisone, suggesting that hydrocortisone can protect against degradation of the BBB (F€ orster et al., 2007; Hartmann et al., 2009). TIMP-1 is considered the most inducible TIMP, and its expression can also be increased by e.g., EGF, interleukin (IL)-1b and IL-6, phorbol esters, retinoids, transforming growth factor-b1, and tumor necrosis factor (TNF; Gardner and Ghorpade, 2003). Rh2, a metabolite of one of the active compounds from ginseng, decreases MMP-1, MMP-3, MMP-9, and MMP-14 expression and consequently reduces the invasion of astroglioma cells (Kim et al., 2007). The expression levels of RECK and TIMP-3 can be increased by knockdown/ inhibition of the microRNAs miR-15a, miR-21, or miR-125b, which subsequently leads to a downregulation of MMP-2 and MMP-9 (Gabriely et al., 2008; Han et al., 2012; Rahmah et al., 2012; Shi et al., 2012; Xin et al., 2013). Inhibition of miR-21 can be obtained, for instance, by the drug AC1MMYR2, which prevents miR-21 maturation (Shi et al., 2013). A reduction in the transcription or translation of MMP2 and MMP9 has been observed with the angiotensin-converting enzyme inhibitor captopril (Capoten), the antiretroviral drug nelfinavir (Viracept), and with disulfiram. Moreover, captopril and disulfiram have been reported to interact with MMP-2- and MMP-9 directly, and a combination of the drugs has been proposed for the treatment of glioblastoma (Bourlier et al., 2005; Cho et al., 2007; Kast and Halatsch, 2012; Prontera et al., 1999; Shian et al., 2003). A downregulation of MMP-9 expression has also been achieved with siRNA gene silencing (Bonoiu et al., 2009). Luteolin (30 ,40 ,5,7-tetrahydroxyflavone), a flavonoid found in fruit and vegetables, reduces the expression of MMP-9 in MS patients, leading to a reduced proliferation of peripheral blood mononuclear cells and modulation of proinflammatory cytokines (Sternberg et al., 2009).

3 Targeting ECM metabolizing enzymes in CNS diseases

One of the proteins that stimulates expression of MMPs is the transmembrane immunoglobulin (Ig) superfamily member “extracellular matrix metalloproteinase inducer” (EMMPRIN; also known as, e.g., basigin and CD157), and consequently, EMMPRIN has been proposed as an anticancer/anti-inflammation therapeutic target (Agrawal and Yong, 2011; Kanyenda et al., 2011).

3.3.2 Targeting Enzyme Activity Numerous natural compounds inhibit MMPs directly. For instance, compounds extracted from the bark of Magnolia obovata and Euonymus alatus inhibit the activity of MMP-9 (Jin et al., 2005; Nagase et al., 2001; Park et al., 2005), and compounds extracted from pine bark inhibit MMP-1, MMP-2, and MMP-9 (Grimm et al., 2004). Also, anacardic acid, a major constituent of cashew nut shell liquid, inhibits MMP-2 and MMP-9 through a direct interaction where the carboxylate group of anacardic acid chelates the Zn2+ ion in the active site of the proteases (Omanakuttan et al., 2012). Moreover, several compounds extracted from marine organisms have been found to inhibit MMPs (Thomas and Kim, 2010). Within the marine-derived compounds, several studies have focused on Neovastat (AE 941), a mixture of compounds extracted from shark cartilage. Neovastat has multiple reported effects including inhibition of MMP-1, MMP-7, MMP-9, MMP-12, MMP-13, and (predominantly) MMP-2, but phase I/II and III trials on patients with different types of cancer were unable to demonstrate any effects of Neovastat on tumor progression (Patra and Sandell, 2012). Most investigated MMPIs, however, are synthetic compounds. These can be divided into three groups depending on whether they have amino acids on the left-hand, right-hand, or both sides of the zinc-binding group in the active site of the MMPs, and of these, the right-hand side inhibitors are generally the most potent (Patil and Gupta, 2013). Moreover, MMPIs can be divided according to the type of Zn2+-binding group they contain. Thus, MMPIs include compounds with a carboxylic (–COOH) group, a hydroxamic (–C(O)NHOH) group, a sulfhydryl (–SH) group, or a phosphonate (–PO(OH)2 or –PO(OR)2) group (Patil and Gupta, 2012, 2013; Vargova´ et al., 2012). Most focus has been on hydroxamic acid MMPIs because these compounds generally have a high affinity towards the active site of MMPs and are more potent than other types of MMPIs (Verma, 2012), and most MMPIs developed by pharmacological companies fall within this group. For descriptions of hydroxamic acid- and sulfonamide-based MMPIs and of gelatinase and collagenase inhibitors, see Patil and Gupta (2012), Patil and Gupta (2013), Swarnakar et al. (2012), Verma (2012), and Yadav et al. (2012). In addition to the modulation of enzyme activities by natural or synthetic compounds, enzyme activities in vivo can also be modulated by administration of recombinant enzymes. One example is recombinant chondroitinase ABC (chABC), which when injected can retain its enzyme activity for several days (Crespo et al., 2007; Kwok et al., 2008).

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3.4 DRUGS TARGETING ECM-MODULATING ENZYMES For a number of reasons, phase I/II/III trials with MMPIs have generally been disappointing: In contrast to the preceding animal studies, the drugs have often been tested in patients with diseases at an advanced stage; the tested doses have often been too low, and more studies with combination therapy rather than monotherapy should have been performed. Moreover, some tested drugs have a poor bioavailability (see below) or a decreased potency in vivo. Moreover, a problem related to MMPIs is that MMPs have highly similar structures in their active sites. This makes the design of specific MMPIs very difficult. Consequently, MMPIs may inhibit antitargets (see below) hence counteracting the beneficial effects of inhibiting the target MMPs and potentially causing adverse effects (see Iyer et al., 2012; Verma, 2012 for references). Nevertheless, it has been possible to generate selective inhibitors for MMP-2/MMP-9, MMP-13, and MMP-14 (Iyer et al., 2012) and at least on MMPI (Periostat™) has been approved for treatment of periodontal disease by the FDA (Verma, 2012). One proposed alternative approach to the design of MMPIs is the design of recombinant TIMPs with a higher degree of specificity than endogenous TIMPs (Brew and Nagase, 2010). The subsequent sections summarize, for selected diseases of the nervous system, the changes observed for ECM-metabolizing enzymes and the experiences and strategies for treating the diseases (Table 1).

3.4.1 Multiple Sclerosis In vivo models for MS include experimental autoimmune encephalomyelitis (EAE) and related types of encephalomyelitis. Such models have demonstrated disease stage-related changes in the expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-19; ADAMTS-1, ADAMTS-4, and ADAMTS-5; and TIMP-1 and TIMP-3 (Cross et al., 2006; Kim and Joh, 2012; Moore and Crocker, 2012; Ulrich et al., 2006). Moreover, upregulation of kallikrein 6 contributes to degradation of the BBB and of myelin-associated proteins. Antikallikrein 6 antibodies delay the onset and reduce the severity of EAE, but surprisingly, the expression of kallikrein 6 seems also to preserve myelination by maintaining the expression of myelin-basic protein (Sotiropoulou and Pampalakis, 2010). Thus, targeting of kallikrein 6 seems to have conflicting effects. The progression of EAE is also affected by the plasminogen-activating system, and treatment of animals with PAI-1dp, an 18-amino acid-long peptide corresponding to a sequence in PAI-1, significantly reduces the clinical symptoms of the disease (Gur-Wahnon et al., 2013). Increased levels of TNF in the brain lead to an increased expression and activity of MMP-3 and MMP-9 and a subsequent increase in the permeability of the BBB, whereas treatment with prostaglandin inhibitors like indomethacin reduces the expression of MMP-3 and MMP-9 and protects against BBB disruption (CandelarioJalil et al., 2009). However, MMP-9 is also important for oligodendrocyte maturation

Table 1 Selected direct and indirect activators and inhibitors of selected ECM-degrading enzymes Gene symbol1 MMP1

Direct or indirect activators

Direct or indirect inhibitors/downregulators

EMMPRIN (Agrawal and Yong, 2011); Kallikrein 1 (Sotiropoulou and Pampalakis, 2010)

Batimastat (BB-94) (Chaudhary et al., 2013); marimastat (BB-2516) (Chaudhary et al., 2013); metastat (col-3; tetracycline derivative) (Chaudhary et al., 2013);MMI 270 B (CGS27023A) (Chaudhary et al., 2013); Neovastat (Patra and Sandell, 2012); Rh2 (Kim et al., 2007); TFPI-2 (Gessler et al., 2011); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012); pine bark extract (Grimm et al., 2004) Metastat (col-3; tetracycline derivative) (Chaudhary et al., 2013); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) Metastat (col-3; tetracycline derivative) (Chaudhary et al., 2013); Neovastat (Patra and Sandell, 2012); prinomastat (AG 3340) (Chaudhary et al., 2013); tanomastat (BAY 12-9566) (Chaudhary et al., 2013); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) Anacardic acid (cashew nut shell) (Omanakuttan et al., 2012); batimastat (BB-94) (Chaudhary et al., 2013); captopril (Kast and Halatsch, 2012; Prontera et al., 1999); disulfiram (Cho et al., 2007; Shian et al., 2003); EGCG (Annabi et al., 2002; Ferreira et al., 2012); EPO (Li et al., 2008); Marimastat (BB-2516) (Chaudhary et al., 2013); metastat (col-3; tetracycline derivative) (Chaudhary et al., 2013) MMI 270 B (CGS27023A) (Chaudhary et al., 2013); pine bark extract (Grimm et al., 2004); prinomastat (AG 3340) (Chaudhary et al., 2013); RECK (Meng et al., 2008); tanomastat (BAY 12-9566) (Chaudhary et al., 2013); TFPI-2 (Gessler et al., 2011); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012); Unsaturated long chain fatty acids (Berton et al., 2001) Anacardic acid (cashew nut shell) (Omanakuttan et al., 2012); batimastat (BB-94) (Chaudhary et al., 2013); captopril (Kast and Halatsch, 2012); Disulfiram (Cho et al., 2007; Shian et al., 2003); EGCG (Annabi et al., 2002; Ferreira et al., 2012); EPO (Souvenir et al., 2011); luteolin (Sternberg et al., 2009); marimastat (BB-2516) (Chaudhary et al., 2013); Magnolia obovata, Euonymus alatus, and pine bark extracts (Grimm et al., 2004; Jin et al.,

MMP8 MMP13

MMP2

EMMPRIN (Agrawal and Yong, 2011); Kallikrein 3 (Sotiropoulou and Pampalakis, 2010)

MMP9

EMMPRIN (Agrawal and Yong, 2011); kallikrein 1 (Sotiropoulou and Pampalakis, 2010)

Continued

Table 1 Selected direct and indirect activators and inhibitors of selected ECM-degrading enzymes—cont’d Gene symbol1

MMP3

MMP10 MMP11 MMP7

MMP26 MMP14

MMP15 MMP16

Direct or indirect activators

EMMPRIN (Agrawal and Yong, 2011); Plasmin (Rosenberg, 2002)

EMMPRIN (Agrawal and Yong, 2011)

Plasmin (Rosenberg, 2002)

Direct or indirect inhibitors/downregulators 2005; Nagase et al., 2001; Park et al., 2005); metastat (col-3; tetracycline derivative) (Chaudhary et al., 2013); nelfinavir, indinavir, ritonavir, saquinavir (Bourlier et al., 2005); Neovastat (Patra and Sandell, 2012); prinomastat (AG 3340) (Chaudhary et al., 2013); Prostaglandin inhibitors (indomethacin) (Candelario-Jalil et al., 2009); RECK (Meng et al., 2008); Rh2 (Kim et al., 2007); tanomastat (BAY 12-9566) (Chaudhary et al., 2013); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012); unsaturated long chain fatty acids (Berton et al., 2001) Marimastat (BB-2516) (Chaudhary et al., 2013); MMI 270 B (CGS27023A) (Chaudhary et al., 2013); prinomastat (AG 3340) (Chaudhary et al., 2013); prostaglandin inhibitors (indomethacin) (Candelario-Jalil et al., 2009); Rh2 (Kim et al., 2007); tanomastat (BAY 12-9566) (Chaudhary et al., 2013); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) Batimastat (BB-94) (Chaudhary et al., 2013); marimastat (BB-2516) (Chaudhary et al., 2013); Neovastat (Patra and Sandell, 2012); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012); Cholesterol (Selvais et al., 2011); EGCG (Annabi et al., 2002; Ferreira et al., 2012); prinomastat (AG 3340) (Chaudhary et al., 2013); RECK (Meng et al., 2008); Rh2 (Kim et al., 2007); tanomastat (BAY 12-9566) (Chaudhary et al., 2013); TIMP-2–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-2–4 (Murphy, 2011; Vargova´ et al., 2012)

MMP17 MMP24 MMP25 MMP23A/B MMP12 MMP19 MMP20 MMP27 MMP28 ADAM10

Retinoids (Tamibarotene, Acitretin) (Endres and Fahrenholz, 2012)

ADAM12 ADAM17 ADAM19 ADAM28 ADAM33 ADAMTS1 ADAMTS4 ADAMTS5 uPA 1

TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-2–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) Marimastat (BB-2516) (Chaudhary et al., 2013); Neovastat (Patra and Sandell, 2012); TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-2–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) TIMP-1–4 (Murphy, 2011; Vargova´ et al., 2012) RECK (Muraguchi et al., 2007); TIMP-1, TIMP-3 (Brew and Nagase, 2010) Cholesterol (Selvais et al., 2011); TIMP-2, TIMP-3 (Brew and Nagase, 2010) TIMP-3, TIMP-4 (Brew and Nagase, 2010) TIMP-3 (Brew and Nagase, 2010) TIMP-3, TIMP-4 (Brew and Nagase, 2010) TIMP-3 (Brew and Nagase, 2010) TIMP-2, TIMP-3 (Salter et al., 2010) TIMP-3 (Salter et al., 2010) TIMP-3 (Salter et al., 2010)

Kallikrein 4 and 15 (Sotiropoulou and Pampalakis, 2010)

HUGO Gene Nomenclature Committee (HGNC) (http://www.genenames.org/).

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and myelin in the CNS, and in the peripheral nervous system, MMP-2 also facilitates myelination (Verslegers et al., 2013). Erythropoietin (EPO) is known to have neuroprotective effects and to affect the expression of MMPs and TIMPs (see below). Consistently, an EPO analog, darbepoetin alfa, reduces the clinical symptoms of EAE, possibly through an increase in TIMP-1-expressing astrocytes in the brain and spinal cord (Thorne et al., 2009).

3.4.2 Alzheimer’s Disease One of the hallmarks of AD is the accumulation of amyloid plaques. Consequently, an increase in the activity or expression of Ab-degrading enzymes (ADEs), i.e., proteases involved in the degradation and clearance of Ab peptides, could potentially have beneficial effects on AD. ADEs include MMP-2, MMP-3, and MMP-9, plasmin, angiotensin-converting enzyme (ACE), neprilysin (NEP), endothelin-converting enzyme (ECE-1), ADAM10, and several other proteases (Endres and Fahrenholz, 2012; Yoon and Jo, 2012). Modulation of ADE activities can be obtained by the administration of drugs that promote the activity/expression of ADEs, by gene therapy with genes expressing or promoting the expression of ADEs, or by stem cell transplantations. Studies with gene and stem cell therapies are few but demonstrate that delivery of the gene encoding NEP, or transplantation with mesenchymal stem cells expressing NEP, leads to a reduction in the amyloid load. Compounds promoting the expression or activity of NEP include the tetracycline minocycline, EPO, somatostatin, estrogen, HDACs, and compounds from red wine, green tea, and ginseng (see Yoon and Jo, 2012 for references). However, minocycline at the same time acts as an MMPI (Siller and Broadie, 2012), hence potentially leading to opposing effects. Plasminogen activation by tPA has a protective role in relation to AD, and Ab-plaque formation in itself stimulates the expression of tPA. Consequently, PAI-1 inhibitors alleviate the symptoms of AD (Ortolano and Spuch, 2013). Using a more indirect approach, plasmin expression can be increased with HDACs (Yoon and Jo, 2012). ADAM10 is one of the enzymes facilitating a nonamyloidogenic cleavage of APP, and consequently, stimulation of ADAM10 expression is a strategy for AD therapy (Saftig and Reiss, 2011). One way of stimulating ADAM10 expression is via the retinoids tamibarotene and acitretin. Such treatments subsequently lead to a reduction in the amount of Ab (Endres and Fahrenholz, 2012).

3.4.3 Hypoxia and Ischemia In addition to the abovementioned effects on MS and AD, administration of EPO also has positive effects on trauma caused by hypoxia and ischemia. EPO increases the expression of TIMP-1 and TIMP-2 while decreasing the expression of MMP-2 and MMP-9 (Li et al., 2008; Souvenir et al., 2011). Likewise, EPO protects against damage in aneurysm tissue and in response to hyperoxia, also in part through effects on MMP-2 and MMP-9 expressions (Sifringer et al., 2009; Xu et al., 2011).

3 Targeting ECM metabolizing enzymes in CNS diseases

The expression of ADAMTS-1, ADAMTS-4, ADAMTS-8, and ADAMTS-9 is also increased during cerebral ischemia (Rivera et al., 2010), suggesting that administration of ADAMTS inhibitors may also have beneficial effects on ischemia.

3.4.4 Cancer A beneficial modulation of MMP activities as a part of cancer treatment is difficult to achieve. MMPs and other proteases facilitate degradation of the ECM, hence promoting invasion (e.g., by facilitating deadhesion), and MMP-2 and MMP-9 secreted by leukemia cells increase the permeability of the BBB, thereby facilitating their invasion into the CNS (Feng et al., 2011). Such effects suggest that anticancer treatment should include MMPIs. However, MMPs can also counteract angiogenesis. For instance, MMP-9 mediates the formation of the antiangiogenic proteins angiostatin, tumstatin, and endostatin by cleavage of plasmin and collagen types IV and XVIII, respectively. Thus, some MMPs (MMP-1, MMP-2, MMP-7, and MMP-17) are targets for cancer treatment; others (MMP-3, MMP-8, MMP-12, and MMP-19) are antitargets, and some (MMP-9 and MMP-14) can be both targets and antitargets, depending on the circumstances (Bourboulia and Stetler-Stevenson, 2010; Iyer et al., 2012; Verma, 2012). Metzincins upregulated or otherwise involved in the progression of gliomas include MMP-1, MMP-7, MMP-10, MMP-11, MMP-14, MMP15, MMP-19, MMP-24, and MMP-26 and ADAM-8, ADAM-10, ADAM-12, and ADAM-19. Moreover, TIMP-3 and MMP-3, MMP-8, MMP-9, MMP-11, MMP12, MMP-19, and MMP-26; ADAM-23; and ADAMTS-1, ADAMTS-8, ADAMTS-9, ADAMTS-15, and ADAMTS-18 have anticancer effects (Levicar et al., 2003). Using MMPIs or other protease antagonists or agonists in cancer treatment therefore requires that the drugs are highly specific and are used in the proper spatiotemporal manner. Some of the first hydroxymates studied for the treatment of cancer were marimastat (BB-2516) and batimastat (BB-94) (Patil and Gupta, 2013). Marimastat has been tested in several phase I, II, and III trials, mainly for the treatment of different types of cancer, including gliomas. However, in general, treatment with marimastat at best has moderate positive effects and is accompanied by serious adverse effects (joint and tendon pains) (Groves et al., 2002, 2006; Larson et al., 2002; Levin et al., 2006). Batimastat has also been tested in several phase I and II trials. However, the compound cannot be administered orally (Macaulay et al., 1999) and has never been marketed for anticancer treatment. Focusing on cancers in the CNS, one of the hallmarks of primary brain tumors is an increased expression of the CSPG brevican. The cleavage of brevican by ADAMTS-4 and ADAMTS-5, which are overexpressed in gliomas, is crucial for the cancer invasion process, and therefore, inhibitors of ADAMTS enzymes will probably greatly reduce glioma invasiveness (Levicar et al., 2003; Stanton et al., 2011). As mentioned above, the expression of RECK is often reduced in cancer. A low expression of RECK has been reported to be associated with a poor prognosis, whereas overexpression of RECK reduces glioma migration and invasion (Silveira Correa et al., 2010). An increased RECK expression can, as mentioned

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above, be obtained, e.g., by knockdown of miRs or by HDACs or anti-inflammatory drugs (Chen and Tseng, 2012; Gabriely et al., 2008). However, recent studies have demonstrated a correlation between the glioma tumor grades and the expression of RECK in the surrounding endothelium (Rahmah et al., 2012). The exact role of RECK in relation to different types of cancer is therefore not clear. The expressions of the proteases cathepsin B, cathepsin D, and cathepsin L correlate with glioma grades, and selective cathepsin B inhibitors reduce the invasion of glioblastomas. Likewise, the expressions of uPA, PAI-1, and the uPA receptor correlate with tumor grades or invasiveness, suggesting that the plasminogen system also contains potential targets for cancer therapy (Levicar et al., 2003).

4 INTEGRIN TARGETING IN CNS DISEASES Integrins constitute a large family of CAMs which play a key role in development and frequently are involved in pathological processes. Integrins form heterodimers of noncovalently bound a and b subunits, which both represent type 1 transmembrane proteins with large extracellular domains (80–150 kD). In total, 18 a and 8 b subunits have been discovered forming at least 24 functional receptors. Many integrins bind specific sequences, like asparagine–glycine–aspartate (RGD), in their target ECM proteins. In addition, integrins bind to other CAMs (e.g., ICAM (intercellular adhesion molecule) and VCAM) or soluble proteins like fibrinogen (reviewed in Barczyk et al., 2010; Plow et al., 2000). Very attractive for drug development is the class of integrins that can recognize the RGD sequence (a5b1, a8b1, aIIbb3, and avb). Many drugs in development attempt either to inhibit the function of this class of integrins (Cox et al., 2010; Line et al., 2005; Yang et al., 2006) or to rely on the ability of the integrins to become internalized upon activation, hence providing a mechanism for the intercellular drug delivery, for example, for siRNA, in order to induce cell apoptosis ( Juliano et al., 2011; Line et al., 2005; Sugahara et al., 2009; Wang et al., 2008a). Below, we discuss integrins as potential targets for drug development for the treatment of diseases in the CNS and summarize the use of some existing integrin-targeting drugs.

4.1 GLIOBLASTOMA Certain integrins are strongly expressed on the surface of many malignant tumors (particularly avb3) and thereby stimulate angiogenesis and tumor progression (Desgrosellier and Cheresh, 2010; Lu et al., 2008; Millard et al., 2011; Weis and Cheresh, 2011). Thus, the inhibition of integrin signaling has a therapeutic potential, particularly in some complicated cases such as glioblastoma multiforme cancers. Indeed, clinical trials with the synthetic drug cilengitide, which is based on a cyclo (–RGDfV–) peptide, a specific inhibitor of av-containing integrins, have reached phase III (Desgrosellier and Cheresh, 2010; Reardon et al., 2008; Stupp et al., 2010).

4 Integrin targeting in CNS diseases

An interesting drug delivery approach is to use multifunctional nanoparticles, which can specifically enter tumor cells via binding to RGD-recognizing integrins. A number of research groups try to develop complexes that are either liposomalbased (lipoplexes), polymeric carriers, or dendrimers (reviewed in Juliano et al., 2011), which seem to be promising for the treatment of gliomas. Upon internalization via RGD-containing integrins, these complexes may deliver into the tumor cells siRNA or other compounds for tumor growth inhibition or for the promotion of apoptosis (Wang et al., 2009). Thus, enhanced angiogenesis and increased expression of integrins avb3 and avb5 in malignant tumors provide an opportunity to develop nanoparticles, which despite of their size (30–100 nm) can specifically deliver siRNA or proapoptotic drugs into tumor cells. This may be also the case for other diseases in the CNS, since nanoparticles can be optimized to deliver the drugs across the BBB in order to reach their targets (Chaturvedi et al., 2014). Another anticancer approach is based on the development of specific antiintegrin antibodies. Originally, the mouse monoclonal antibody LM609 was developed to study integrin function (Cheresh, 1987). Keeping the same epitope, the “humanized” modifications of this antibody and some other independent “humanized” monoclonal antibodies were developed for clinical trials (reviewed in Millard et al., 2011). Several preclinical studies and early phase clinical trials were performed and some antibodies proved to be effective in the induction of tumor apoptosis. There have been no attempts to treat gliomas in a similar manner, but potentially, this approach can be of interest for further drug development.

4.2 MULTIPLE SCLEROSIS AND NEUROINFLAMMATION MS is an autoimmune disease of the CNS. The pathology of the disease includes a destruction of the BBB and entry of active immune cells into the CNS. Integrins a4b1 and a4b7 are leukocyte- and lymphocyte-specific. Thus, targeting a4-containing integrins can inhibit the migration of lymphocytes, retarding the disease development. So far, the only anti-integrin drug approved for MS treatment is natalizumab, which can be used for treatment of relapsing–remitting forms of MS. The drug is a monoclonal antibody, which binds to both a4b1 and a4b7 integrins. It prevents the integrins from binding to VCAM-1 and MadCAM expressed on endothelial cells, and hence, the lymphocytes and leucocytes cannot extravasate through the endothelium (reviewed in Millard et al., 2011). A potential side effect of the treatment is progressive multifocal leukoencephalopathy (Tan and Koralnik, 2010), which can be lethal. Thus, the use of this drug is accompanied by strong limitations and scrutiny (reviewed in Cox et al., 2010).

4.3 INJURY AND STROKE Integrin a5b1 and fibronectin are comparatively highly expressed by developing peripheral nerves in both axons and nonneuronal cells (Lefcort et al., 1992), whereas the expression is lower in maturating nerves. Following a lesion, the regenerating

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peripheral nerves display an increased expression of a5b1 in both neurites and Schwann cells. In contrast, in the CNS, the majority of mature neurons have very low abilities to regenerate. However, if they are transduced by a viral vector expressing just integrin subunits a1 and a5, their abilities to grow neurites are restored, at least in vitro (Condic, 2001). This study clearly indicates that integrins a1 and a5 potentially can be used in a gene delivery approach for the treatment of stroke by targeting the injured CNS neurons. Another interesting observation regarding a4-containing integrins was done in an experimental model of stroke. Male Lewis rats underwent 3 h of middle cerebral artery occlusion followed by 45 h of reperfusion. As has been already mentioned for MS, the blockage of a4 integrin subunits may prevent the extravasation of leucocytes and lymphocytes into inflamed tissue. Thus, the animals were treated with a4specific antibodies (Becker et al., 2001). This resulted in a decreased infarct size and less pronounced neurological deficits in the anti-a4-treated animals as compared to controls. Thus, a4-containing integrins are potentially good targets for stroke treatment, if their inhibitors are injected shortly after the stroke onset.

4.4 EPILEPSY The role of integrins in brain pathologies related to neural plasticity is very complex. Many neurons and glial cells express a number of integrins. In the mature CNS, integrins regulate many processes related to synaptogenesis, synaptic plasticity, and homeostatic regulation (reviewed in Dityatev and Schachner, 2003, 2006; Dityatev et al., 2010a; Wlodarczyk et al., 2011). These processes are obviously altered in pathological conditions such as epilepsy and AD (Caltagarone et al., 2007; Clegg et al., 2003; Dityatev and Fellin, 2008; Gall and Lynch, 2004). Epilepsy is characterized by a shifted balance between excitation and inhibition in the brain leaning towards uncontrolled synchronized excitation (Browne and Holmes, 2001). Seizures cause significant changes in the expression of many ECM and ECM-related proteins. This is termed the “matrix response” (Gong et al., 2007; Hoffman et al., 1998a,b; Naffah-Mazzacoratti et al., 1999; Perosa et al., 2002a,b). Seizures are accompanied by a release of proteases, changes in the localization and synthesis of ECM molecules, and activation of integrinmediated intracellular signaling pathways. The resulting pathological remodeling of the ECM may trigger structural and functional changes in the CNS, which can determine the progression of the epileptogenesis (Soleman et al., 2013). As mentioned above, the brain expresses a number of different integrin subunits (Fasen et al., 2003; Pinkstaff et al., 1999; Wu and Reddy, 2012). After pilocarpineinduced seizures, a significant increase in the expression of a1, a2, a4, a5, b1, b3, and b4 integrin subunits is observed in reactive astrocytes and in the expression of av and a1 in neurons (Fasen et al., 2003). A number of studies also report an increased expression of the b1 subunit after seizures (reviewed in Gall and Lynch, 2004; Pinkstaff et al., 1998). Elevated levels a2 and b1 subunits are also observed in epileptic patients (Wu et al., 2011). Interestingly, the selective ablation of the av

5 Targeting CAMs in CNS diseases

subunit in CNS glial and neurons leads to cerebral hemorrhage, seizures, axonal degeneration, and premature death (McCarty et al., 2005). In GABAergic neurons, the integrin expression is rather low, whereas in glutamatergic neurons, it is high and associated with synaptic contacts (Gall and Lynch, 2004). This potentially allows looking for an integrin-based therapy strategy towards the treatment of overexcitatory neurons. Studies indicate that a reduced expression of a3, a5, and a8 subunits results in impaired Hebbian synaptic plasticity (failure to maintain LTP) and spatial memory (Chan et al., 2003). Interestingly, a5 and a8 integrin subunits are RGD receptors. In an animal kindling model, the treatment of rat brain slices with RGD based peptides, which prevents integrin binding to the ECM, decreased the spontaneous burst rate (seizure-like activity; Grooms and Jones, 1997). However, the effects remain to be verified by in vivo experiments. Also, integrin b3-directed inhibitory treatments are of high interest, since overexpression of b3 integrins is a part of the mechanism underlying synaptic upscaling by inhibition of GluR2 endocytosis (Cingolani et al., 2008), and erroneous activation of this mechanism in post-status epilepticus periods could lead to elevated excitation of excitatory neurons.

4.5 ALZHEIMER’S DISEASE Due to the complexity of the CNS and AD, it is difficult on the basis of the available data to predict whether integrins can be used as drug targets for the treatment of AD. However, there are several recent interesting studies related to this issue. The inhibition of a2b1 integrin by perlecan domain V (DV) prevents Ab-mediated toxicity in cell culture (Wright et al., 2012). DV helps to restore the function of endothelial cells treated with Ab in vitro in an a5b1-dependent manner (Parham et al., 2014). DV-treated endothelial cells produced more VEGF, restoring their angiogenic function, which might be useful for the treatment of cerebral amyloid angiopathy. Overexpression of a5b1 in neuroblastoma cells also leads to higher levels of internalization and degradation of Ab 1–40 when compared to controls, indicating that a5b1 activation or overexpression might stimulate endocytosis of Ab and be an interesting new approach for treatment of AD. Interestingly, the activation of b1-containing integrins can be regulated by APP itself. Thus, APP can bind to and thereby inhibit b1 integrin. APP shedding by alpha secretase removes the inhibitory activity of APP and thus allows neurite outgrowth to be triggered via integrins (Young-Pearse et al., 2008). This makes APP shedding by alpha secretase another process that can be targeted in AD.

5 TARGETING CAMs IN CNS DISEASES CAMs play a fundamental role in the formation, maintenance, and function of the nervous system. Their function is based on their ability to interact with each other in a homophilic and/or heterophilic manner (i.e., one CAM interacts with another

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type of CAM). In general, these interactions result in the clustering of CAMs on the cell surface followed by transduction of signals into the cell via association/ dissociation of a variety of intracellular signaling partners and/or activation of protein kinases. Many CAMs, such as NCAM1 (neural cell adhesion molecule 1), L1-CAM, N-cadherin, neuroplastin, neurofascin, nectin-1, and neurexin, extracellularly can interact with and activate the signaling machinery of fibroblast growth factor (FGF) receptors (see, e.g., Bojesen et al., 2012). Interactions of CAMs with ECM molecules are much less studied. These interactions, however, might have a modulatory effect on both CAM function and ECM reorganization and thus represent important targets for therapeutic intervention. A number of CAMs have been identified as interaction partners of ECM molecules and/or ECM receptors, such as integrins. The latter indicates indirect interference of CAMs with ECM functioning via integrins. These CAMs, their association and intervening with ECM molecules, pharmacological tools to modulate these interactions, and the implications for CNS disorders are summarized in Table 2 and discussed below.

5.1 THY-1 MEMBRANE GLYCOPROTEIN, THY-1 Thy-1 or CD90 is a GPI-linked glycoprotein consisting of a single extracellular Ig module. Neurons express high levels of Thy-1, which interacts with avb3 integrin present on astrocytes. The Thy-1 Ig module possesses an RGD-like tripeptide known to be the integrin-binding region. In astrocytes, Thy-1 also interacts with the HSPG syndecan-4. The interaction with avb3 integrin inhibits neuritogenesis and causes retraction of neurites. Neurological abnormalities seen in Thy-1-null mice include inhibition of LTP in the hippocampus (dentate gyrus) and an inability to spread social cues regarding food selection. Potential pharmacological tools to interfere with Thy-1 interactions are heparin (competitively interfering with the interaction with syndecan-4) and RGD-containing peptides (competitively interfering with the interaction with integrins) (Avalos et al., 2009; Cardenas et al., 2014; Herrera-Molina et al., 2012).

5.2 COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR, CAR Coxsackievirus and adenovirus receptor, CAR, is composed of one V-set and one C2-set Ig module, a single transmembrane helix, and an intracellular domain. Homophilic interactions are mediated by the two Ig modules. Heterophilically, CAR interacts with the ECM molecules fibronectin, tenascin-R, and the HSPG agrin. These interactions are mediated by the Ig-C2 module. CAR is strongly expressed in the developing nervous system, indicating that it is implicated in the formation of neuronal circuits. Early embryonic lethality of CAR knockout hindered studies of the role of CAR–ECM interactions in the adult CNS. Potential pharmacological tools to interfere with these interactions are HSPGs and other glycans (Dorner et al., 2005; Patzke et al., 2010).

Table 2 CAMs as receptors of ECM Ligands

CAM

ECM and ECM receptors

Other ligands

Function in CNS

Thy 1

avb3 integrin Syndecan-4

Thy-1

Mediates interaction between neurons and astrocytes

CAR

Fibronectin Tenascin-R Agrin

CAR Adenovirus and coxsackieviruses

Strongly expressed in the developing nervous system

ICAM-5

aLb2 integrin a5b1 integrin Vitronectin

ICAM-5 HSV-1 gene product UOL

NCAM1

HSPG CSPG Collagens

NCAM1 L1 FGFR Prion protein TAG-1 RABV

Regulates outgrowth and maturation of dendritic spines. sICAM-5 increases neuronal excitability and is immunosuppressive Modulates neuron migration, neurite outgrowth, synaptogenesis, spine dynamics, synaptic plasticity, learning/memory

Pharmacological tools/drugs

Implications for CNS diseases

Heparin: competitive inhibitor of Thy-1– syndecan-4 interactions

Interaction with avb3 integrin inhibits neuritogenesis and causes retraction of neurites In null mice: inhibits LTP and transfer of social cues Implicated in the formation of neuronal circuits

References Avalos et al. (2009), Cardenas et al. (2014), and Herrera-Molina et al. (2012)

Methamphetamine induces of ICAM-5 cleavage by activating MMPs

Hypoxic-ischemic injury increases degradation of ICAM-5

Dorner et al. (2005) and Patzke et al. (2010) Furutani et al. (2012), Ning et al. (2013), and Tian et al. (2007)

Antibodies Recombinant domains Peptide mimetics

NCAM1 deficiency results in impaired synaptic vesicle endocytosis and cognitive deficit

Berezin and Bock (2010), Nielsen et al. (2010), and Shetty et al. (2013)

Continued

Table 2 CAMs as receptors of ECM—cont’d Ligands

CAM L1-CAM

LRRC15

ECM and ECM receptors a5b1 integrin avb1 integrin avb3 integrin aIIBb3 integrin a9b1 integrin Fibronectin Matrigel Collagen IV Laminin

Pharmacological tools/drugs

Implications for CNS diseases

Neuron–neuron adhesion, neurite fasciculation, synaptogenesis Neuronal cell migration

Antibodies Recombinant domains Peptide mimetics

Various inherited neurodevelopmental disorders

Gast et al. (2008), Kulahin et al. (2009), Mechtersheimer et al. (2001), and Schafer and Altevogt (2010)

Expressed in neurons, but also in astrocytes surrounding senile plaques of AD patients

Proinflammatory cytokines and preaggregated Ab peptides strongly increase LRRC15 expression

Relationship of LRRC15 expression pattern to AD progression

Satoh et al. (2005, 2002)

Other ligands

Function in CNS

L1 NCAM1 FGFR

References

5 Targeting CAMs in CNS diseases

5.3 INTERCELLULAR ADHESION MOLECULE 5 ICAM-5 is a neuronal dendritic CAM involved in immune and neuronal functions. Extracellularly, it is composed of nine Ig modules, of which the distal modules are involved in binding to b1 (Ig1 and 2) and b2 (Ig1) integrins and the ECM molecule vitronectin (Ig2), whereas Ig4–5 mediate homophilic binding. Its binding to vitronectin induces changes in ezrin–radixin–moesin proteins, resulting in the recruitment of actin filaments. ICAM-5 regulates the maturation of dendritic spines and synapse formation, depending on the ICAM-5–b1 integrin interactions. The interaction between ICAM-5 and LFA-1 integrin (aLb2) expressed on microglial cells can disrupt dendrite binding to axonal b1 integrins, hence affecting synapse function. Cleavage by secretases, activated during hypoxic-ischemic injury, leads to accumulation of functional soluble ICAM-5, a marker of neurodegeneration. Methamphetamine is a potential pharmacological tool to induce ICAM-5 cleavage by MMPs (Furutani et al., 2012; Ning et al., 2013; Tian et al., 2007).

5.4 NEURAL CELL ADHESION MOLECULE 1 NCAM1 is the most studied neural CAM. Its ectodomain interacts with a great number of ligands, such as other CAMs (L1-CAM, TAG-1), prion protein, RABV, FGF receptor, and ECM molecules (HSPGs, CSPGs, and collagen) (Nielsen et al., 2010). Interactions between polysialylated NCAM and HSPGs have been shown to stimulate synaptogenesis through FGF and NMDA receptor-dependent mechanisms (Dityatev et al., 2004). NCAM1 deficiency leads to impaired synaptic vesicle endocytosis and cognitive deficits. A variety of pharmacological tools to interfere and/or mimic NCAM1 functions have been developed, including epitope-specific antibodies, recombinant modules, and peptide mimetics. Some of these mimetics are now in the development for the treatment of demented patients (http://www. enkam.com/content/us/fgls) (Berezin and Bock, 2010; Shetty et al., 2013). Considering high levels of NCAM expression in the CNS, peptides targeting NCAM–ECM interactions may be quite powerful to modulate cell–ECM communication.

5.5 NEURAL CELL ADHESION MOLECULE L1 L1-CAM is a founding member of a subgroup of neuronal Ig superfamily CAMs with a large ectodomain possessing six Ig and five fibronectin type III modules. It plays an important role in cell migration, axon guidance, and synapse formation. It is involved in cell-to-cell adhesion by homophilic interactions and uses FGF receptors as one of the signaling branches. The importance of L1-CAM is reflected in a variety of pathological mutations in the gene encoding L1, which result in neurological conditions (including mental retardation and spastic paraplegia and hydrocephalus) known as CRASH syndrome or L1 syndrome. Remarkably, L1-CAM can directly interact with integrins including a5b1, avb1, avb3, aIIBb3, and a9b1, through an RGD sequencecontaining binding site localized in Ig module 6. As for NCAM1, pharmacological

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tools to interfere with L1-CAM–ECM interactions/functions include epitopespecific antibodies, recombinant modules, and peptide mimetics (Gast et al., 2008; Kulahin et al., 2009; Mechtersheimer et al., 2001; Schafer and Altevogt, 2010).

5.6 LEUCINE-RICH REPEAT CONTAINING 15 Leucine-rich repeat containing 15 (LRRC15), was originally described as a protein upregulated in astrocytes in response to treatment of cells with Ab peptides or proinflammatory cytokines. It mediates cell–ECM interactions, thereby promoting glioma and breast carcinoma invasion into Matrigel. LRRC15 binds to fibronectin, collagen IV, and laminin, but not the CSPG aggrecan. In the cerebral cortex of humans without AD, it is expressed in neurons. In AD patients, however, the protein is expressed in the reactive astrocytes surrounding senile plaques, but not in neurons. Thus, Ab deposits induce LRRC15 expression in the brain (Satoh et al., 2002, 2004, 2005).

6 CONCLUSIONS ECM molecules, MMPs, and integrins are very attractive target molecules for the treatment of CNS diseases, since they have been already shown to be involved in many cellular functions in the CNS. Depending on pathology, it may be beneficial to weaken or strengthen the ECM. Correspondingly, enzymatic digestion of ECM and molecules blocking interactions between ECM molecules and their binding partners or ECM cross-linkers, MMPIs, and drugs promoting expression of ECM molecules can be employed. Similarly, integrins can be targeted with integrin-blocking antibodies or RGD-containing peptides, which block the integrin-mediated ECM binding, or they can be stimulated by direct gene delivery or stimulatory antibodies. All of these strategies can be potentially applied to a number of CNS diseases. However, to avoid unwanted side effects, more “intelligent” reagents probably should be developed first to target specific ECM-related molecules in specific populations of neural cells under specific conditions.

ACKNOWLEDGEMENTS This work was initiated and supported by COST Action BM1001 “Brain Extracellular Matrix in Health and Disease.”

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