Integrins as receptor targets for neurological disorders

“…Ca2+ and K+ ion channels, intracellular Ca2+ concentrations, cellular contractile properties, protein kinase activity, and growth factor receptors (Hynes, 1992; Yip & Marsh, 1997; Porter & Hogg, 1998; Wu et al., 1998; Barouch et al., 2000; Chan et al., 2001; Danen & Yamada, 2001; Davis et al.,…”

“Co-stimulation of integrins and epidermal growth factor (EGF) receptors activates Pyk2 and FAK to promote outgrowth of neurite via paxillin induced cytoskeletal changes (Ivankovic-Dikic et al., 2000).”

“This signal transduction has been also shown to result in protein phosphorylation, increased intracellular calcium concentration, activation of glutamate receptor, gene transcription, and the release of neurotransmitters (Clark & Brugge, 1995).”

“The third strategy is to bypass the BBB and deliver the drugs to CNS through an intraventricular/intrathecal route, the olfactory pathway, an interstitial/intracranial drug delivery via releasing drugs from biological tissues, nanoparticles and pumps.”

“Mice lackingαvβ6 integrin develop exaggerated inflammation (Munger et al., 1999).”

“Sniffing (intranasal) neuropeptides of melanocortin, vasopressin and insulin achieved direct access to the cerebrospinal fluid within 30 min, bypassing the bloodstream in human trials (Born et al., 2002).”

“Since the discovery of the first integrin receptor for ECM protein fibronectin (FN) in 1986 (Tamkun et al., 1986), eighteen α-subunits and eight β-subunits have been identified (Hynes, 2002).”

“Integrin recruitment and relocalization has been observed in migrating cells, and integrin– ECM attachments and focal adhesions have been reported to dynamically change their position at leading and rear edges (Becchetti & Arcangeli, 2010; Huttenlocher & Horwitz, 2011).”

“The β1-integrin receptors were first identified as mediators of neurite outgrowth on ECM components (Reichardt & Tomaselli, 1991).”

“Furthermore, ECM–integrin–CSK interactions play crucial roles in gene expression, cell proliferation, migration and differentiation, and cell survival (Hynes, 1992; Yamada & Miyamoto, 1995; Schwartz, 2001; Kim et al., 2011).”

“…pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard et al., 2011; Reichardt & Prokop, 2011).”

“(Dityatev & Schachner, 2003; Gall et al., 2003; Gall & Lynch, 2004; Dityatev et al., 2010).”

“(Dityatev & Schachner, 2003; Gall et al., 2003; Gall & Lynch, 2004; Dityatev et al., 2010).”

“In temporal lobe epilepsy (TLE), the hippocampus plays a key role in epileptogenesis and epileptic seizures (Schwartzkroin, 1994; Reddy, 2010).”

“However, the disadvantages associated with antibody therapeutics are the high cost of production, the need for intravenous administration, and the propensity for host immunogenicity and infusion reactions (Cox et al., 2010; Millard et al., 2011).”

“…and growth factor receptors (Hynes, 1992; Yip & Marsh, 1997; Porter & Hogg, 1998; Wu et al., 1998; Barouch et al., 2000; Chan et al., 2001; Danen & Yamada, 2001; Davis et al., 2001; Wu et al., 2001; Davis et al., 2002; Waitkus-Edwards et al., 2002; Martinez-Lemus et al., 2003;…”

“Both neuronal activity and vascular reactivity are modulated by integrin signaling through the generation or exposure of new integrin ligands from limited degradation of ECM and/or turnover of new integrins during wound healing (Davis et al., 2000; Gui et al., 2006).”

“For instance, CSK talin binding, known for forming the initial contacts between integrin β-subunit intracellular tails and the actin cytoskeleton, is a pivotal event and is required specifically for integrin–ECM–CSK axis signaling and for activation of integrin (Kim et al., 2011; Millard et al., 2011).”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“LN, VN, reelin and chondroitin sulfates are reported to be involved in neuronal development (Heinrich et al., 2006; Dityatev et al., 2007).”

“Cleavage of integrin–ECM focal adhesive connections could be an early step in the formation of new synaptic configurations from inside–out signaling, followed by rapid formation of new focal contacts (Hoffman et al., 1998a).”

“LN, VN, reelin and chondroitin sulfates are reported to be involved in neuronal development (Heinrich et al., 2006; Dityatev et al., 2007).”

“In LN receptor α6-integirn KO mice, the cortical basement membrane is disrupted with alterations of LN deposition, ectopic neuroblastic outgrowths are found on the brain surface and in the vitreous body in the eye, and myelin-forming oligodendrocytes show increased cell death (Georges-Labouesse et al., 1998).”

“Furthermore, ECM–integrin–CSK interactions play crucial roles in gene expression, cell proliferation, migration and differentiation, and cell survival (Hynes, 1992; Yamada & Miyamoto, 1995; Schwartz, 2001; Kim et al., 2011).”

“RGD and soluble FN can decrease voltage gated L-type Ca2+ currents (CaL) and dilate the arterioles, while LDV in FN and insoluble FN can increase Ca2+ currents and constrict the arterioles (D'Angelo et al., 1997; Wu et al., 1998; Waitkus-Edwards et al., 2002).”

“Conditional expression of an integrin subunit rescued the memory deficits (Grotewiel et al., 1998).”

“radial glial cells and Schwann cell differentiation (Forster et al., 2002; Pietri et al., 2004).”

“Interactions between α6-integrin and growth factor enable newly formed oligodendrocytes to survive in response to limiting concentrations of soluble growth factors (Colognato et al., 2002).”

“2) (Pinkstaff et al., 1999; Renaudin et al., 1999; Yanagida et al., 1999; Chun et al., 2001; Chan et al., 2003; Morini & Becchetti, 2010).”

“The addition of cilengitide to chemoradiotherapy based treatment regimens has shown promising preliminary results in ongoing clinical trials in newly diagnosed and progressive glioblastoma multiforme patients by inhibiting angiogenesis (Millard et al., 2011).”

“…and synthesis of ECM molecules (e.g. FN, reelin, and glycosaminoglycans), and activation of integrin– intracellular signaling pathways following seizure activity in the hippocampus (Hoffman et al., 1998b, 1998c; Naffah-Mazzacoratti et al., 1999; Perosa et al., 2002a, 2002b; Gong et al., 2007).”

“…Ca2+ concentrations, cellular contractile properties, protein kinase activity, and growth factor receptors (Hynes, 1992; Yip & Marsh, 1997; Porter & Hogg, 1998; Wu et al., 1998; Barouch et al., 2000; Chan et al., 2001; Danen & Yamada, 2001; Davis et al., 2001; Wu et al., 2001; Davis et…”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“Co-stimulation of integrins and epidermal growth factor (EGF) receptors activates Pyk2 and FAK to promote outgrowth of neurite via paxillin induced cytoskeletal changes (Ivankovic-Dikic et al., 2000).”

“The LTP has long been regarded as a plausible cellular substrate for learning and memory.”

“In addition,αvβ1 integrins mediate oligodendrocyte migration, α6β1 integrin facilitates oligodendrocyte proliferation and Schwann cell adhesion and migration, α1β1 integrin is involved in remodeling in Schwann cells, αvβ3 integrin allows astrocytes to adhere to osteopontin following PNS or CNS injury and oligodendrocy…”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“…are attractive pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard et al., 2011; Reichardt &…”

“…oligodendrocyte differentiation and blockage of migration, and αvβ8 promotes astrocyte migration (Fernandez-Valle et al., 1994; Milner et al., 1996; 1997; Stewart et al., 1997; Milner et al., 1999; Blaschuk et al., 2000; Dubovy et al., 2001; Colognato et al., 2004; Colognato & Tzvetanova, 2011).”

“…the maintenance of use-dependent synaptic reorganization and LTP. Hippocampal synapses are enriched in FN receptors (i.e. α5β1 integrin) that contribute importantly to the stabilization of LTP (Bahr et al., 1997; Staubli et al., 1998; Rohrbough et al., 2000; Chun et al., 2001; Kramar et al., 2002).”

“Recent reports support the utility of integrin ligands as potential biomarkers for diagnosis and treatment of tumor and cardiovascular diseases (Cai et al., 2008; Martin-Ventura et al., 2009).”

“Studies of integrin-initiated intracellular signaling have shown that integrins modulate Ca and K ion channels, intracellular Ca concentrations, cellular contractile properties, protein kinase activity, and growth factor receptors (Hynes, 1992; Yip & Marsh, 1997; Porter & Hogg, 1998; Wu et al., 1998; Barouch et al., 2…”

“…could be primary events leading to development of the epilepsy (Tauck & Nadler, 1985; Sutula et al., 1988; de Lanerolle et al., 1989; Chang et al., 1993; Wuarin & Dudek, 2001; Smith & Dudek, 2002; Lin et al., 2003; Bernard-Trifilo et al., 2005; Lin et al., 2005; Gui et al., 2006; Lin et al., 2008).”

“Transfection of adult neuronal cells with α1-integrin results in increased neurite outgrowth on LN, while transfection with α5-integrin enhances neurite outgrowth on FN in vitro (Condic, 2001).”

“growth factor receptors (Lee et al., 2011).”

“In addition, the β1-integrin receptors and their ECM ligands (FN, LN and CN) have been implicated in the process of neurite outgrowth and LTP (Venstrom & Reichardt, 1993; Chan et al., 2003; Huang et al., 2006).”

“…astrocyte adhesion and oligodendrocyte differentiation and blockage of migration, and αvβ8 promotes astrocyte migration (Fernandez-Valle et al., 1994; Milner et al., 1996; 1997; Stewart et al., 1997; Milner et al., 1999; Blaschuk et al., 2000; Dubovy et al., 2001; Colognato et al., 2004;…”

“…pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard et al., 2011; Reichardt & Prokop, 2011).”

“…could be primary events leading to development of the epilepsy (Tauck & Nadler, 1985; Sutula et al., 1988; de Lanerolle et al., 1989; Chang et al., 1993; Wuarin & Dudek, 2001; Smith & Dudek, 2002; Lin et al., 2003; Bernard-Trifilo et al., 2005; Lin et al., 2005; Gui et al., 2006; Lin et al., 2008).”

“In addition, many senile plaques and neurofibrillary tangles in Alzheimer brain tissue are prominently stained for high level VN and VN receptor β3-integrin (Akiyama et al., 1991).”

“A peptide that mimics the first coiledcoil domain of Fer prevents Fer accumulation in the integrin cytoplasmic domain and reverses the inhibitory effect of JMP (Arregui et al., 2000).”

“The expression of ECM molecule tenascin-C, which could bind to α8β1, α9β1, αvβ3 and αvβ6 in nervous system (Varnum-Finney et al., 1995; Nakic et al., 1996; Shapiro et al., 1996; Clegg et al., 2003), reaches peak upregulation at 24 h after kainic acid-induced limbic seizures in the CA1 and granule cell layer of adult r…”

“Following cilengitide treatment, endothelial and glioma cells show disassembly of cytoskeleton and disruption of tight junction formation (Oliveira-Ferrer et al., 2008).”

“Wilson et al. (2008) have used polynanoparticles for the targeted delivery of rivastigmine into the rat brain to treat Alzheimer's disease.”

“However, in mesial TLE patients, tubulin α-1 chain, β-tubulin, profilin II, and neuronal tropomodulin are significantly reduced, whereas ezrin and vinculin are significantly increased (Yang et al., 2006).”

“Emerging evidence shows that integrin and ECM production are altered in physiological and pathological conditions such asmemory, tumor, Alzheimer's disease, stroke, and epilepsy (Clegg et al., 2003; Gall & Lynch, 2004; Dityatev & Fellin, 2008).”

“After focal ischemic stroke, increased synthesis and release of matrix proteins osteopontin to the normal brain, and the increased expression of integrin αvβ3 indicated that osteopontin plays a novel role in glial activation, organization, and repair functions (Ellison et al., 1999).”

“Therefore, integrins as cell surface receptors are attractive pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard…”

“Antibodies against the α4-integrin subunit and a FN specific antibody also stained the taupositive plaques (i.e. neuritic-type plaques) in Alzheimer's disease and Down's syndrome, while ‘preamyloid’ plaques remained negative (Van Gool et al., 1994).”

“Other than RGD, the IIICS region of FN contains a 25-amino acid sequence, including the leucine–aspartate–valine (LDV) motif that binds the α4β1 integrin (Geiger et al., 2001).”

“BBB structure could be compromised during stroke, tumor metastasis, and injury (Ueno et al., 2004; Pelegri et al., 2007; Cox et al., 2010).”

“The α4β1 and αLβ2 integrins in activated microglial cells adjacent to amyloidal plaques indicate inflammatory responses in Alzheimer disease (Preciado-Patt et al., 1996).”

“…oligodendrocyte differentiation and blockage of migration, and αvβ8 promotes astrocyte migration (Fernandez-Valle et al., 1994; Milner et al., 1996; 1997; Stewart et al., 1997; Milner et al., 1999; Blaschuk et al., 2000; Dubovy et al., 2001; Colognato et al., 2004; Colognato & Tzvetanova, 2011).”

“Growth cone extension requires a permissive range of intracellular Ca2+ concentration, whereas the frequency of Ca2+ waves and spikes controls the rate of axonal elongation/spreading (Becchetti & Arcangeli, 2010).”

“These reports concluded that α4β1, α4β7, and αEβ7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis (Bartt, 2006; Engelhardt & Kappos, 2008…”

“…the maintenance of use-dependent synaptic reorganization and LTP. Hippocampal synapses are enriched in FN receptors (i.e. α5β1 integrin) that contribute importantly to the stabilization of LTP (Bahr et al., 1997; Staubli et al., 1998; Rohrbough et al., 2000; Chun et al., 2001; Kramar et al., 2002).”

“Microtubule formation may contribute to synaptic remodeling, such as mossy fiber sprouting and reorganization of neural networks of kindling-induced epileptogenesis (Pollard et al., 1994; Hendriksen et al., 2001; Sato & Abe, 2001).”

“However, in mesial TLE patients, tubulin α-1 chain, β-tubulin, profilin II, and neuronal tropomodulin are significantly reduced, whereas ezrin and vinculin are significantly increased (Yang et al., 2006).”

“In temporal lobe epilepsy (TLE), the hippocampus plays a key role in epileptogenesis and epileptic seizures (Schwartzkroin, 1994; Reddy, 2010).”

“In this section, we will discuss recent reports on integrin role in the pathophysiology of learning and memory, and selected brain disorders.”

“ECM protein tenascin-R-deficient mutant mice show impaired LTP, elevated levels of excitatory synaptic transmission, and reduced levels of perisomatic inhibitory currents mediated by GABAA receptors in CA1 of the hippocampus (Bukalo et al., 2007).”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“In epileptic conditions, increased neuronal proliferation in the DGCs which are principal excitatory glutamatergic phenotype neurons, cause hypersynchronization (Kokaia, 2011).”

“β1-integrin mRNA levels increased first in neurons and peaked with predominant astroglial expression at 24 h after seizure (Pinkstaff et al., 1998).”

“…Momota et al., 1998; Wu et al., 1998; Endo et al., 1999; Davis et al., 2000; Wu et al., 2000; Davis et al., 2002; Waitkus-Edwards et al., 2002; Kramar et al., 2003; Lin et al., 2003; Martinez-Lemus et al., 2003; Bernard-Trifilo et al., 2005; Gui et al., 2006;Wu et al., 2008b; Yang et al.,…”

“Microtubule formation may contribute to synaptic remodeling, such as mossy fiber sprouting and reorganization of neural networks of kindling-induced epileptogenesis (Pollard et al., 1994; Hendriksen et al., 2001; Sato & Abe, 2001).”

“Other than RGD, the IIICS region of FN contains a 25-amino acid sequence, including the leucine–aspartate–valine (LDV) motif that binds the α4β1 integrin (Geiger et al., 2001).”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“tex (Bi et al., 2001).”

“radial glial cells and Schwann cell differentiation (Forster et al., 2002; Pietri et al., 2004).”

“(1999); Chun et al. (2001); Moiseeva (2001); Ross and Borg (2001); Chan et al.”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“The β1-integrin expression is reported broadly increased and have been implicated in the process of neurite outgrowth during the seizure episode (Venstrom & Reichardt, 1993; Gall & Lynch, 2004).”

“neuronal activity and vascular reactivity from tissue injury rapidlymodulate integrin signaling with consequent modulation of ion channels and activities, the generation or exposure of new integrin ligands from limited degradation of extracellular matrix through increased extracellular proteases, and/or turnover of ne…”

“PDGF stimulated a protein kinase C-dependent activation of αvβ3 integrin, which in turn induced oligodendrocyte proliferation via a phosphatidylinositol 3-kinase-dependent signaling pathway (Baron et al., 2002).”

“…peripheral nervous system, including failure of normal nerve arborization, delay in Schwann cell migration, survival, proliferation, and differentiation, and defective neuromuscular junction differentiation (GrausPorta et al., 2001; Haack & Hynes, 2001; Feltri et al., 2002; Pietri et al., 2004).”

“…extracellular proteases, and/or turnover of new integrins (Banes et al., 1995; Fukai et al., 1995; Jones et al., 1995; Gualandris et al., 1996; Hoffman et al., 1998a, 1998b; Momota et al., 1998; Wu et al., 1998; Endo et al., 1999; Davis et al., 2000; Wu et al., 2000; Davis et al., 2002;…”

“…support the utility of integrin ligands as potential biomarkers for diagnosis and treatment of tumor and cardiovascular diseases (Cai et al., 2008; Martin-Ventura et al., 2009). α6β4 integrin to laminin of Schwann cells and myelin is detected in the serum of Guillain–Barre syndrome patients while…”

“Some inhibitors such as HYD1 for α6β1 and ATN-161 for FN sequence to block signaling have been studied in clinical or pre-clinical trials (Cianfrocca et al., 2006; Sroka et al., 2006).”

“…ion channels, intracellular Ca2+ concentrations, cellular contractile properties, protein kinase activity, and growth factor receptors (Hynes, 1992; Yip & Marsh, 1997; Porter & Hogg, 1998; Wu et al., 1998; Barouch et al., 2000; Chan et al., 2001; Danen & Yamada, 2001; Davis et al., 2001; Wu et…”

“A series of observations from our previous studies show that at least 3 different integrins regulate CaL, Ca activated K channels and myogenic responses in vascular systems, and in heterologously expressed smooth muscle CaL in HEK cells through inside–out and outside–in signaling between integrin and FAC (Wu et al., 1…”

“Data compiled from: Horwitz (1997); Clemetson and Clemetson (1998); Wu and Davis (1998); Ross and Borg (2001); Staunton et al.”

“These reports concluded that α4β1, α4β7, and αEβ7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis (Bartt, 2006; Engelhardt & Kappos, 2008…”

“This study suggested that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites (Darius et al., 2000).”

“Integrin neurobiology may provide a novel target to develop new drug candidates as ‘anti-epileptogenic’ (Reddy, 2010; Pack et al., 2011).”

“…extracellular proteases, and/or turnover of new integrins (Banes et al., 1995; Fukai et al., 1995; Jones et al., 1995; Gualandris et al., 1996; Hoffman et al., 1998a, 1998b; Momota et al., 1998; Wu et al., 1998; Endo et al., 1999; Davis et al., 2000; Wu et al., 2000; Davis et al., 2002;…”

“…and synthesis of ECM molecules (e.g. FN, reelin, and glycosaminoglycans), and activation of integrin– intracellular signaling pathways following seizure activity in the hippocampus (Hoffman et al., 1998b, 1998c; Naffah-Mazzacoratti et al., 1999; Perosa et al., 2002a, 2002b; Gong et al., 2007).”

“…and oligodendrocyte differentiation and blockage of migration, and αvβ8 promotes astrocyte migration (Fernandez-Valle et al., 1994; Milner et al., 1996; 1997; Stewart et al., 1997; Milner et al., 1999; Blaschuk et al., 2000; Dubovy et al., 2001; Colognato et al., 2004; Colognato & Tzvetanova,…”

“Aberrant expressions of neurotransmitter receptors, cytoskeletal proteins, synaptic proteins, antioxidant proteins, and MEK have been found in the hippocampus of patients with TLE (Furtinger et al., 2003; Notenboom et al., 2006; Yang et al., 2006; Perosa et al., 2007).”

“There are several reports regarding β1-integrin family activated excitatory NMDA currents and Ca currents in neurons as discussed above (Lin et al., 2003; Bernard-Trifilo et al., 2005; Lin et al., 2005; Gui et al., 2006; Lin et al., 2008).”

“Furthermore, disruption of the integrin-associated protein produces memory deficits in mice (Huang et al., 1998; Chang et al., 1999, 2001).”

“Data compiled from: Horwitz (1997); Clemetson and Clemetson (1998); Wu and Davis (1998); Ross and Borg (2001); Staunton et al.”

“Therefore, integrins as cell surface receptors are attractive pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard…”

“After pilocarpine-induced status epilepticus, strong immunoreactivity for α1-, α2-, α4-, α5-, β1-, β3-, and β4-integrins is observed in reactive astrocytes (Fasen et al., 2003).”

“The increased concentration of hyaluronic acid and chondroitin sulfate in the hippocampus of TLE patients demonstrates the importance of the matrix compounds during neosynaptogenesis, neurite outgrowth, and the mossy fiber sprouting found in temporal lobe epilepsy phenomena (Perosa et al., 2002a).”

“2) (Pinkstaff et al., 1999; Renaudin et al., 1999; Yanagida et al., 1999; Chun et al., 2001; Chan et al., 2003; Morini & Becchetti, 2010).”

“…could be primary events leading to development of the epilepsy (Tauck & Nadler, 1985; Sutula et al., 1988; de Lanerolle et al., 1989; Chang et al., 1993; Wuarin & Dudek, 2001; Smith & Dudek, 2002; Lin et al., 2003; Bernard-Trifilo et al., 2005; Lin et al., 2005; Gui et al., 2006; Lin et al., 2008).”

“Genetic variants with integrin α2-subunit have been reported to be associated with an increased risk for ischemic stroke (Matarin et al., 2008).”

“…neurons, and could be primary events leading to development of the epilepsy (Tauck & Nadler, 1985; Sutula et al., 1988; de Lanerolle et al., 1989; Chang et al., 1993; Wuarin & Dudek, 2001; Smith & Dudek, 2002; Lin et al., 2003; Bernard-Trifilo et al., 2005; Lin et al., 2005; Gui et al., 2006;…”

“There is increasing evidence for a functional correlation between the localization of integrins in the hippocampus and the role that integrins may play in neuronal epileptiform activities (Chang et al., 1993; Grooms & Jones, 1997).”

“Following stroke, β1-integrin is increased in cerebral blood vessel in ipsilateral ischemic cortex, and is involved in modulating angiogenesis in ischemic stroke (Lathia et al., 2010).”

“…pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard et al., 2011; Reichardt & Prokop, 2011).”

“2) (Pinkstaff et al., 1999; Renaudin et al., 1999; Yanagida et al., 1999; Chun et al., 2001; Chan et al., 2003; Morini & Becchetti, 2010).”

“…receptors are attractive pharmacological targets for designing new therapies for brain diseases (Horwitz, 1997; Clemetson & Clemetson, 1998; Wu & Davis, 1998; Davis et al., 2001; Ross & Borg, 2001; Gall & Lynch, 2004; Jin & Varner, 2004; Lal et al., 2007; Cox et al., 2010; Millard et al., 2011;…”

“Most of the eight RGD binding integrins are expressed at elevated levels in various cancer types where they contribute to crucial pathophysiological functions in cancer as well as in other diseases, such as neurological disorders [36], sepsis [37], fibrosis [38], cardiovascular diseases [39], and viral infections [40].”

“Mechanosensitive activation of these transcription factors likely occurs via integrins, the family of extracellular matrix receptors that has been widely implicated in a range of functions including gene expression, cell proliferation, migration and differentiation, and cell survival (Wu and Reddy, 2012).”

“Integrins are known to control cell development, mediate cell interaction and modulate immune signalling in glial cells [29].”