Potential Drug Targets for Neuroregeneration and Repair

Journal of Analytical & Pharmaceutical Research

Abstract Review Article

Unlike the peripheral nervous system (PNS) the adult mammalian central Volume 4 Issue 4 - 2017 nervous system (CNS) does not spontaneously regenerate after injury. Numerous axon-inhibitory molecules are present in the injured CNS and various strategies for overcoming these obstacles and enhancing CNS regeneration had been experimentally developed. Adult neuroregeneration is a complex process, beyond the common knowledge of neurogenesis that also comprises endogenous neuroprotection leading to neuroplasticity and neurorestoration, a therapeutical approach of implantation of viable cells. Regeneration in the CNS implies Department of Molecular Bioprospection, India that new neuron generate either through proliferation of endogenous stem/ progenitor cells or by administration of exogenous stem/precursor cells with *Corresponding author: Dharmendra Saikia, CSIR- Central potential to substitute for lost tissue, or can be maintained by targeting the axon Institute of Medicinal and Aromatic Plants, Lucknow 226 inhibitory molecule in the CNS. Here, the main focus of review emphasis on the 015, Uttar Pradesh, India, Tel: 0522-2718650; Email: axon inhibitory molecules, which prevents neuroregeneration and repair.

Keywords: Neuroregeneration; Proteoglycans; NOGO; Sema-4D; Mesenchymal Received: March 22, 2017 | Published: April 07, 2017 stem cells; Carbon nanotubes

Abbreviations: PNS: Peripheral Nervous System; CNS: Central Nervous System; MAG: Myelin Associate Glycoprotein; CSPGs: are able to re-grow as long as the cell body is intact. Unlike PNS Chondroitin Sulphate Proteoglycans; ECM: Extracellular Matrix; injury,they enter CNS theinjury distal is notstump. following Previous the findingextensive explains regeneration that axons [3]. HSPGs: Heparin Sulphate Proteoglycans; GFAP: Glial Fibrillary Acidic Protein; KSPGs: Keratan Sulphate Proteoglycans; GlcNAc: glial cells and the complex, impermissible extracellular growth Galactose and N-Acetylglucosamine; environment,Regeneration inwhich the CNS is isformed limited by due the to inhibitorymigration influences of myelin- of associated inhibitors, astrocytes, microglia, oligodendrocytes and Introduction their forerunner. The environment in the CNS, especially after trauma and invasive damage, prevents the repair of myelin and Neuroregeneration refers to the repair or re-growth of neurons [4]. In addition to myelin, glial scar tissue that forms at nervous tissues by generation of new neurons, axons, glial cells, myelin, or synapses [1]. Since perpetuity, damage to the CNS was and axonal debris not cleared rapidly after CNS injury, which may untreatable. No effective treatment regimen was available for contributethe lesion siteto glial also scar suppresses formation. fiber The growth. proximal Inhibitory axons attempt myelin rejuvenate nerve function after injury to the CNS, and multiple to regenerate after injury; however, their growth is affected by attempts at neural re-growth were unsuccessful [2] simply due the glial scar formation. It is important to note that the primary to a lack of knowledge of CNS regeneration. In recent past, the problem with axonal regeneration in the CNS is to waive the discovery that adult CNS neurons are able to reproduce after inhibitory environment associated with axonal regeneration [5]. injury has overcome this therapeutic nihilism. Nervous system injuries affected the lives of thousands of Inhibition of Axonal Regrowth people every year. Due to high incidence of neurological injuries, Earlier studies have reported that glial scar formation may

rapidly over the past few years and has provided attractive new to the CNS [6]. In addition, the adverse environment is a the field of neuroregeneration research has been advancing insights into the physiological functions and pathogenic roles majorsignificantly inhibitor inhibit of fruitful nerve recovery regeneration after injury following to the damage CNS. of a broad range of molecules linked with several annihilating neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Amyotrophic lateral sclerosis, Down syndrome, Fronto-temporal proteoglycans,Molecules, such phosphacan, as transforming and neurocan growth believed factors beta-1(β-1)to promote dementia and Huntington’s disease. glialand beta-2(β-2),scar formation cytokines, (gliosis). interleukins,Further, astrocytes chondroitin may aid sulphate in the Nervous system is divided into two major parts viz. CNS, which upregulation of chondroitin sulphate proteoglycans, thereby consists of the brain and spinal cord, and the PNS, which consists inhibiting nerve regeneration. These upregulated molecules may of cranial and spinal nerves along with the associated ganglia. affect the composition of the extracellular matrix and inhibit Previous studies reveals that neuroregeneration in the PNS is not neurite outgrowth in the CNS. Additionally, molecules such as uncommon. Damage of neurons in the PNS immediately induces chondroitin sulphate proteoglycans, ephrins, EphA4, and Sema3A the migration of macrophages and phagocytes to the lesion site. provoke inhibition of axonal regeneration. Previous studies Axonal sprouts then form at the proximal stump and grow until in glial scar tissue in comparison to normal brain tissue. In revealed that the expression of phosphacan significantly declined

addition, neurocan level was elevated in astrocytes in glial scars production of several CSPGs family members is affected by spinal and it remains elevated one month after the initial injury. Nogo, cord injury, overall establishing a CSPGs-rich matrix that persists a protein family has been associated with the inhibition of re- for up to 8 weeks following injury. Optimization of strategies to myelination in the CNS. Studies suggested that Nogo A may play reduce CSPGs expression to enhance regeneration may need to a key role in autoimmune-mediated de-myelination. Nogo-66 is target several different family members over an extended period responsible for neurite outgrowth inhibition. Nogo A functions following injury. [8-10]. via its amino-Nogo terminus or by its Nogo-66 terminus. Keratan Sulphate Proteoglycans Oligodendrocyte myelin glycoprotein and myelin associate glycoprotein (MAG) may activate receptor NgR a protein that Keratan sulphate proteoglycans (KSPGs) augmented after CNS in humans encoded by RTN4G gene mediates plasticity and injury and act as inhibitory cues. KSPGs induced in the lesion of regulates axonal regeneration. Additionally, lipopolysaccharide CNS injury and regarded as nonpermissive cue to neuronal axon or lipooligosaccharide may impart a protective mechanism regeneration [11,12]. However, roles of KSPGs in CNS injury have in neuroregeneration. Recently, Bingham et al. reported not studied extensively. KSPGs a glycosaminoglycan, which is lipopolysaccharide treatment after injury protects rat neuronal elongated from N- or O-glycans covalently, attached to scaffold and glial cell cultures [7]. proteins. KSPGs composed of repeating disaccharide units of galactose and N-acetylglucosamine (GlcNAc), with sulphate Chondroitin Sulphate Proteoglycans residues at the C6 position of galactose and GlcNAc. As GlcNAc sulfation at the C6 position is necessary for KSPGs chain elongation Chondroitin sulphate proteoglycans (CSPGs) are extracellular [13] failure in this sulfation may lead to loss of KSPGs synthesis. matrix (ECM) component that are generally expressed in cartilage Previous studies reported that KSPGs expression in the developing and in the developing and adult CNS, these molecules impart a key characteristics in neuronal development and glial scar formation. antibody. These 5D4 immuno-reactivities can eliminate in mice They are also involved in cell processes, such as adhesion, growth, brain is detectableN-acetylglucosamine with 5D4, a6- O KSPGs-sulfotransferase-1. -specific monoclonal In mice, receptor binding, migration, and interaction of cell with the other brain injury upregulates mRNA expression of N-acetylglucosamine extracellular matrix constituents. They are also certain to acts 6-deficientO-sulfotransferase-1 in as well as 5D4-reactive KSPGs in the wounded area. Intriguingly, the expression of 5D4-reactive KSPGs protein in ECM [8]. CSPGs generally secreted from cells. They are and reactive astrocyte accumulation in the wounded area found ofbetween, two types, among chondroitin with laminin, sulphate fibronectin, (CSPGs) tenascin, and heparin and sulphatecollagen (HSPGs). The CSPGs acts as a barrier-forming molecule, whereas the HSPGs stabilise the communication of receptors and ligands. enhancementdecreased in theof neuronal sulfotransferase-deficient regeneration after mice. brain Consequently, injury. Thus, During developmental stage CSPGs patterns the cell migration, N-theacetylglucosamine deficient mice exhibit 6-O a-sulfotransferase-1 marked reduction inplays scar formationindispensable and axon growth pathways and axon terminations. Later in adulthood, roles in brain KSPGs biosynthesis and glial scar formation after CSPGs associate with some classes of neuron and control plasticity. brain injury [14,15]. After damage to the CNS, CSPGs are the major axon growth inhibitory, smallest unit of the glial scar tissue that keeps from Growth-Inhibitory Molecules in the CNS doing good regeneration. CSPGs have a diverse role in the nervous system, including binding to the molecules and blocking their A variety of molecule’s known to exist in the adult CNS have action, presenting molecules to cells and axons, localising active been shown through in vitro and in vivo studies to demonstrate molecules to particular sites and presenting growth factors to their axonal growth-inhibitory properties. More importantly, many receptors. In vitro studies demonstrate their potential to restrict neurite outgrowth and it is believed to inhibit axonal regeneration after CNS injury in vivo. Previous studies indicate that CSPGs are types:of these myelin-associated molecules are specific molecules to, or upregulatedand Extracellular in the injuredmatrix generally upregulated after spinal cord injury, and more recent constituents.CNS environment. These molecules classified into two main research have begun to identify individual proteoglycans that may play dominant roles in limiting axonal regeneration. The Myelin Associated Molecules study examined the extended deposition patterns after CNS injury In the late 1980s Schwab and colleagues demonstrated that a of four putatively inhibitory CSPGs that has not been extensively substrate non-permissive to growth exists in CNS white matter investigated previously in vivo: neurocan, brevican, phosphacan, [16-19] leading to the hypothesis that where myelinated axons are and versican. After injury to spinal cord, neurocan, brevican, disrupted, debris containing myelin-associated axon-inhibitory and versican immunolabeling raised within days in injured molecules will be present around the lesion. spinal cord parenchyma surrounding the lesion site and spike at 2 weeks. Neurocan and versican were persistently elevated A number of myelin-associated molecules have since been for 4 weeks postinjury, and brevican expression persisted for at isolated that have axon-inhibitory properties, including the two least 8 weeks. On the other hand, phosphacan immunolabeling neurite growth inhibitors Nogo (originally called NI-250) and decreased in the same region immediately following injury but myelin-associated glycoprotein (MAG). later recovered and then peaked after 8 weeks. Combined glial Extracellular Matrix Constituents (ECM) Constituents in situ hybridization demonstrated that GFAP astrocytes constituted a For many neurons, their migration and axon elongation occurs sourcefibrillary of acidicneurocan protein production (GFAP) immunohistochemistry after spinal cord injury. and Thus, the through the ECM. In the CNS the ECM is largely devoid of cells

Citation: Kumar A, Rawat NS, Kurmi A, Tripathi SB, Chauhan S (2017) Potential Drug Targets for Neuroregeneration and Repair. J Anal Pharm Res 4(4): 00109. DOI: 10.15406/japlr.2017.04.00109 Copyright: Potential Drug Targets for Neuroregeneration and Repair ©2017 Kumar et al. 3/7

but contains several types of molecules with which neurons increased our understanding of the mechanisms underlying spinal cord injury, multiple sclerosis, and neurodegenerative many aspects of a cell’s behaviour. The extracellular space diseases. Research suggests that blocking Nogo-A during neuronal and glia interact, and these can have important influences on damage will help to protect or restore the damaged neurons [42]. a network of glycoproteins, proteoglycans and hyaluronan, The investigation into the mechanisms of this protein presents closesurrounding to the manymembrane nonneuronal of such cellscells inthe the ECM CNS becomes is filled more with a great potential for the treatment of auto-immune mediated dense, forming a basement membrane composed principally of demyelinating diseases and spinal cord injury regeneration. It has collagens; glycoproteins – particularly tenascin- C and tenascin-R; also been found to be a key player in the process whereby physical chondroitin sulphate proteoglycans and heparan sulphate exercise enhances learning and memory processes in the brain. proteoglycans; hyaluronic acid; cell adhesion molecules and Understanding the biological functions of Nogo family members integrins. ECM molecules expressed in the developing CNS may may open up a new avenue for the development of therapeutic have both growth-promoting and growth-inhibitory effects on agents. axons [20-25]. Many of these molecules are upregulated in the adult ECM following a lesion to the CNS and have been shown to Myelin-associated glycoprotein and its axonal receptors have inhibitory properties towards regenerating axons. Tenascin Myelin-associated glycoprotein (MAG) is a cell surface is an important secreted ECM component with a range of binding sites and functions [26-30]. Tenascin is abundant in the basement extracellular Ig-like domains, a single transmembrane domain, membrane, being produced by astrocytes during development, andmember one of of two the alternatively immunoglobulin-like spliced short (Ig) cytoplasmic superfamily, tails with [43]. five with important roles in mediating axon-glia interactions It is coded by a single gene that is conserved among vertebrates [27,30,31]. There are two members of the tenascin gene family: [44], human and rodent MAG are 95% identical at the amino acid tenascin-C and tenascin-R; tenascin-C is expressed as numerous level over the entire extracellular expressed domain (5 Ig-like alternatively spliced variants with various functions [32-34]. domains, 500 amino acids). MAG is produced only in myelinating The same tenascin molecule may have either growth-inhibitory glial cells: oligodendrocytes in the CNS and Schwann cells in or growth promoting effects towards different neurons within different contexts; a number of studies have demonstrated the (comprising 1% of CNS and 0.1% of PNS myelin protein) MAG is neurite growth-inhibitory properties of tenascin in vitro [35,36]. notthe expressed PNS, although uniformly it is athroughout quantitatively myelin. minor In the myelin CNS, proteinMAG is It also has growth-promoting effects ascribed to the alternatively located on the inner-most (periaxonal) non-compacted myelin spliced A-D and D5 domains [37,38]. Tenascin is found in the wrap [45]. In the PNS MAG is found on periaxonal myelin, and on normal adult CNS although at lower levels than in the developing other noncompacted myelin (paranodal loops, Schmitt-Lanterman CNS. Production is up-regulated in the glial scar after injury incisures, and the mesaxon). Myelination of axons provides for the increased tenascin has been co-localized with reactive glial rapid nerve conduction that is essential to vertebrate nervous system function. In addition to providing segmental insulation, known to interact with many CSPGs in vitro [28] and thus may myelin enhances axon survival, regulates the axon cytoskeleton, befibrillary capable acidic of forming protein (axon (GFAP) inhibitory) and astrocytes complexes [39]. with Tenascin CSPGs inis directs the distribution of molecules at nodes of Ranvier, and injured CNS tissue. inhibits axon regeneration after injury [46-48]. Knowledge of the myelin molecules and axon receptors responsible for the nurturing Other Inhibitory Factors and inhibiting effects of myelin on axons may provide insight into Nogo the basis of dysmyelinating disorders and provide lead molecules to enhance axon regeneration after injury or disease. Nogo, also known as Reticulon-4, is a protein, in humans Sema-4D Semaphorin 4D (Sema 4D) is an axon guiding molecule which inhibitoris encoded of byneurite the RTN4outgrowth. gene Reticulons [40,41] that are is associated specific to with the is secreted by oligodendrocytes and induces growth cone collapse thecentral endoplasmic nervous systemreticulum, (CNS), and andare involved has been in identifiedneuroendocrine as an isolated in the immune system where it is involved in B and T cell Nogo-A is the largest member of the Nogo family and is responsible activation.in the central Sema4D nervous is expressedsystem. Sema4D, in cells also throughout called CD100, the CNS was white first forsecretion inhibition or of in CNS membrane regeneration. trafficking There in are neuroendocrine three isoforms: Nogo cells. matter, with a peak during the myelination period. There are more A, B and C. Nogo-A has two known inhibitory domains including than 20 known semaphorins grouped into eight classes: classes amino-Nogo, at the N-terminus and Nogo-66, which makes up the 1 and 2 are invertebrate semaphorins, classes 3 to 7 are found in molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong neurotropic DNA viruses. Sema4D is composed of a Sema domain, inhibitor of neurite outgrowth, and Nogo-66 is involved in growth avertebrates, Cystine Rich and domain class also5 and called 8, has the been Plexin identified Repeat Domain in some or non- the cone destruction. The Nogo-66 receptor (NgR), a membrane protein which binds to Nogo, may play an important role in function but is found in several different receptors. Three copies signal transduction for several myelin-associated inhibitors. The ofMet this Related repeat Sequence. are found The in CystinePlexin-B1, Rich the domain receptor has foran unknownSema 4D discovery of the Nogo family and the NgR provides an opportunity [49], while the Met receptor contains one copy. Immunoglobulin to develop interventions to promote axonal regeneration in the family members include components of immunoglobulins and CNS after brain injury. Basic and clinical research of Nogo has

cell surface glycoproteins such as the T-cell receptors CD2, CD4, some extent into neuronal and glial cells. Over 10 years ago, it was and CD8. The function of the Sema4D intracellular domain is not claimed that MSC are not only able to differentiate into the cells known, but it has been associated with a serine kinase activity, of mesenchymal lineages but also into neurons [60] and glial cells suggesting bi-directional signaling may take place. By binding [61] based on expression of neuronal and glial markers in vitro. with plexin B1 receptor it functions as an R-Ras GTPase-activating protein (GAP) and repels axon growth cones in both the mature observations [62]. Earlier studies claims MSC exert neurotrophic central nervous system [50,51]. In the immune system, CD100 effectsIn the subsequentby releasing years,a complement several reports of molecules have confirmed that directly those or binds CD72 to activate B cells and dendritic cells, though much indirectly promote endogenous repair. Such molecules may about this interaction is still under investigation [52,53]. include neurotrophic growth factors, chemokines, cytokines, and extracellular matrix proteins. The effect of such factors can be very During skin damage repairs, SEMA4D interacts with Plexin B2 on gamma delta t cells to play a role in the healing process [54]. synaptogenic and inhibition of scarring [63]. Paracrine effects Soluble forms of Sema4D had neurotrophic effects which were involvebroadly direct classified neurotrophic as angiogenic, and/or neurogenic, neuroprotective neuroprotective, activity on inhibited by neutralizing antibodies to Sema4D. Sema4D strikingly either resident progenitor cells, hence inducing neurogenesis/ potentiated neurite outgrowth in the presence of 50ng/ml NGF oligodendrogenesis, or protective, anti-apoptotic effects on and increased sensitivity to NGF. Cells responded to very low neurons or glia cells, neurite outgrowth and angiogenesis. Potent concentrations of NGF in the presence of 1nM Sema4D. Activation of following signal proteins, protein kinase C (PKC), L-type of voltage-dependent Ca2+ channel, and phosphatidylinositol (PI) relatedanti-inflammatory to these effects and has immunoregulatory been obtained in vitro effects; however, represent it is 3-kinase mediated neurotrophic neurite-outgrowth action of conceivableunique features that of MSC MSC, may among have allsimilar stem regulatory cell types. Mostfunction of the in vivodata, either in their perivascular location or after grafting [64]. neurotrophic signal in PC12 cells [55]. Sema4D. These findings suggest a new function of Sema4D as a Carbon nanotubes Treatment Strategies for Neuroregeneration A decade of advances in nanotechnology has disclosed exciting Living scaffolds for neuroregeneration perspectives and innovative approaches for tissue regeneration Neural tissue engineers are working out on key mechanisms and, more recently, for nerve tissue repair and tune nerve cell behaviour [65,66]. In this scenario, carbon nanotubes are placed early embryonic development to make come into existence living as promising players. Such materials are at the leading edge of scaffoldsimportant for for neuroregeneration axonal pathfinding following and neural damage cell moving and disease. during nanotechnology, due to carbon nanotube well documented Mechanistic approach involve the combined use of haptotactic, electrical, thermal and mechanical properties [67]. Carbon chemotactic, and mechanical cues to explicit cell movement and nanotube cylindrical morphology is reminiscent of that of distal re-growth. Living scaffolds provide these cues through the use neuronal dendrites [68], small cellular processes crucially involved in the ability of neurons to express complex computational skills. combination with biomaterial strategies. Although several hurdles This similarity, together with carbon nanotube topographic existof cells in the engineered implementation in a predefined of living regenerative architecture, scaffolds, generally there in features, physical properties, as conductivity, and surface-to- are considerable therapeutic advantages to using living cells volume ratio [69], sets the stage for carbon nanotube exploitation in conjunction with biomaterials. The leading contemporary in devices able to interface neuronal physiology. The use of living scaffolds for neuro repair are utilizing aligned glial cells nanomaterials in the design of tissue scaffolds in the CNS is and neuronal/axonal tracts to direct regenerating axons across primarily due to their abilities to favour neuronal adhesion, to damaged tissue to appropriate targets, and in some cases to re-create an ECM-like microenvironment and to interact with directly replace the function of lost cells. Future advances in neuronal membranes at the nanoscale. In fact, a fundamental technology, including the use of exogenous stimulation and step, in any strategies aimed at improving CNS regenerative genetically engineered stem cells, will further the potential of ability, is the manufacturing of scaffolds which are able to control living scaffolds and drive a new era of personalized medicine for and tune cellular adhesion [70], to govern axonal regrowth and neuroregeneration [56]. neuronal physiology [71,72]. The achievements in chemically functionalizing carbon nanotubes pushed the development of Mesenchymal stem cells a variety of soluble forms of nanotubes for molecular sensing, diagnostics, drug delivery and for use as contrast agents. Mesenchymal stem cells (MSC) initially termed mesenchymal From the neuronal perspective, soluble functionalized carbon nanotubes can be internalized by neurons and usually affect workers. Stem cell-based therapies emerge as a possible strategy tostromal treat diseases cells, were of the first CNS identified [57]. MSC by are Friedenstein of particular andinterest co- carbon nanotubes on neuronal morphology came in 2005, when for regenerative therapies not only due to their multipotentiality, Nineuronal and colleagues performance. [73] Thedemonstrated first evidence that of water-soluble an impact of solublecarbon but also mainly because these cells have proregenerative and nanotubes functionalized with PABS or PEG applied to dissociated immunomodulatory properties The bone marrow-derived MSC is hippocampal neurons in vitro induce an increase in neurite length, the most studied type of MSC. They have potential to differentiate paralleled by a reduction in the number of neurites and growth into adipocytes, chondroblasts and osteoblasts [58]. Several cones. Calcium imaging experiments allowed the same authors authors have described differentiation into myocytes [59] and to

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Citation: Kumar A, Rawat NS, Kurmi A, Tripathi SB, Chauhan S (2017) Potential Drug Targets for Neuroregeneration and Repair. J Anal Pharm Res 4(4): 00109. DOI: 10.15406/japlr.2017.04.00109