Glial scar formation (

gliosis Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, ...

) is a reactive cellular process involving

astrogliosis Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, a ...

that occurs after injury to the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. As with

scarring A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a na ...

in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system. In the context of neurodegeneration, formation of the glial scar has been shown to have both beneficial and detrimental effects. Particularly, many neuro-developmental

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

molecules are secreted by the cells within the scar that prevent complete physical and functional recovery of the central nervous system after injury or disease. On the other hand, absence of the glial scar has been associated with impairments in the repair of the

blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells, and transports Metabolic waste, metabolic waste products away from th ...

Scar components

The glial scar is composed of several components briefly discussed below.

Reactive astrocytes

Reactive

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

are the main cellular component of the glial scar. After injury, astrocytes undergo morphological changes, extend their processes, and increase synthesis of

glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astroc ...

(GFAP). GFAP is an important

intermediate filament Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma''. Intermedia ...

protein that allows the astrocytes to begin synthesizing more cytoskeletal supportive structures and extend

pseudopod A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filamen ...

ia. Ultimately, the astrocytes form a dense web of their plasma membrane extensions that fills the empty space generated by the dead or dying neuronal cells (a process called astrogliosis). The heavy proliferation of astrocytes also modifies the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

surrounding the damaged region by secreting many molecules including

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

tenascin C Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the ''TNC'' gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous sys ...

, and

proteoglycans Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...

. These molecules are important modulators of neuronal outgrowth. Accordingly, their presence after injury contributes to inhibition of regeneration. Another important caveat of the astrocytic response to CNS injuries is its heterogeneity. Particularly, the response of the astrocytes to the injury varies depending on factors such as the nature of the injury and the microenvironment at the injury location.David S, Ness R. (1993). "Heterogeneity of reactive astrocytes." In: Fedoroff S (ed) ''Biology and pathology of astrocyte-neuron interactions''. Plenum Press, New York, pp. 303-312.Fernaud-Espinosa I, Nieto-Sampedro N, Bovolenta P. (1993). "Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue." ''Glia'' 8: 277-291. Further, the reactive astrocytes in the immediate vicinity of the injury increase gene expression, thus compounding the response of other astrocytes and contributing to the heterogeneity. Particularly, astrocytes closest to the lesion generally secrete more inhibitory molecules into the extracellular matrix.

Microglia

Microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

are the second most prominent cell type present within the glial scar. They are the nervous system analog of immune system

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

. Microglia rapidly activate near the injury and secrete several

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

, bioactive lipids, coagulation factors, reactive oxygen intermediates, and

neurotrophic factors Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...

.Elkabes S, DiCicco-Bloom EM, Black IB (1996). "Brain microglia/ macrophages express neurotrophins that selectively regulate microglial proliferation and function", ''Journal of Neuroscience'' 16: 2508–2521 The expression of these molecules depends on the location of the microglial cells relative to the injury, with the cells closest to the injury secreting the largest amount of such biologically active molecules.

Endothelial cells and fibroblasts

The various biologically active molecules secreted by microglia stimulate and recruit

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

and

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

. These cells help stimulate

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

and collagen secretion into the injured area. Ultimately, the amount of capillaries extended into the injured area is twice that of uninjured central nervous system regions.Jaeger CB, Blight AR (1997). "Spinal compression injury in guinea pigs: structural changes of endothelium and its perivascular cell associations after blood–brain barrier breakdown and repair." ''Experimental Neurology'' 144: 381-399.

Basal membrane

The basal membrane is a

histopathological Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...

feature that forms at the center of injury and partially covers the astrocytic processes. It is composed of three layers with the

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

as the prominent layer. Molecularly, the basal membrane is created by glycoprotein and proteoglycan protomers. Further, two independent networks are formed within the basal membrane by

collagen IV Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...

and

for structural support. Other molecular components of the basal membrane include

fibulin Fibulin (FY-beau-lin) (now known as Fibulin-1 FBLN1) is the prototypic member of a multigene family, currently with seven members. Fibulin-1 is a calcium-binding glycoprotein. In vertebrates, fibulin-1 is found in blood and extracellular matrices ...

-1,

entactin Nidogen-1 (NID-1), formerly known as entactin, is a protein that in humans is encoded by the ''NID1'' gene. Both nidogen-1 and nidogen-2 are essential components of the basement membrane alongside other components such as type IV collagen, proteogl ...

, and heparin sulfate proteoglycan perlecan. Ultimately, the astrocytes attach to the basal membrane, and the complex surrounds the blood vessels and nervous tissue to form the initial wound covering.

Beneficial effects of the scar

The ultimate function of the glial scar is to reestablish the physical and chemical integrity of the CNS. This is done by generating a barrier across the injured area that seals the nervous/non-nervous tissue boundary. This also allows for the regeneration of the selective barrier to prevent further microbial infections and spread of cellular damage. Moreover, the glial scar stimulates

revascularization In medical and surgical therapy, revascularization is the restoration of perfusion to a body part or organ that has had ischemia. It is typically accomplished by surgical means. Vascular bypass and angioplasty are the two primary means of reva ...

of blood capillaries to increase the nutritional, trophic, and metabolic support of the nervous tissue.

Detrimental effects of the scar

The glial scar also prevents neuronal regrowth. Following trauma to the CNS, axons begin to sprout and attempt to extend across the injury site in order to repair the damaged regions. However, the scar prevents axonal extensions via physical and chemical means. Astrocytes form a dense network of

gap junctions Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

that generates a physical barrier to axonal regrowth. Further, the astrocytes secrete several growth-inhibitory molecules that chemically prevent axonal extensions. Moreover, the basal membrane component is expected to generate an additional physical and chemical barrier to axonal extensions.

Primary scar molecular inducers

The formation of the glial scar is a complex process. Several main classes of molecular mediators of gliosis have been identified and are briefly discussed below.

Transforming growth factor β

Two neuronally-important subclasses of

transforming growth factor Transforming growth factor (, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ. The name "Transforming Growth Factor" is somewhat arbitrary, since the two classes of TGFs are not structurally or genetically rel ...

family of molecules are TGFβ-1 and TGFβ-2 that directly stimulate astrocytes, endothelial cells, and macrophages. TGFβ-1 has been observed to increase immediately after injury to the central nervous system, whereas TGFβ-2 expression occurs more slowly near the injury site. Further, TGFβ-2 has been shown to stimulate growth-inhibitory

proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...

s by astrocytes.Asher RA, ''et al.'' (2000). "Neurocan is upregulated in injured brain and in cytokine-treated astrocytes." ''Journal of Neurosciemce'' 20, 2427–2438. Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring.Moon LDF, Fawcett JW. (2001). "Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFβ1 and β2." ''European Journal of Neuroscience'' 14, 1667–1677.

Interleukins

Interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...

s are another potential family of scar-inducing cellular messengers. Particularly, interleukin-1, a protein produced by mononuclear

phagocyte Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...

s, helps to initiate the inflammatory response in astrocytes, leading to reactive astrogliosis and the formation of the glial scar.Giulian D, ''et al.'' (1988). "Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization." ''Journal of Neuroscience'' 8, 2485–2490.Silver J, Miller J. (2004). "Regeneration beyond the glial scar." ''Nature Reviews Neuroscience''. 5(2): 146-156.

Cytokines

The

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

family of glial scar inducers include interferon-γ (IFNγ) and fibroblast growth factor 2 (FGF2). IFNγ has been shown to induce astrocyte proliferation and increase the extent of glial scarring in injured brain models.Yong VW ''et al.'' (1991). "γ-Interferon promotes proliferation of adult human astrocytes ''in vitro'' and reactive gliosis in the adult mouse brain ''in vivo''." ''PNAS USA'' 88, 7016–7020. Further, FGF2 production increases after injury to the brain and spinal cord. FGF2 has also been shown to increase astrocyte proliferation ''in vitro''.Lander C, ''et al.'' (1997). "A family of activity-dependent neuronal cell-surface chondroitin sulfate proteoglycans in cat visual cortex." ''Journal of Neuroscience'' 17, 1928–1939.Mocchetti I, ''et al.'' (1996). "Increased basic fibroblast growth factor expression following contusive spinal cord injury." ''Experimental Neurology'' 141, 154–164.

Ciliary neurotrophic factor

Ciliary neurotrophic factor (CNTF) is a cytosolic protein that is not secreted. CNTF has been shown to promote the survival of neuronal cultures ''in vitro'', and it can also act as a differentiator and

trophic factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...

on glial cells. Further, CNTF has been previously shown to affect the differentiation of glial precursor cells ''in vitro''; however, the influence of CNTF in the ''in vivo'' setting has only recently been determined. Winter ''et al.'' used CNTF over-expressing transgenic mice as well as wildtype controls that had CNTF levels artificially elevated via injection, were subjected to neuronal damage using ZnSO₄ (a known neuronal degenerative factor), which was injected intranasally in the

olfactory The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste. In humans, it ...

epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...

. The

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...

was then assessed for the expression of GFAP

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

- a common marker for the glial scar. It was determined that mice with elevated levels of CNTF increased their GFAP mRNA expression two-fold. This data suggests that CNTF may mediate glial scar formation following CNS damage.Winger, CG, ''et al.'' (1995). "A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury", ''Proc. Natl. Acad. Sci, USA'', 92, 5865 - 5869.

Upregulation of nestin intermediate filament protein

Nestin is an

(IF) protein that assists with IF polymerization and macromolecule stability. Intermediate filaments are an integral part of cell motility, a requirement for any large migration or cellular reaction. Nestin is normally present during (CNS) development and reactivates after minor stresses to the nervous system. However, Frisen ''et al.'' determined that nestin is also

upregulated In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

during severe stresses such as lesions which involve the formation of the glial scar. Mid-thoracic spinal cord lesions,

optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...

lesions, but not lesions to the

sciatic nerve The sciatic nerve, also called the ischiadic nerve, is a large nerve in humans and other vertebrate animals which is the largest branch of the sacral plexus and runs alongside the hip joint and down the lower limb. It is the longest and widest si ...

, have shown marked increases in nestin expression within the first 48 hours after trauma. Further, nestin upregulation was shown to last for up to 13 months post-injury. This data suggests that nestin upregulation may be associated with CNS glial scarring.Frisen, J. (1995). "Rapid, widespread, and long lasting induction of nestin contributes to the generation of glial scar tissue after CNS injury", ''The Journal of Cell Biology'' 131(2): 453-464.

Suppression of glial scar formation

Several techniques have been devised to impede scar formation. Such techniques can be combined with other neuroregeneration techniques to help with functional recovery.

Olomoucine

Olomoucine, a purine derivative, is a

cyclin-dependent kinase Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...

(CDK) inhibitor. CDK is a cell-cycle promoting protein, which along with other pro-growth proteins is abnormally activated during glial scar formation. Such proteins can increase astrocyte proliferation and can also lead to

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

, thus exacerbating cellular damage at the lesion site. Administration of olomoucine

peritoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...

ly has been shown to suppress CDK function. Further, olomoucine has been shown to reduce neuronal cell death, reduce astroglial proliferation (and therefore reduce astrogliosis), and increase GAP-43 expression, a useful protein marker for neurite growth. Moreover, reduced astrocyte proliferation decreases expression of

chondroitin sulfate proteoglycan Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles i ...

s (CSPGs), major extracellular matrix molecules associated with inhibition of neuroregneration after trauma to the CNS.Tian D, ''et al.'' (2006). "Suppression of Astroglial Scar Formation and Enhanced Axonal Regeneration Associated with Functional Recovery in a Spinal Cord Injury Rat Model by the Cell Cycle Inhibitor Olomoucine", ''Journal of Neuroscience Research'' 84: 1053-1063. Recent work has also shown that olomoucine suppresses

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

l proliferation within the glial scar. This is particularly important because microglia play an important role in the secondary damage following lesion to the CNS, during the time of scar formation. Microglial cells are activated via various pro-inflammatory cytokines (some discussed above). Rat spinal cord injury models have shown remarkable improvements after the administration of olomoucine. One hour-post administration, olomoucine suppressed microglial proliferation, as well as reduced the tissue

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

normally present during the early stages of glial scar formation. Further, 24 hours post-administration, a reduction in concentration of interleukin-1β was observed. Additionally, the administration of olomoucine has also been shown to decrease neuronal

.Tian D., ''et al.'' (2007). "Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats." ''Brain Research'' 1135: 177-185.

Inhibition of phosphodiesterase 4 (PDE4)

Phosphodiesterase 4 is a member of the

phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

family of proteins that cleave

phosphodiester In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is d ...

bonds. This is an important step in degrading

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP), a major intracellular signaling molecule; conversely, blocking PDE4 will increase cAMP. Increased intracellular cAMP levels in neurons has been previously shown to induce axonal growth.Neumann, S., ''et al.'' (2002). "Regeneration of Sensory Axons within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation." ''Neuron'' 34, 885–893. In 2004, Nikulina ''et al.'' showed that administration of ''

rolipram Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts ...

'', a PDE4 inhibitor, can increase cAMP levels in neurons after

spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal cor ...

. This is partially possible because rolipram is sufficiently small to pass through the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

and immediately begin to catalyze reactions in neurons. 10 day administration of rolipram in spinal cord injured rodents resulted in considerable axonal growth associated with a reduction in glial scarring at 2 weeks post-injury. The mechanism for this reduction in glial scarring is currently unknown, but possible mechanisms include axonal extensions that physically prevent reactive astrocytes from proliferating, as well as chemical signaling events to reduce reactive astrogliosis.Nikulina, E. ''et al.'' (2004). "The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery", ''Proc Natl Acad Sci USA'' 101(23): 8786–8790.

Ribavirin

Ribavirin Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...

is a purine nucleoside analogue that is generally used as an anti-viral medication. However, it has also been shown to decrease the amount of reactive astrocytes. Daily administration for at least five days following brain trauma was shown to significantly decrease the number of reactive astrocytes.Pekovic, S., ''et al.'' (2006). "Downregulation of glial scarring after brain injury", ''Annals of the New York Academy of Sciences'' 1048(1): 296-310.

Antisense GFAP retrovirus

An antisense GFAP retrovirus (PLBskG) to reduce GFAP

expression, has been implemented in suppressing growth and arresting astrocytes in the G1 phase of the cell cycle. However, a main caveat to the clinical application of retroviral use is the non-discriminatory effects of PLBskG on normal as well as injured astrocytes. Further ''in vivo'' studies are needed to determine the systemic effects of PLBskG administration.Huang QL, Cai WQ, Zhang KC. (2000). "Effect of the control proliferation of astrocyte on the formation of glial scars by antisense GFAP retrovirus", ''Chinese Science Bulletin'' 45(1): 38-44.

Recombinant monoclonal antibody to transforming growth factor-β2

As noted in the above section, transforming growth factor-β2 (TGFβ2) is an important glial scar stimulant that directly affects astrocyte proliferation. Logan ''et al.'' developed monoclonal antibodies to TGFβ2, cerebral wounds were generated in rat brains, and the antibodies were administered via the ventricles, daily for 10 days. Subsequent analysis showed a marked reduction in glial scarring. Particularly, extracellular matrix protein deposition (

, and

s) was closer to baseline (levels of protein expression in an uninjured animal). Further, a reduction in astrocytes and microglia, as well as a reduction in inflammation and

, were observed.Logan A, ''et al.'' (1999). "Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to transforming growth factor-β2", ''European Journal of Neuroscience'' 11: 2367-2374.

Recombinant monoclonal antibody to interleukin-6 receptor

Interleukin-6 (IL-6) is thought to be a molecular mediator of glial scar formation. It has been shown to promote differentiation of

neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...

s into astrocytes. A monoclonal antibody, MR16-1, has been used to target and block the IL-6 receptors in rat spinal cord injury models. In a study by Okada ''et al.'', mice were intraperitoneally injected with a single dose of MR16-1 immediately after generating a spinal cord injury. Blockade of IL-6 receptors decreased the number of astrocytes present at the spinal cord lesion and this decrease was associated with a reduction in glial scarring.Okada S, ''et al.'' (2004). "Blockade of Interleukin-6 Receptor Suppresses Reactive Astrogliosis and Ameliorates Functional Recovery in Experimental Spinal Cord Injury", ''Journal of Neuroscience Research'' 76: 265-276.

Glial scar treatment or removal

Chondroitinase ABC has been shown to degrade glial scars. Degrading the glial scar with chondroitinase has been shown to promote recovery from spinal cord injury, especially when combined with other techniques such as

nerve guidance conduit A nerve guidance conduit (also referred to as an artificial nerve conduit or artificial nerve graft, as opposed to an autograft) is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical trea ...

s, schwann cell transplants, and peripheral nerve autografts.

References

{{Medical resources , ICD10 = , OMIM = , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = Brain disorders