Glial scar
Encyclopedia
Glial scar formation is a reactive cellular process involving astrogliosis
that occurs after injury to the Central Nervous System
. As with scarring 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
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.
After injury, astrocytes undergo morphological changes, extend their processes, and increase synthesis of glial fibrillary acidic protein
(GFAP). GFAP is an important intermediate filament
protein that allows the astrocytes to begin sythesizing more cytoskeletal supportive structures and extend pseudopod
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
surrounding the damaged region by secreting many molecules including laminin
, fibronectin
, tenascin C
, and proteoglycans. 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. 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.
are the second most prominent cell type present within the glial scar. They are the nervous system analog of immune system macrophages. Microglia rapidly activate near the injury and secrete several cytokines, bioactive lipids, coagulation factors, reactive oxygen intermediates, and neurotrophic factors
. 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.
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.
feature that forms at the center of injury and partially covers the astrocytic processes. It is composed of three layers with the basal lamina
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
and laminin
for structural support. Other molecular components of the basal membrane include fibulin
-1, fibronectin
, entactin
, and hepparan 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.
of blood capillaries to increase the nutritional, trophic, and metabolic support of the nervous tissue.
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
s by astrocytes.
Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring.
s are another potential family of scar-inducing cellular messengers. Particularly, interleukin-1, a protein produced by mononuclear phagocyte
s, helps to initiate the inflammatory response in astrocytes, leading to reactive astrogliosis and the formation of the glial scar.
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. Further, FGF2 production increases after injury to the brain and spinal cord. FGF2 has also been shown to increase astrocyte proliferation in vitro.
. The olfactory bulb
was then assessed for the expression of GFAP
mRNA- 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.
is an intermediate filament
(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 during severe stresses such as lesions which involve the formation of the glial scar. Mid-thoracic spinal cord lesions, optic nerve
lesions, but not lesions to the sciatic nerve
, 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.
to help with functional recovery.
(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
, thus exacerbating cellular damage at the lesion site. Administration of olomoucine peritoneally 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 proteoglycans
(CSPGs), major extracellular matrix molecules associated with inhibition of neuroregneration after trauma to the CNS.
Recent work has also shown that olomoucine suppresses microglial
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 microlgial proliferation, as well as reduced the tissue edema
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 cell death
.
family of proteins that cleave phosphodiester bonds. This is an important step in degrading cyclic adenosine monophosphate
(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. In 2004, Nikulina et al. showed that administration of rolipram
, a PDE4 inhibitor, can increase cAMP levels in neurons after spinal cord injury
. This is partially possible because rolipram is sufficiently small to pass through the blood-brain barrier
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.
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 5 days following brain trauma was shown to significantly decrease the number of reactive astrocytes.
, fibronectin
, and chondroitin sulfate proteoglycans
) 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 angiogenesis
, were observed.
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.
Astrogliosis
Astrocytosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons, typically because of hypoglycemia or oxygen deprivation .It usually takes place in prion infections...
that occurs after injury to the Central Nervous System
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. As with scarring 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
Something that restrains, blocks, or suppresses.Inhibitor or inhibition may refer to:* Corrosion inhibitor, a substance that decreases the rate of metal oxidation...
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.
Reactive astrocytes
Reactive astrocytes 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
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
(GFAP). GFAP is an important intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
protein that allows the astrocytes to begin sythesizing more cytoskeletal supportive structures and extend pseudopod
Pseudopod
Pseudopods or pseudopodia are temporary projections of eukaryotic cells. Cells that possess this faculty are generally referred to as amoeboids. Pseudopodia extend and contract by the reversible assembly of actin subunits into microfilaments...
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
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
surrounding the damaged region by secreting many molecules including laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, tenascin C
Tenascin C
Tenascin is a protein that in humans is encoded by the TNC gene.-Interactions:Tenascin C has been shown to interact with fibronectin.-Further reading:...
, and proteoglycans. 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. 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
MicrogliaMicroglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
are the second most prominent cell type present within the glial scar. They are the nervous system analog of immune system macrophages. Microglia rapidly activate near the injury and secrete several cytokines, bioactive lipids, coagulation factors, reactive oxygen intermediates, and neurotrophic factors
Neurotrophic factors
Neurotrophic factors are a family of proteins that are responsible for the growth and survival of developing neurons and the maintenance of mature neurons...
. 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 and fibroblasts. These cells help stimulate angiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
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.
Basal membrane
The basal membrane is a histopathological extracellular matrixExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
feature that forms at the center of injury and partially covers the astrocytic processes. It is composed of three layers with the basal lamina
Basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....
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
Type-IV collagen
Type-IV collagen is a type of collagen found primarily in the basal lamina. The type IV collagen 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, type-IV lacks the regular glycine in every third residue...
and laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
for structural support. Other molecular components of the basal membrane include fibulin
Fibulin
Fibulin 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. In the extracellular matrix, fibulin-1 associates with basement membranes and elastic fibers...
-1, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, entactin
Entactin
Entactin also known as nidogen-1 is a protein that in humans is encoded by the NID1 gene. Entactin is a component of the basement membrane alongside other components such as collagen type IV, proteoglycans , laminin and fibronectin.- Function :Entactin is a member of the nidogen family of basement...
, and hepparan 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 revascularizationAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
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 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 (TGF-β)
Two neuronally-important subclasses of transforming growth factorTransforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
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
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
s by astrocytes.
Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring.
Interleukins
InterleukinInterleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
s are another potential family of scar-inducing cellular messengers. Particularly, interleukin-1, a protein produced by mononuclear phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
s, helps to initiate the inflammatory response in astrocytes, leading to reactive astrogliosis and the formation of the glial scar.
Cytokines
The cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
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. Further, FGF2 production increases after injury to the brain and spinal cord. FGF2 has also been shown to increase astrocyte proliferation in vitro.
Ciliary neurotrophic factor (CNTF)
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 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 epitheliumEpithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. The olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
was then assessed for the expression of GFAP
Glial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
mRNA- 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.
Upregulation of nestin intermediate filament protein
NestinNestin (protein)
Nestin is a type VI intermediate filament protein. These intermediate filament proteins are expressed mostly in nerve cells where they are implicated in the radial growth of the axon...
is an intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
(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 during severe stresses such as lesions which involve the formation of the glial scar. Mid-thoracic spinal cord lesions, optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
lesions, but not lesions to the sciatic nerve
Sciatic nerve
The sciatic nerve is a large nerve fiber in humans and other animals. It begins in the lower back and runs through the buttock and down the lower limb...
, 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.
Suppression of glial scar formation
Several techniques have been devised to impede scar formation. Such techniques can be combined with other neuroregeneration techniquesNerve guidance conduit
A nerve guidance conduit is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries...
to help with functional recovery.
Olomoucine
Olomoucine, a purine derivative, is a cyclin-dependent kinaseCyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, thus exacerbating cellular damage at the lesion site. Administration of olomoucine peritoneally 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 proteoglycans
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
(CSPGs), major extracellular matrix molecules associated with inhibition of neuroregneration after trauma to the CNS.
Recent work has also shown that olomoucine suppresses microglial
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
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 microlgial proliferation, as well as reduced the tissue edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
normally present during the early stages of glial scar formation. Further, 24 hours post-administration, a reduction in concentration of interleukin-1β
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
was observed. Additionally, the administration of olomoucine has also been shown to decrease neuronal cell death
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Inhibition of Phosphodiesterase 4 (PDE4)
Phosphodiesterase 4 is a member of the phosphodiesterasePhosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
family of proteins that cleave phosphodiester bonds. This is an important step in degrading cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(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. In 2004, Nikulina et al. showed that administration of rolipram
Rolipram
Rolipram is a PDE4-inhibitor. Like most PDE4-inhibitors, it is an anti-inflammatory drug. Rolipram is being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects...
, a PDE4 inhibitor, can increase cAMP levels in neurons after spinal cord injury
Spinal cord injury
A spinal cord injury refers to any injury to the spinal cord that is caused by trauma instead of disease. Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence...
. This is partially possible because rolipram is sufficiently small to pass through the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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.
Ribavirin
RibavirinRibavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
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 5 days following brain trauma was shown to significantly decrease the number of reactive astrocytes.
Antisense GFAP retrovirus
An antisense GFAP retrovirus (PLBskG) to reduce GFAP mRNA 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.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 (lamininLaminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, and chondroitin sulfate proteoglycans
Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans are proteoglycans consisting of a core protein and chondroitin sulfate. They are structural components of a variety of human tissues, for example of cartilage.The following CSPGs have been identified:...
) 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 angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, were observed.
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 cellsNeural stem cell
Neural stem cells are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain . In 1992, Brent A...
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.