9-Review Glial scar-modulation as therapeutic tool in spinal cord injury in animal models1 Jéssica Rodrigues OrlandinI, Carlos Eduardo AmbrósioIII, Valéria Maria LaraII IFellow Master degree, Postgraduate Program in Animal Bioscience, Veterinary Medicine Department, Faculty of Animal Science and Food Engineering, Universidade de São Paulo (FZEA/USP), Pirassununga-SP, Brazil. Intellectual, scientific, conception and design of the study; acquisition, analysis and interpretation of data; manuscript writing. IIPostdoctoral Researcher, Postgraduate Program in Animal Bioscience, Veterinary Medicine Department, FZEA/USP, Pirassununga-SP, Brazil. Conception and design of the study, critical revision, final approval. IIIResearcher, CNPq Grant Level 1A – CA VT, Veterinary Medicine Department, FZEA/USP, Pirassununga-SP, Brazil. Conception and design of the study, manuscript writing, critical revision, final approval. Abstract Purpose: Spinal Cord injury represents, in veterinary medicine, most of the neurological attendances and may result in permanent disability, death or euthanasia. Due to inflammation resulting from trauma, it originates the glial scar, which is a cell interaction complex system. Its function is to preserve the healthy circuits, however, it creates a physical and molecular barrier that prevents cell migration and restricts the neuroregeneration ability. Methods: This review aims to present innovations in the scene of treatment of spinal cord injury, approaching cell therapy, administration of enzyme, anti-inflammatory, and other active principles capable of modulating the inflammatory response, resulting in glial scar reduction and subsequent functional improvement of animals. Results: Some innovative therapies as cell therapy, administration of enzymes, immunosuppressant or other drugs cause the modulation of inflammatory response proved to be a promising tool for the reduction of gliosis Conclusion: Those tools promise to reduce gliosis and promote locomotor recovery in animals with spinal cord injury. Key words: Stem Cells. Inflammation. Neuroprotection. Models, Animal. DOI: http://dx.doi.org/10.1590/s0102-865020170209 Acta Cir Bras. 2017;32(2):168-174 168 Acta Cir Bras. 2017;32(2):168-174 Glial scar-modulation as therapeutic tool in spinal cord injury in animal models Orlandin JR et al. ■ Spinal cord injury in veterinary After the injury, fibroblasts migrate medicine into the epicenter of the lesion, forming a fibrotic scar filled with extracellular fibronectin, Spinal Cord Injury (SCI) may have an collagen and laminin16. The proliferation of endogenous or exogenous origin. Regardless of A-type pericytes contributes to the formation the cause, SCI are related to injury, compression, of the fibrosis, even in contused injuries, when transaction, laceration, traction of the neural meninges are intact and responsible for most tissue, hemorrhage and hematoma, hypoxia, of the components of the fibrotic scar. The spinal cord laceration or the associated roots glial scar appears in its mature form within two and others injuries resulting in varying degrees weeks after injury17,18. of neurological disorders1,2. Furthermore, Actived macrophages and microglia physical interruption of nerve impulses and increase significantly the expression of matrix loss of blood flow and auto regulation, other metalloproteinases (MMPs), which contributes biochemical, vascular and inflammatory events to vascular permeability and accumulation of are involved in the neuronal destruction and more inflammatory cells in the lesion, which necrosis3,4. reaches its peak around thirty days after Endogenous capacity of self-repair injury19-21. Therefore, these activated cells, and regenerate of the spinal cord is limited although important for the debridement of after injury5,6, due to the minor capacity of the injured tissue, may also lead to secondary replacement of damaged nerve cells7, as well damage by inflammatory process22. Studies as the production of growth inhibitory myelin have shown that activated macrophages are associated axon and the formation of glial responsible for the gradual and progressive scar8. death of axons after injury, trough the activity The consequences of SCI in veterinary of MMPs and direct physical interaction with medicine, depending on the injured segment injured cells19,20. can lead to permanent disability or euthanasia. The glial response is mainly characterized by hypertrophy of astrocytes migrate out of the ■ Glial scar inflammatory epicenter, where they increase in size and present high gene expression of Glial scar consists predominantly of Glial Fibrillary Acidic Protein (GFAP), vimetin reactive astrocytes, macrophages, microglia and nestin23,24. Hyperatrophic astrocytes and Chondroitin Sulfate Proteoglycans (CSPGs)9, are restructured into a network of tangled that leads to a dense deposit of extracellular filamentous process, which acts protecting collagen matrix, acting as protective barrier scar, viable neural cells, however, resulting in a however, inhibits cell and axonal migration10. major physical barrier for axonal regeneration. Damage of the blood-brain barrier, Furthermore, studies suggest that glial scar leukocytes extravasations and accumulation of prevents the inflammatory process to spread inflammatory cells in the center of the lesion the healthy tissue25,26 are crucial events in the formation of the gliosis. Several molecules derived from blood or ■ Inflammatory response produced via inflammatory has been identified modulation as a therapeutic approach as a trigger for their induction, including interleukin-1, Transformation Growth Factor Several authors associated gliosis beta (TGFβ) and fibrinogen11-15. modulation with the clinical response of spinal 169 Glial scar-modulation as therapeutic tool in spinal cord injury in animal models Acta Cir Bras. 2017;32(2):168-174 Orlandin JR et al. cord injury in animais. In one study, Granulocyte- injury31. Macrophage Colony-Stimulating Factor (GM- Studies using curcimun – an active CSF) was administered intraperitoneally, from component of turmeric, which acts as an anti- 3 to 4 weeks after spinal cord injury in rats. inflammatory – demonstrated the ability of There was a decrease in the expression of the substance to reduces local inflammation, CSPGs and neurocan, intense expression of suppressing the formation of glial scar by GFAP, preservation of axonal arrangement and inhiniting the process of reactive astrocytes structure in inflammatory myelin and improved cytokines and pro-inflammatory such as TNF- gray matter and gliosis reduction27. TNF-α, IL-1β e NK- κb, in addition to promote Yazdani et al.28 compared the protection of neurons and axons after spinal transplantation of cells from the olfactory cord injury in rodents32,33. epithelium and bone marrow-derived Rapamycin – an immunosuppressant mesenchymal stem cells, neurally induced in used for the prophylaxis of organ transplant rats with spinal cord injury. They concluded that rejection – reduces infiltration of neutrophils the induced cells caused significantly motor and macrophages in the lesion, microglial improvement, reduction of the size of injury activation, secretion of TNFβ, the number of and axonal regeneration, making this strategy cells expressing GFAP, inhibited the proliferation promising candidate for future therapies. of astrocytes and promoted neuronal survival Another study has shown that and axiogenesis around the injury, being a Hepatocyte Growth Factor (HGF) has curative good tool in the treatment of spinal cord injury capacity by regulating TGFβ, completely in mice34. blocking the secretion of these factors on Naïve Schwann cells and Schawann cells reactive astrocytes in vitro. The transplantation transduced to express GDNF which were seeded of cells capable of secrete HGF reduced into guidance channels and implanted at the neurocan expression and glycosaminoglycan spinal cord injury by Do-Thi et al.35, inhibit the deposition in the lesion and promoted axonal formation of glial scar by promoting functional growth around the gliosis and functional improvement in rats, when expressed Lv- improvement of the hindlimbs in rats29. shGFAP (lentiviral-mediated RNA-interference Ahmed et al.30 used decorin – a against GFAP). It was also observed growing proteoglycan associated with collagen fibers – axons and increased serotonergic innervation, to block the glial scar and cystic cavitation and suggesting that this type of therapy aids in the induce fibrotic dissolution of gliosis in rats with treatment of spinal cord injury. chronic spinal cord injury. These mechanisms Several studies using the enzyme have been attributed to the induction capacity chondroitinase ABC36-39 in ratis demonstrated of MMPs and plasminogen activity, modulation their potential in digesting CSPGs – inhibitory of inflammation, removal of growth inhibitors molecules predominant in glial scar – modifying and axonal regeneration promotion in the the intra and extracellular architecture, lesion. reducing the formation of gliosis, regenerating Another study demonstrated the axons injured by improving neural connections efficacy of transplantation dedifferentiated and promoting neuroprotection. adipocytes in promoting locomotor By intrathecal bone marrow cells improvement, remyelination, glial scar transplantation, Zhu et al.40 demonstrated that reduction and increased expression of gliosos is more associated with macrophages neurotrophic factors in mice with spinal cord than microglia in mice. Depletion of