Redalyc.Animal Model of Cognitive Decline and Neural Transplantation

Avances en Psicología Latinoamericana ISSN: 1794-4724 [email protected] Universidad del Rosario Colombia

Domingues Bertuzzi, Leticia; Santos da Silva, Patricia; Pereira Neto, Élida Fluck; Nicolaidis, Rafael; Alves de Oliveira Jr, Alcyr Animal Model of Cognitive Decline and Neural Transplantation of Stem Cells as a Prospective Therapy Avances en Psicología Latinoamericana, vol. 35, núm. 1, 2017, pp. 165-175 Universidad del Rosario Bogotá, Colombia

Available in: http://www.redalyc.org/articulo.oa?id=79949625013

How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative Animal Model of Cognitive Decline and Neural Transplantation of Stem Cells as a Prospective Therapy

Modelos animales de degeneración cognitiva y uso de transplantes neurales de células madre como terapia Modelos animais de declínio cognitivo e uso de transplantes neurais de células-mãe como terapia

Leticia Domingues Bertuzzi*, Patrícia Santos da Silva*, Élida Fluck Pereira Neto*, Rafael Nicolaidis*, Alcyr Alves de Oliveira Jr* *Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.

Doi: http://dx.doi.org/10.12804/revistas.urosario.edu.co/apl/a.4665

Abstract highlight cell-based therapies as prospective treatment of peripheral and central nervous system disorders. There are few animal models of cognitive decline that Keywords: Animal models of cognitive decline; Alzhei- could be considered as prominent as the cholinergic le- mer’s disease; stem cell based therapy. sion model of Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative disorder associated with aging Resumen with accentuated progressive cognitive impairment. Its multiple complex sequential and interactive neural Existen pocos modelos animales de degeneración cogni- pathways may lead to the understanding that a single tiva que podrían ser considerados tan importantes como agent intervention might be insufficient to impact the el modelo de lesión colinérgica de la enfermedad de Al- course of this disease. The current pharmacological zheimer. La enfermedad de Alzheimer es una patología treatment is palliative and, although it may slow down neurodegenerativa asociada con el envejecimiento y con the disease’s progression, it still cannot offer cure. The degeneración cognitiva acentuada y progresiva. Sus combination of drugs and antioxidant substances has complejas y múltiples vías neurales secuenciales pueden been investigated, nevertheless there are few studies conducir a la comprensión de que las intervenciones de demonstrating optimal and consistent results based on agente único pueden ser insuficiente para impactar el this combination. Thus, the purpose of this paper is to curso de esta enfermedad. El tratamiento farmacológico

* Leticia Domingues Bertuzzi, Patrícia Santos da Silva, Élida Fluck Pereira Neto, Rafael Nicolaidis, Alcyr Alves de Oliveira Jr, Programa de Pós-Graduação em Ciências da Reabilitação, Curso de Psicologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil. Correspondence concerning this article should be addressed to Alcyr Alves de Oliveira Jr., BSc, MSc, MPhil, PhD, Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Departamento de Psicologia, Rua Sarmento Leite, 245 - CEP: 90050- 170 Porto Alegre, RS – Brasil, Phone: 55(51)8125-7582. E-mail: [email protected]

Cómo citar este artículo: Bertuzzi, L. D., Silva, P. P., Fluck, E., Nicolaidis, R., & Oliveira, A. A. (2017). Animal Model of Cognitive Decline and Neural Transplantation of Stem Cells as a Prospective Therapy. Avances en Psicología Latinoamericana, 35(1), 165-175. doi: http://dx.doi.org/10.12804/revistas.urosario.edu.co/apl/a.4665

Avances en Psicología Latinoamericana / Bogotá (Colombia) / Vol. 35(1) / pp. 165-175 / 2017 / ISSNe2145-4515 165 Leticia Domingues Bertuzzi, Patrícia Santos da Silva, Élida Fluck Pereira Neto, Rafael Nicolaidis, Alcyr Alves de Oliveira Jr

actual es paliativo y, aunque pueda retardar el progreso of a specific cell population such as dopaminergic de la enfermedad, no es capaz de ofrecer una cura. La neurons in Parkinson’s disease (PD) or a wide- combinación de drogas y sustancias antioxidantes han spread degeneration of many types of neurons over sido investigadas, sin embargo, existen pocos estudios a period of several years such as in Alzheimer’s que demuestran resultados consistentes basados en esta disease (AD) (Lindvall & Kokaia, 2010). presunción. Así, el objetivo de este artículo fue desta- Alzheimer’s disease is the most prevalent neu- car las terapias basadas en la reposición celular como rodegenerative disorder associated with aging (Nie- potencial tratamiento para enfermedades del sistema dowicz, Nelson, & Murphy, 2011) and its incidence nervioso periférico y central. is expected to grow intensively such that by 2050 Palabras clave: modelos animales de degeneración more than 100 million people worldwide will have cognitiva; enfermedad de Alzheimer; terapia de células developed this dementia (Prince, Bryce, & Ferri, troncales. 2011). AD is characterized by the progressive loss of cognitive functions, specially, memory. Howev- Resumo er, besides compromising the memory, AD is also responsible for deficits in attention, orientation, or- Existem poucos modelos animais de declínio cognitivo ganization, executive functions such as the capacity que poderiam ser considerados tão importantes como o of planning and judging (Weintraub et al., 2009) modelo de lesão colinérgica da doença de Alzheimer. A leading to the inability of living independently. doença de Alzheimer é uma patologia neurodegenera- Pathological hallmarks of AD are dystrophic tiva associada com o envelhecimento e com acentuada neuritis associated with plaques and neurofibril- e progressiva disfunção cognitiva. Suas complexas e lary tangles within nerve cell bodies in the basal múltiplas vias neurais sequenciais e pode conduzir à forebrain and neocortical cholinergic pathways compreensão de que as intervenções de agente único (Wszolek, 2008). The widespread loss of neu- pode ser insuficiente para impactar o curso desta doença. rons and synaptic connectivity in AD seem to O tratamento farmacológico atual é paliativo e, embora be caused by the accumulation of toxic species possa retardar a progressão da doença, não é capaz de of the β-Amyloid (Aβ) peptide (Chen & Blur- oferecer a cura. A combinação de drogas e substâncias ton-Jones, 2012). antioxidantes tem sido investigada, no entanto, existem It has been reported that the toxic deposit of poucos estudos que demonstram resultados consistentes Aβ causes membrane blebbing and cell shrinkage baseados nesta presunção. Assim, o objetivo deste artigo followed by DNA damage, generation of nuclear foi destacar as terapias baseadas na reposição celular apoptotic bodies, DNA fragmentation, and other como potencial tratamento para doenças do sistema classic hallmarks of apoptosis (Paradis, Douil- nervoso periférico e central. lard, Koutroumanis, Goodyer, & LeBlanc, 1996). Palavras-chave: modelos animais de declínio cognitivo; Preventing the apoptosis induced by Aβ and re- doença de Alzheimer; terapia de células tronco. constructing the cholinergic circuitry could be an optimal treatment for AD. However, since the relationship among pathological features remains In acute cases of neurological damages such elusive, pharmacological therapies keeps the focus as stroke or spinal cord injury, different types of on the function of acetylcholine through cholin- neurons and glial cells die within restricted areas esterase inhibitors (ChE-I) while stem cells (SC) of the central nervous system (CNS) area over a researchers look for a cell-based therapy (Oliveira short period of time (Lindvall & Kokaia, 2010). In & Hodges, 2005). chronicle situations, there is either selective loss

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Pharmacotherapy flavan-3-ol that can be found in food and beverages such as chocolate in natura, red wine, some fruit Multiple complex sequential and interactive and teas, especially the traditional green tea Camel- pathways are involved in the AD’s neurobiology, lia sinensis, can exert neuroprotective properties and interventions with a single agent could be (Aktas, Waiczies, & Zipp, 2007). Fruit and vege- insufficient to impact the disease’s course (Cum- tables rich in flavonoid played an important role mings, Gould, & Zhong, 2012). Pharmacological in the prevention of motor and cognitive declines treatment for AD is palliative, having the prop- related to aging (Bickford, Shukitt-Hale, & Joseph, erty of slowing down the speed of the disease’s 1999). In an in vitro experiment, epichatechin’s progression. Several studies have shown that the antioxidant property could be responsible for the combination treatment of acetylcholinesterase in- prevention of cells deaths by reducing the oxida- hibitor (AChE-I) and memantine prolongs the time tive stress (Schroeter, Williams, Matin, Iversen, & an AD’s patient is able to live more independently Rice-Evans, 2000). (Pfeil, Kressig, Thomas, & Szucs, 2012). Howev- Limited data are available considering an- er, according to Pfeil et al. (2012) these benefits tioxidant treatments in dementia. According to can only be seen after a year of this combination Weinmann, Roll, Schwarzbach, Vauth and Wil- therapy. lich (2010), the extract of Ginkgo Biloba, an herb Cholinesterase inhibitors increase cholinergic considered to have potent antioxidant property due synaptic transmission by holding back acetylcho- to the presence of flavonoids and terpenoids, is linesterase in the synaptic cleft, thereby decreasing not truly recommended for AD’s treatment. Even the hydrolysis of acetylcholine released from the though in the subgroup of patients with AD there presynaptic neurons (Chu, 2012). Despite the ex- was a significant advantage of Ginkgo Biloba com- tensive discussion on the effectiveness of AChE-I pared to placebo in the conducted study, there was donepezil, galantamine and rivastigmine, these no relevant benefit of the herb in the treatment of are the drugs currently approved by the FDA for neuropsychiatric symptoms. Therefore, addition- treating AD’s patients in moderate and mild stages al studies comparing the relative effectiveness of (Mini Mental State Examination scores between Gingko Biloba and AChE-I should be conducted 10 and 24), showing a delay in the cognitive im- (Weinmann et al., 2010). pairment and some of the behavioral problems Huperzine-A (Hup-A), an alkaloid isolated from (Sadowsky & Galvin, 2012). Huperzia serrata, an herb used in the traditional In general, AChE-I drugs are well tolerated; Chinese medicine for treating fevers, swellings, nevertheless, dose-related adverse effects may hypertension and memory impairment is consid- occur. It is not possible yet to identify which AD ered to be a potent AChE–I proven to effectively patient will respond best to each one of these drugs, improve the learning, memory performance and nor predict who will develop more intense adverse behavioral dysfunction in Chinese with AD (Gao, reactions such as vomiting, nausea and diarrhea, the Zheng, Yang, Tang, & Zhang, 2009; Wang, Yan, most prevalent ones (Sadowsky & Galvin, 2012). & Tang, 2006). In a study with rats, an isolation Meanwhile, studies of AD’s patients treated by of brain mitochondria demonstrated the protective rivastigmine, donepezil and galantamine for up to effects of Hup-A on mitochondrial function and on 4 years demonstrated fewer declines in cognitive mitochondria’s extended noncholinergic functions functions than expected (Chu, 2012). as well, providing a significant potential for the Some studies have investigated the role of anti- design of anti-AD drugs (Gao et al., 2009). oxidant treatment in AD. Epicatechin, a polyphenol

Avances en Psicología Latinoamericana / Bogotá (Colombia) / Vol. 35(1) / pp. 165-175 / 2017 / ISSNe2145-4515 167 Leticia Domingues Bertuzzi, Patrícia Santos da Silva, Élida Fluck Pereira Neto, Rafael Nicolaidis, Alcyr Alves de Oliveira Jr

Animal Models for Alzheimer’s Disease Neuropathway mechanical lesions in the electrolytic model by direct target destruction or fim- Animal models have been very important to bria-fornix’ transaction by pathway axotomy can understand the complex pathogenic mechanism also be an option; nevertheless there are chances underlying neurodegenerative diseases. The use of unspecific results (Oliveira & Hodges, 2005). of neurotoxins characterizes an alternative to re- In addition to the models presented, others can produce an AD model. The cytotoxin infusion of be pointed such as aging animals characterized by agents capable of destroying cell populations or an overall age related deficits of neurotransmitter brain structures is a common method for this (see systems. This senescence model favors the natural table 1). Even though the neurotoxins’ actions decline of neurotransmitter systems, however it is destroy neuronal cells by a massive postsynaptic not a widespread model due to its long time period depolarization (Barker & Dunnett, 1999), they have keeping and maintaining the animals as well as the their own specificities and limitations. animals’ inconsistence cognitive decline (Oliveira Transgenic models have also been developed, & Hodges, 2005). providing considerable information about the AD’s neuropathology. According to Granic, Masman, Stem Cells Therapy for Luiten and Eisel (2010) transgenic models of AD Neurodegenerative Diseases rely on inherited forms of the disease and present indistinguishable clinical and histopathological In the 80’s, researchers believed that neurode- features. It is important to highlight that, even generative diseases such as AD and PD could bene- though there is a great quantity of transgenic AD fit from SCs once there would be an increase of the models, there is no perfect model that incorporates cells in the brain (Gash, Collier, & Sladeck, 1985). all aspects of AD and some effective results in the Almost 30 years later, stem cell-based therapies animals fail on clinical trials. have aimed to replace missing or defective cells

Table 1 Animal models – Alzheimer’s disease

Model Mechanism Anatomic target References Cytotoxin infusion Waite, Chen, Wardlow, & Thal (1994); Dunnett, Quisqualic acid, Ibotenic Glutamate overexci- Whishaw, Jones, & Bunch, (1987); Waite & Thal Basal forebrain acid, Kainic acid, AMPA tation (1996); Inglis & Semba (1997); Yamada & Nabeshi- ma (2000). Trangenics Amyloid Precursor Pro- Hippocampus, Aβdeposition tein (APP) cortex, thalamus Yamada & Nabeshima (2000); Kulnane & Lamb Neurofibrillary (2001); Gordon et al. (2001); Pennanen, Welzl, Amygdala, basal Tau Protein tangles, filamentous D’Adamo, Nitsch, & Gotz (2004); Lee et al. (2012). forebrain tau aggregate Mechanical destruction Fimbria-Fornix tran- Fimbria-Fornix Yamada & Nabeshima (2000); Krugel, Bigl, Es- section chrich, & Bigl (2001); Vale-Martinez et al. (2002); Electrolytic NBM, amygdala Xuan, Luo, Ji, & Long (2009).

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in many disorders, but a lot is to be known about stromal cells (Phinney, 2002). Even though these the mechanism of the SCs inside the organism. SCs have more limited ability of differentiation Shortly, SCs are classically defined as cells that than the embryonic SCs, MSCs have important have the ability to renew themselves continuously advantages such as the facility for isolation, the ca- and possess totipotent, pluripotent or multipotent pacity to propagate in culture, besides the non-im- ability to differentiate into various cell types (Wis- munogenic characteristics (Bydlowski, Debes, let-Gendebien, Laudet, Neirinckx, & Rogister, Maselli, & Janz, 2009). 2011). Studies indicate that different lineages of Cova et al. (2010) found that human MSCs SCs promote a series of changes throughout the promoted an effective neuronal survival and sup- recipient’s CNS not restricted only to the specific ported the development of immature cells in a area (Giusto, Donegá, Cossetti, & Pluchino, 2013; PD’s animal model. According to them, neuronal Bonnamain, Neveu, & Naveilhan, 2012). proliferation and maturation were found after the According to Dunnett, Low, Iversen, Stenevi implants in animals that had the striatum injured and Björkland (1982), implanted animals with by 6-hydroxydopamine (6-OHDA). The same was cholinergically rich cells were able to perform not found in sham animals implanted with the a requested task as the control animals; howev- same cell line. The results suggest the existence of er, the time required for its execution was much a mutual influence between the grafted cells and higher than that expended by the control animals. endogenous neural precursors, becoming important A cholinergic reinnervation is known to be need- to determine the effect on survival neuronal cells ed; nevertheless in the study it was insufficient to in other brain regions. a successful functional recovery (Dunnet et al., Naive human MSCs consistently synthesize a 1982). Some years later, ectopic implantation of variety of trophic factors that play an important role forebrain ventral cells (cholinergically rich) attenu- on the improvement observed in implanted animals ated learning deficits in rats with cholinergic lesions (Cova et al., 2010). However, despite the promising in a study proposed by Barker and Dunnet (1999). outcomes, important issues such as tissue’s viabil- Modo et al. (2002) reported that the privileged ity, logistic and ethical concerns surrounding the immune characteristics of CNS can be attributed to use of human material, cell’s purity and viability, numerous factors such as the low immunogenetic- deleterious side effects, to site some, need to be ity of neuronal tissues, the protection of the blood- better evaluated and understood until this practice brain barrier and the absence of lymphatic drainage becomes commonly used (Barker, Barrett, Mason, in the brain. However, CNS immune’s protection & Björklund, 2013). is only partial once there are differences in species Bone marrow mesenchymal SCs (BM-MSC) between the donor and the host and rejection oc- show a great potential of proliferating and differ- curs (Modo et al. 2002). Thus, the treatment with entiating into several types of cells, and present immunosuppressive drugs is necessary in cases of two major advantages over other cell sources: allogeneic transplants. accessibility and immunological features (Olivei- MSCs may be defined as progenitor cells ca- ra, Haeser, & Pranke, 2008). Besides this, the use pable of giving rise to a number of unique, differ- of BM-MSC’s for grafts circumvents the ethical entiated cells from all three germ layers (Caplan, concerns attached to the use of embryonic cells. It 1991). First described as fibroblast precursors from also brings technical and practical solutions, such bone marrow (BM) by Friedenstein, Chailakhjan as simpler cell collection since it has been practiced and Lalykina (1970), MSCs may be also referred in BM transplants. to as a fibroblast colony-forming units or marrow

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Recent studies show that BM-MSCs are satis- have been shown to differentiate into the three germ factory used in intracerebral procedures for neuro- layers, also displaying a potency that was widely degenerative diseases in animal models. According thought to be exclusive from embryonic SCs (Jane- to Lee, Jin and Bae (2009), BM-MSCs promoted bodin et al., 2011; Miura et al., 2003). When com- microglial activation and reduced significantly the pared to BM-MSCs, ETSCs present more active Aβ deposit in a mouse model. Hence, BM-MSCs and developed metabolic cells (Karaoz, Sağlam, can increase the number of activated microglia, Aksoy, Kaymaz, & Duruksu, 2011). which supports the hypothesis that BM-MSCs These characteristics were corroborated in a might be an effective therapeutic vehicle to reduce study on the differentiation process of human exfo- Aβ deposits in AD patients (Lee et al., 2009). liated deciduous teeth SCs into neurons that perfor- Adipose-derived MSCs (AMSC) isolated from med a dopaminergic function (Wang et al., 2010). adipose tissue can be differentiated into neuronal As a result, it is estimated that the dental pulp SCs SCs, and so improve the feasibility for neurodegen- become an alternative source of human MSCs, on- erative diseases’ treatment. Besides this, AMSCs ce they offer promising differentiation properties, secret anti-apoptotic growth factors, reproducing high proliferative capacity, and don’t raise ethical cytoprotective effects in animal models (Im et al., concerns as embryonic SCs (Ibarretxe et al., 2012). 2013). Studies have investigated the neuroprotec- Few studies have identified kidney-derived SCs tive effects of the AMSC in animal models of intra- (KSCs), especially considering neurodegenerative cerebral hemorrhage and found out evidences of a diseases. Studies about the isolation of kidney-de- reduction in the acute cerebral inflammation and in rived cells showed consistent characteristics of the chronic brain’s degeneration after implantation, renal SCs, without evidences of cell senescence or which corroborated to improve functional recovery transformation into malignant tumors (Gupta et al., (Kim et al., 2007). 2006). According to Ranghini et al. (2013), studies Therapeutic potential of intracerebral injection have shown that some kidney stem/progenitor cells of human AMSCs in neurodegenerative diseases (KSPCs) can differentiate into a variety of renal was previously reported in Huntington’s disease, cell types (Lee et al., 2010). PD and ischemia mouse models, but not in AD However, in most cases, differentiation was (Kim et al., 2012). In a carefully designed study defined solely on the basis of marker analysis, re- on therapeutic effects of intravenous human ad- maining unknown whether these stem/progenitor ipose-derived SCs in an AD model, Kim et al. cell-derived renal cell types display any functio- (2012) observed that intravenous or intracerebral nality. Nevertheless, another study suggested that human AMSC transplantation rescued memory human KSPCs cells improve renal function by impairments, besides reducing the number of Aβ secreting paracrine factors that promote tubular plaques in the mice’s brain. There was no notifica- repair (Ranghini et al., 2013; Sallustio et al., 2013). tion sign of tumorigenisis in this study; nevertheless Gimble, Bunnell, Chiu and Guilak (2011) identified Conclusions the formation of sarcomas in vivo after the implantation of AMSCs in immunodeficient mice. The development of models for behavior and Dental and periodontal tissues constitute a re- cognitive decline in neurodegenerative diseases is a cent source of neural SCs, presenting a substantial constant challenge for comparative psychology re- advantage among other SCs: their neural crest searchers. Associate the search for a comprehensive phenotype (Ibarretxe et al., 2012). Dental pulp SCs model of a multifactorial condition that may cause (DPSC) and human exfoliated teeth SCs (ETSC) cognitive impairment is a methodological hotspot.

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Although it is difficult sometimes to consider a yet clearly understood and it is likely involved in model of disease as a useful tool for knowledge the production of paracrine, anti-inflammatory achievement, models for non-pathological ques- and anti-apoptotic factors (Roux, Leotot, Cheval- tions might be even more difficult. lier, Bierling, & Rouard, 2011). Paracrine effect is The existing animal models for aging patholo- defined as a form of communication between two gies have been used in the development of various different cells. One releases chemical mediators to treatments and helped to bring discovery for sev- its immediate environment, resulting in a change in eral advances in the health sciences. The models the behavior of a cell in its adjacent environment of cognitive impoverishment such as the lesion (Anthony & Shiels, 2013). animal model of Alzheimer’s disease has open Several experiments have demonstrated that fields for the study of memory and attention and SCs’ grafts ameliorate a variety of CNS conditions. is an important tool for the search of its treatment. However, crucial issues such as functional connec- A substantial segment of the aging population tivity, in vivo differentiation and survival, potential constitutes the primary risk factor for AD and other for migration to areas of lesion, host’s immune re- neurodegenerative disorders. Intensive efforts have actions or mechanisms regulating these functions, been dedicated to improve old people’s life style are still to be addressed (Oliveira et al., 2008). habits such as exercise and dietary supplements Existing clinical data suggest that transplantation in combination with symptomatic treatment drugs is technically feasible and can be carried out safe- to improve age-related cognitive decline and to ly. Nevertheless, data on functional outcome and attenuate motor and neurological dysfunction in long-term efficiency remains preliminary (Andresa neurodegenerative diseases (Mandel & Youdim, et al., 2008). A greater understanding of the neuro- 2012). However, the adult brain has limited re- biological and molecular factors that determine the generative capacity and no effective treatment progress of the brain disorder will probably lead to options are available (Andresa, Meyerb, Ducraya, safer treatments (Oliveira et al., 2008). & Widmera, 2008). Stem cells based therapies represent an emerg- Stem cells-derived therapy constitute promising therapeutic approach by which incurable dis- ing prospects for the treatment of CNS disorders, eases may be treated (Marchetti, Krohne, Fried- once it is known that SCs have a great potential lander, & Friedlander, 2010). This search is deeply to develop into many types and subtypes of cells, influenced by the development of new models and besides being able of in vitro long-term survival the comprehension of the relationship between and self-renewal (Ibarretxe et al., 2012). Implants behavior, cognition and its biological somatic cor- from SCs demonstrated an improvement in the respondent. performance of rats in a model for AD in behav- In neural transplantation, although more should ioral tests (Bertuzzi et al., n/d). The existence of be known to clarify all the mechanisms of cellular these behavioral improvement is not exclusively paracrine effects in the host’s tissues, there is a associated to implants survival. Rehabilitation of good perspective that cell therapies being played tissues may occur due to innate mechanisms of in the right models might be used to treat neuro- the SCs to migrate to the lesion site, in particular, degenerative diseases. inflammations, apoptosis or hypoxia, releasing trophic factors that accelerate the endogen repair References (Joyce et al., 2010). The migration of the SCs to injured tissues in Aktas, O., Waiczies, S., & Zipp, F. (2007). Neuro- animal models is associated to a mechanism not degeneration in autoimmune demyelination:

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Received: February 3, 2016 Accepted: June 27, 2016

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