Transplante de células mononucleares da medula óssea modulam a expressão de fatores tróficos em modelo animal de epilepsia crônica induzida por pilocarpina

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DADOS DE CATALOGAÇÃO NA PUBLICAÇÃO

Isabel Merlo Crespo - Bibliotecária CRB 10/1201

Isabel Merlo Crespo - Bibliotecária CRB 10/1201 Z31t Zanirati, -abriele -oulart

Transplante de células mononucleares da medula óssea modulam a expressão de fatores tróficos em modelo animal de epilepsia crônica induzida por pilocarpina / -abriele -oulart Zanirati. Porto Alegre: PUCRS, 2013.

103 p.: il. tab. Inclui um artigo científico submetido à publicação. Orientador: Prof. Dr. Jaderson Costa da Costa.

Co-orientador: Dr. Fabrício Simão.

Dissertação (Mestrado) – Pontifícia Universidade Católica do Rio -rande do Sul. Faculdade de Medicina. Mestrado em Medicina e Ciências da Saúde. Área de Concentração: Neurociências.

1. EPILEPSIA. 2. PILOCARPINA. 3. CÉLULAS MONONUCLEARES DA MEDULA ÓSSEA. 4. FATORES TRÓFICOS. 5. ESTUDO EXPERIMENTAL. I. COSTA, JADERSON COSTA DA. II. TÍTULO.

CDD617.63

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((

$4 $ 3 %: % %#& % &# '$" )+ & $%,# ") "$ % $ Referência Modelo; animal;

período de tratamento Tipo celular; concentração; via de administração Resultados Comportamentais Resultados Morfológicos, Celular e Molecular

Migração e Diferenciação Celular

(Chu et al. 2004)

Litio-pilo; ratos Sprague–Dawley; período agudo.

NSC; 5x106; i.v. ↓CERs; ↓ excitabilidade neuronal em CA3, através da avaliação do fEPSP extracelular.

NA As análises imunohistoquímicas

mostraram que as NSCs migraram para regiões de ambos os hipocampos. NSCs diferenciara-se em -ABA+ no hipocampo (6 semanas após o SE).

(-uttinger et al. 2005)

Abrasamento, ratos Sprague–Dawley; período crônico.

Adk−/− ES; 1.5 × 105; i.c.v

-rupos tratados com as Adk−/− ES mostraram resistência a crises e ↓ atividades

eletroencefalográficas.

Adk−/− ES se encontravam viáveis na análise histológica 2 dias após o transplantes.

NA

(Ruschenschmi dt et al. 2005)

Pilo; ratos Wistar; período crônico

ESN; 5–8 x 104; intrahipocampal

ESNs possuíam a capacidade de gerar potenciais de ação e expressar correntes de voltagem dependentes de Na+ e K+, bem como a hiperpolarização das correntes ativadas.

ESNs exibiram propriedades intrínsecas e sinápticas características de neurônios após transplante em controles e ratos epilépticos.

Permaneceram clusters nos locais do transplante ou próximos aos canais de injeção. Deram origem a uma densa rede de processos que se estendem ao longo de grandes distâncias para as regiões do corpo caloso, CA1 e CA3.

(Carpentino et al. 2008) KA; camundongos B6.CB17 SCID; crônico. ESNP; 50.000 células; intrahipocampal

NA As crises causam alterações

moleculares em CA3 e D- que promovem regiões específicas de diferenciação neuronal e suprime a formação de tumores.

ESNP migraram de CA3 para o D- 4-8 semana pós-transplante, a maioria diferenciaram-se em neuroblastos ou neurônios granulares e astrócitos. ENSPs transplantadas na fímbria migraram ao longo dessa região e se diferenciaram em oligodendrócitos ou astrócitos.

(Hattiangady et al. 2008)

KA, Ratos Fischer 344; período crônico

Precursores do estriado; 2x105; intrahipocampal

↓frequência de (67 - 89%) em 9-12 meses pós-transplante

Transplante das células preservou a expressão de calbindina no hipocampo, mas não teve efeito sobre o

(&

Referência Modelo; animal; período de tratamento Tipo celular; concentração; via de administração Resultados Comportamentais Resultados Morfológicos, Celular e Molecular

Migração e Diferenciação Celular

brotamento de fibras musgosas

(Baraban et al. 2009) Camundongos Kv1.1/Kcna1; pré-epilepsia (P1-P3) Precursores de interneurônios -ABAérgicos; 4x105; intracortical

Redução na atividade eletrográfica de crise; tendência ao aumento da sobrevida.

NA Células expressaram -ABA, PV, SOM,

NPY e CR.

(Jing et al. 2009)

KA; ratos F344; período crônico

NSCs adultas com ou sem infusão de EPO; 1.2×106; intrahipocampal

↓frequência dos picos anormais nos animais tratados com as NSCs quando comparados com os não tratados no EE-.

↑interneurônios NPY+ e -AD67+. NSCs suprimiu também o brotamento de fibras musgosas e ↓excitabilidade do hipocampo, impedindo desenvolvimento de CERs.

Maioria das NSCs diferenciaram-se em células -FAP+. A infusão de EPO ↑ sobrevivência das NSCs (5 semanas em CA3 e S-Z), mas não influenciou na diferenciação neuronal ou na migração.

(Li et al. 2009) KA; camundongos C57BL/6 com epileptogênese CA3-seletiva, período agudo

Adk -/- hMSC; 50.000 células; intrahipocampal

↓ intensidade das crises, mediada pela secreção de adenosina e ativação de receptores.

NA Células presentes somente na fissura

intrahipocampal ipsilateral.

(Waldau et al. 2010)

KA; Ratos Fischer 344; período crônico

NSCs a partir da M-E

embrionária; 80.000 células; intrahipocampal

↓ frequência, duração e gravidade das crises. Não houve melhora na aprendizagem e memória dos animais.

M-E-NSC não melhorou a neurogênese nos ratos com epilepsia.

A maioria das M-E-NSC

transplantadas se diferenciaram em células que expressam S-100β+ e -DNF. E migraram principalmente para regiões de CA3.

(Costa-Ferro et al. 2010)

Lítio-Pilo; ratos Wistar; período agudo

CMMO; 1x107; i.v 15 dias pós-transplante animais não desenvolveram CERs; 120 dias após o transplante somente 25% dos animais transplantados desenvolveram CERs versus

CMMO preservam a densidade de neurônios e o volume hipocampal.

CMMO encontradas no hipocampo, córtex perirrinal e amígdala

()

Referência Modelo; animal; período de tratamento Tipo celular; concentração; via de administração Resultados Comportamentais Resultados Morfológicos, Celular e Molecular

Migração e Diferenciação Celular

100% dos controles; CMMO preservam a LTP.

(Hartman et al. 2010) KA, camundongos B6.CB17-Prkdc scid/SzJ, período crônico ESNP; 50.000 células; intrahipocampal

NA As ESNPs mostraram

quimiotaxia para CXCL12, tanto

in vitro como in vivo. As crises

↑ a expressão de CXCL12 no hipocampo dos animais, com isso a migração das ENPS.

ESNPs transplantadas no D- mostraram migração através da camada superior, ao longo do eixo septotemporal do hipocampo. ESNPs sobreviveram e se diferenciaram em neuroblastos e subsequente em neurônios granulares do D-. (Shen et al.

2010)

KA; ratos Wistar, período agudo

HSC; 100.000 -150.000 células; intrahipocampal

HSC ↓ descargas elétricas no tecido epiléptico

HSC ↓ a ocorrência de

brotamento de fibras musgosas e restauraram parte da população de neurônios piramidais de CA3

NA

(Shindo et al. 2010)

Abrasamento; camundongos C57BL/6N, período crônico

ESNP, 2x105; intrahipocampal

ESNP promoveu

recuperação dos animais 6 dias pós-transplante.

NA Observadas células positivas para Hu,

-AD67 e -FAP

(Abdanipour et al. 2011)

Pilo; ratos Sprague-Dawley; período crônico

BMSC; 3x106; i.v Animais tratados com as BMSCs ↓ crises.

↑ densidade neuronal no grupo tratado com as BMSC.

BMSC migraram para o hipocampo lesado e se diferenciaram em neurofilamentos.

(Jeon et al. 2011)

Pilo; camundongos C57BL/6; período agudo e crônico

ASCs-E humanas; i.p

Transplante realizado antes do SE ↓ o dano à BHE e inibiu o desenvolvimento da epilepsia. Transplante feito no período crônico suprimiu as CERs , e melhorou a locomoção e ansiedade.

A expressão de genes

relacionados com a inflamação ou respostas imunes

apresentaram baixa regulação no grupo ASC-E. A expressão de genes relacionados com canais de íons, incluindo receptor -ABA.

(X

Referência Modelo; animal; período de tratamento Tipo celular; concentração; via de administração Resultados Comportamentais Resultados Morfológicos, Celular e Molecular

Migração e Diferenciação Celular

(Shu et al. 2011)

Lítio-pilo; ratos Wistar, período agudo

NSC e CT1-NSC; 1,5x108; intrahipocampal

NA CT1-NSC ↓ o brotamento de

fibras musgosas.

NA

(Venturin et al. 2011)

Lítio-Pilo; ratos Wistar; período crônico

CMMO; 1x107; i.v CMMO ↓ frequência de CERs e reverteu déficit cognitivo, melhorando a aquisição e retenção da memória espacial dos animais epilépticos.

NA CMMO migraram para o cérebro dos

animais, e estavam presentes nos períodos de 24h, 2 semanas e 1 mês após o transplante.

(Costa-Ferro et al. 2012)

Lítio-Pilo; ratos Wistar; epilépticos crônicos precoces e crônicos tardios

CMMO; 1x107; i.v CMMO ↓ frequência e duração de crises tanto em animais epilépticos crônicos tratados precocemente, quanto tardiamente.

CMMO ↓ níveis de citocinas pró-inflamatórias (TNF-α, IL-1βe, IL-6) e ↑ os níveis da citocina anti-inflamatória IL-10; CMMO foram neuroprotetoras, diminuindo a perda neuronal e gliose; foram detectadas cels positivas para DCX, indicando haver proliferação induzida pelas células.

Células migram até o hipocampo epiléptico, mas não expressam marcadores neurais.

(Maisano et al. 2012) Pilo, camundongos C57BL/6, período crônico ESNP; 100.000 células; intrahipocampal

NA ESNPs estabeleceram

arborização axonal no hilo; não houve alteração no brotamento de fibras musgosas;

identificação de células integradas no sistema por eletrofisiologia. ↑ níveis de -ABA.

Céls nas camadas granular e molecular do giro dentado; Maioria das céls expressando NeuN, PV e CB, indicando diferenciação em interneurônios -ABAérgicos.

(Long et al. 2012)

Pilo; ratos Sprague-Dawley; período agudo

BMSC e H-BMSC; 5x106; i.v

Os resultados mostraram que a frequência de CERs, a mortalidade, e a incidência

↑ densidade neuronal das áreas corticais após transplante.

(Y

Referência Modelo; animal; período de tratamento

Tipo celular; concentração; via de administração

Resultados Comportamentais

Resultados Morfológicos, Celular e Molecular

Migração e Diferenciação Celular

de ondas epileptiformes no EE- apresentaram uma tendência a diminuir após 4 semanas do transplante.

e -FAP, sendo capazes de se

diferenciar em neurônios -ABAérgicos ou astrócitos, após 4 semanas do transplante.

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