Transplante de células mononucleares da medula óssea na epilepsia experimental induzida por lítio e pilocarpina em ratos

A epilepsia é uma condição crônica frequentemente acompanhada de perda celular e distúrbio cognitivo. Na maioria das vezes, é difícil saber o quanto isso se deve à patologia de base que provoca as crises epiléticas, as crises epilépticas por si ou seu tratamento com fármacos antiepilépticos, bem como o contexto sócio-cultural do paciente. Para investigar o efeito das células mononucleares da medula óssea (CMO) sobre a neuroplasticidade no sistema nervoso central, induzida pelo status epilepticus, provocado por lítio e pilocarpina, foram estudados ratos epilépticos e controles que receberam o transplante de (1x107 CMO/100μl ou o mesmo volume de solução salina, na veia da cauda), 90 min após SE (grupo agudo) ou 22 dias após SE (grupo crônico). Aqui mostramos que, no grupo agudo, ao compararmos os ratos controles com os transplantados, as CMO estavam presentes em (1-3, 5, 10 e 120 dias) após o transplante no cérebro epiléptico. Em 10 dias expressavam o marcador de microglia (CD11b), em 120 dias expressaram o marcador de neurônio jovem (doublecortina). Verificamos por vídeo-monitoração, (15-21dias) após o SE, que os ratos do grupo tratado com CMO não apresentaram crises espontâneas recorrentes (CER), e que, entre (120-127 dias) após SE, 20% dos ratos transplantados apresentaram CER. Observamos perda neuronal significativa nas três regiões hipocampais analisadas (CA1, CA3 e hilo do GD) no grupo epiléptico que recebeu o transplante de solução salina, sendo extremamente significativa na região de CA1 (em 10 dias); CA1, CA3 e no hilo do GD em (120 dias) após o SE. Entretanto, no grupo tratado com CMO, a perda neuronal foi menor nas regiões analisadas em 120 dias após SE. As medidas do volume hipocampal revelaram que não foram observadas diferenças significantes entre o grupo epiléptico tratado com CMO quando comparado com o grupo controle não epiléptico, tanto em 10 quanto em 120 dias após SE. O volume hipocampal entre os ratos epilépticos (não-tratado e tratado) apresentou diferença significativa em 120 dias após SE. No estudo da atividade elétrica em fatias hipocampais, ao compararmos os dados dos ratos epilépticos encontramos uma tendência a maior facilidade de se obter LTP no grupo tratado com CMO (80% das fatias) enquanto no grupo tratado com solução salina ocorreu indução em (30% das fatias) 10 dias após SE. Esta facilidade de indução foi maior em 120 dias após SE, onde a indução da LTP ocorreu em 100% das fatias do grupo epiléptico tratado com CMO e em nenhuma do grupo epiléptico tratado com solução salina. O desempenho dos ratos epilépticos de ambos os grupos experimentais foi prejudicada no teste de aprendizagem espacial do labirinto aquático. Embora que esta função foi menos afetada nos ratos epilépticos tratados com CMO do que os ratos não tratados. No grupo crônico, avaliamos por vídeo-monitoração o comportamento dos ratos epilépticos entre os dias 15-21 após SE, no dia 22 os ratos foram transplantados com CMO de dois diferentes doadores (1) ratos Wistar e (2) camundongos EGFP C57/bl6, ou solução salina e foram observados por mais 7 dias (1) e 14 dias (2). Verificou-se que independente do doador os ratos tiveram uma diminuição na freqüência das CER de aproximadamente 50% e de 53,5% [doadores (1) e (2), respectivamente], quando comparado o período pós com o pré-tratamento. Verificamos que as células GFP-positivas foram encontradas dispersas por todo o cérebro dos ratos epilépticos 45 dias após o transplante, e estavam presentes principalmente nas áreas corticais e no giro denteado do hipocampo. Algumas destas células expressaram o marcador de neurônio adulto (NeuN) e de células da glia (GFAP). No entanto, não foram observadas nos grupos agudo e crônico, células GFPpositivas no cérebro dos ratos controle (não epilépticos). A análise quantitativa de secções do cérebro de ratos do grupo epiléptico tratado com CMO mostrou que o número de neurônios não diferiu significativamente do grupo controle (não-epiléptico) nas duas regiões avaliadas (CA1 e hilo). No estudo do brotamento neuronal o grupo de ratos tratado com CMO apresentou aproximadamente 78,6% menos brotamento das fibras musgosas que os ratos epilépticos não tratados. No estudo eletrofisiológico a LTP induzida por estimulação tetânica foi obtida em (100%) das fatias hipocampais obtidas de ratos controles não-epilépticos, em (100%) das fatias de ratos epilépticos tratados com CMO e em nenhuma das fatias dos ratos epilépticos tratados com solução salina. Nossos dados sugerem que o transplante de células mononucleares da medula óssea protege e/ou previne a progressão da epilepsia crônica.The epilepsy is a chronic condition frequently accompanied by cellular loss and cognitive disturbance. Most of the time, it is difficult to know how much this occurs due to the base pathology that provokes epileptic crises, the epileptic crises by themselves or their treatment with anti-epilepsy medications, as well as the patient’s social-cultural context. In order to investigate the effect of bone marrow mononuclear cells (BMCs) on the neuroplasticity in the central nervous system, induced by status epilepticus, provoked by lithium and pilocarpine, epileptic and control rats were studied and received a transplant of (1x107 BMC/100μl or the same volume of saline solution, in the vein of the tail), 90 min after SE (acute group) or 22 days after SE (chronic group). Here we have demonstrated that, in the acute group, when comparing the control rats to the transplanted ones, BMCs were presented in the epileptic brain (1-3, 5, 10 and 120 days) after the transplant. In 10 days they expressed the microglial marker (CD11b), in 120 days they expressed the young neuronal marker (doublecortin). We verified by video monitoring, (15-21 days) after SE, that the rats from the treated group with BMCs did not present spontaneous recurrent seizures (SRS), and that, between 120-127 days after SE, 20% of the transplanted animals presented SRS. We observed significant neuronal loss in the three analyzed hippocampus regions (CA1, CA3 and hilo of GD) in the epileptic group that received the transplant of saline solution, being extremely significant in the region of CA1 (in 10 days); CA1, CA3 and in hilo of GD in (120 days) after the SE. However, in the group treated with BMCs, the neuronal loss was smaller in the areas analyzed in (120 days) after SE. The measures of the hippocampus volume revealed significant differences not observed between the epileptic group treated with BMCs, when compared to the non-epileptic control group, as in 10 as in 120 days after SE. Nevertheless, the hippocampus volume between the epileptic rats (non-treated and treated) presented a significant difference in 120 days. In the study of electrical activity in hippocampal slices, by comparing the epileptic rats data, we found a tendency of a greater facility in obtaining LTP in the treated group with BMCs (80% of the slices) while in the treated group with a saline solution an induction in (30% of the slices) it occurred 10 days after SE. This facility of induction was higher in 120 days after SE, where the induction of LTP occurred in 100% of the slices in the epileptic group treated with BMCs and in none of the epileptic group treated with saline solution. In the spatial reference memory version of the water Maze test, the performance of both epileptic experimental groups was impaired. Although this function was less affected in epileptic rats treated with BMCs than in saline treated rats. In the chronic group, we evaluated the epileptic rats behavior through video monitoring between the days 15-21 after SE, in the day 22 the rats were transplanted with BMCs from two different donors (1) Wistar rats and (2) EGFP C57/bl6 Mice, or saline solution, and were observed for more 7 days (1) and 14 days (2). It was verified that regardless on the donor, the rats had a decrease in the frequency of SRS of approximately 50% and of 53,5% [donors (1) and (2), respectively], when comparing the pos-period with the pre-treatment. We verified that the GFP-positive cells were found scattered through the whole epileptic rats brain 45 days after the transplant, and they were mainly present in the cortical areas and the dentate gyrus of hippocampus. Some of these cells expressed an adult neuronal marker (NeuN) and glial cells (GFAP). Nevertheless, this was not observed in acute and chronic groups, GFP-positive cells in the brain of the control rats (non-epileptic). The quantitative analysis of the sectors from the brain of the epileptic rats group treated with BMCs demonstrated that the number of neurons did not differ significantly from the control group (non-epileptic) in two evaluated regions (CA1 and hilo). In the study of neuronal sprouting, the group of rats treated with BMCs presented approximately 78,6% less sprout than the rats from the non-treated group. In the electrophysiological study LTP induced by tetanic stimulation was obtained in (100%) of the hipocampal slices of nonepileptic control rats, in (100%) of the slices of epileptic rats treated with BMCs and in none of the slices from the epileptic rats treated with saline solution. Our data suggest that the transplant of cells from the bone marrow protects and/or prevents the progression of chronic epilepsy

Modeling Autism Spectrum Disorders with Induced Pluripotent Stem Cell-Derived Brain Organoids

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders that affect communication and social interactions and present with restricted interests and repetitive behavior patterns. The susceptibility to ASD is strongly influenced by genetic/heritable factors; however, there is still a large gap in understanding the cellular and molecular mechanisms underlying the neurobiology of ASD. Significant progress has been made in identifying ASD risk genes and the possible convergent pathways regulated by these gene networks during development. The breakthrough of cellular reprogramming technology has allowed the generation of induced pluripotent stem cells (iPSCs) from individuals with syndromic and idiopathic ASD, providing patient-specific cell models for mechanistic studies. In the past decade, protocols for developing brain organoids from these cells have been established, leading to significant advances in the in vitro reproducibility of the early steps of human brain development. Here, we reviewed the most relevant literature regarding the application of brain organoids to the study of ASD, providing the current state of the art, and discussing the impact of such models on the field, limitations, and opportunities for future development

Prevention of seizures and reorganization of hippocampal functions by transplantation of bone marrow cells in the acute phase of experimental epilepsy.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-28T12:20:49Z No. of bitstreams: 1 Costa-Ferro ZSM Prevention...pdf: 549568 bytes, checksum: d6ff4058b65c2bcac92e9db6c33eaa70 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-28T12:20:57Z (GMT) No. of bitstreams: 1 Costa-Ferro ZSM Prevention...pdf: 549568 bytes, checksum: d6ff4058b65c2bcac92e9db6c33eaa70 (MD5)Made available in DSpace on 2014-11-28T12:45:09Z (GMT). No. of bitstreams: 1 Costa-Ferro ZSM Prevention...pdf: 549568 bytes, checksum: d6ff4058b65c2bcac92e9db6c33eaa70 (MD5) Previous issue date: 2010Universidade Federal do Rio Grande do Sul. Instituto de Ciências Básicas da Saúde. Departamento de Fisiologia. Porto Alegre, RS, Brasil / Pontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Laboratório de Neurociências. Porto Alegre, RS, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Laboratório de Engenharia Tecidual e Imunofarmacologia. Salvador, BA, Brasil /Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Laboratório de Neurociências. Porto Alegre, RS, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Laboratório de Neurociências. Porto Alegre, RS, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Laboratório de Neurociências. Porto Alegre, RS, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Faculdade de Biociências. Departamento de Ciências Fisiológicas. Porto Alegre, RS, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Centro de Terapia Celular. Porto Alegre, RS, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Laboratório de Engenharia Tecidual e Imunofarmacologia. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Laboratório de Engenharia Tecidual e Imunofarmacologia. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilUniversidade Federal do Rio Grande do Sul. Instituto de Ciências Básicas da Saúde. Departamento de Fisiologia. Porto Alegre, RS, Brasil / Pontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Laboratório de Neurociências. Porto Alegre, RS, BrasilIn this study, we investigated the therapeutic potential of bone marrow mononuclear cells (BMCs) in a model of epilepsy induced by pilocarpine in rats. BMCs obtained from green fluorescent protein (GFP) transgenic mice or rats were transplanted intravenously after induction of status epilepticus (SE). Spontaneous recurrent seizures (SRS) were monitored using Racine's seizure severity scale. All of the rats in the saline-treated epileptic control group developed SRS, whereas none of the BMC-treated epileptic animals had seizures in the short term (15 days after transplantation), regardless of the BMC source. Over the long-term chronic phase (120 days after transplantation), only 25% of BMC-treated epileptic animals had seizures, but with a lower frequency and duration compared to the epileptic control group. The density of hippocampal neurons in the brains of animals treated with BMCs was markedly preserved. At hippocampal Schaeffer collateral-CA1 synapses, long-term potentiation was preserved in BMC-transplanted rats compared to epileptic controls. The donor-derived GFP(+) cells were rarely found in the brains of transplanted epileptic rats. In conclusion, treatment with BMCs can prevent the development of chronic seizures, reduce neuronal loss, and influence the reorganization of the hippocampal neuronal network

O potencial terapêutico das células-tronco em doenças do sistema nervoso = The therapeutic potential of stem cells for nervous system disease

Objetivo: Apresentar as evidências científicas do transplante de células-tronco em cinco doenças do sistema nervoso: anóxia neonatal, epilepsia, acidente vascular cerebral, doença de Parkinson e lesão de nervo periférico. Fonte de dados: Revisão bibliográfica utilizando o Medline. Síntese de dados: O transplante de células-tronco é uma importante ferramenta na reparação de distúrbios do sistema nervoso. Estudos experimentais demonstram que a regeneração e a reconstrução do circuito neuronal é possível através da terapia celular. As células-tronco têm demonstrado uma capacidade de se diferenciar em neurônios e glia. Os experimentos utilizando o transplante de células-tronco em modelos animais de anóxia neonatal, isquemia cerebral, epilepsia, doença de Parkinson e lesão de nervo periférico mostraram melhora funcional nos animais tratados. Conclusões: Apesar das evidências científicas favoráveis ao uso de células-tronco em doenças neurológicas, consideráveis avanços necessitam ser feitos para compreender a base biológica das células-tronco, incluindo os sinais que determinam sua proliferação e diferenciação, e a caracterização de suas respostas quando transplantadas em uma área encefálica lesad

Transplantation of bone marrow mononuclear cells decreases seizure incidence, mitigates neuronal loss and modulates pro-inflammatory cytokine production in epileptic rats.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-24T18:20:08Z No. of bitstreams: 1 Costa-Ferro Trnasplantation of bone......pdf: 3506460 bytes, checksum: 4e81f44abdb5f0977809089ae8ceeae8 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-24T18:20:19Z (GMT) No. of bitstreams: 1 Costa-Ferro Trnasplantation of bone......pdf: 3506460 bytes, checksum: 4e81f44abdb5f0977809089ae8ceeae8 (MD5)Made available in DSpace on 2014-11-24T18:35:42Z (GMT). No. of bitstreams: 1 Costa-Ferro Trnasplantation of bone......pdf: 3506460 bytes, checksum: 4e81f44abdb5f0977809089ae8ceeae8 (MD5) Previous issue date: 2012Pontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Porto Alegre, RS, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Hospital São Rafael. Serviço de Anatomia Patológica e Citopatologia. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilPontifícia Universidade Católica do Rio Grande do Sul. Instituto de Pesquisas Biomédicas e Instituto do Cérebro. Porto Alegre, RS, BrasilApproximately 30% of patients with mesial temporal lobe epilepsy do not respond to treatment with antiepileptic drugs. We have previously shown that transplantation of mononuclear bone marrow cells (BMC) has an anticonvulsant effect in acute epilepsy. Here, we used pilocarpine to induce epilepsy in rats and studied the effects of BMC injected intravenously either at the onset of seizures or after 10 months of recurrent seizures. BMC effectively decreased seizure frequency and duration. In addition, decreased levels of proinflammatory cytokines (TNF-α, IL-1ß and IL-6) and increased levels of anti-inflammatory cytokine (IL-10) were observed in the brain and serum of BMC-treated rats. Transplants performed at seizure-onset protected against pilocarpine-induced neuronal loss and gliosis and stimulated the proliferation of new neurons in epileptic rats. Our data demonstrate that BMC transplantation has potent therapeutic effects and could be a potential therapy for clinically intractable epilepsie

Early transplantation of bone marrow mononuclear cells promotes neuroprotection and modulation of inflammation after status epilepticus in mice by paracrine mechanisms.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2015-05-19T17:24:00Z No. of bitstreams: 1 Leal MMT Early....pdf: 781614 bytes, checksum: d9ce1f5869c3b92b18bd5f5dc7f0b8e9 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-05-19T17:50:20Z (GMT) No. of bitstreams: 1 Leal MMT Early....pdf: 781614 bytes, checksum: d9ce1f5869c3b92b18bd5f5dc7f0b8e9 (MD5)Made available in DSpace on 2015-05-19T17:50:20Z (GMT). No. of bitstreams: 1 Leal MMT Early....pdf: 781614 bytes, checksum: d9ce1f5869c3b92b18bd5f5dc7f0b8e9 (MD5) Previous issue date: 2014Hospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilStatus epilepticus (SE) is a severe clinical manifestation of epilepsy associated with intense neuronal loss and inflammation, two key factors involved in the pathophysiology of temporal lobe epilepsy. Bone marrow mononuclear cells (BMMC) attenuated the consequences of pilocarpine-induced SE, including neuronal loss, in addition to frequency and duration of seizures. Here we investigated the effects of BMMC transplanted early after the onset of SE in mice, as well as the involvement of soluble factors produced by BMMC in the effects of the cell therapy. Mice were injected with pilocarpine for SE induction and randomized into three groups: transplanted intravenously with 1 × 10(7) BMMC isolated from GFP transgenic mice, injected with BMMC lysate, and saline-treated controls. Cell tracking, neuronal counting in hippocampal subfields and cytokine analysis in the serum and brain were performed. BMMC were found in the brain 4 h following transplantation and their numbers progressively decreased until 24 h following transplantation. A reduction in hippocampal neuronal loss after SE was found in mice treated with live BMMC and BMMC lysate when compared to saline-treated, SE-induced mice. Moreover, the expression of inflammatory cytokines IL-1ß, TNF-α, IL-6 was decreased after injection of live BMMC and to a lesser extent, of BMMC lysate, when compared to SE-induced controls. In contrast, IL-10 expression was increased. Analysis of markers for microglia activation demonstrated a reduction of the expression of genes related to type 1-activation. BMMC transplantation promotes neuroprotection and mediates anti-inflammatory effects following SE in mice, possibly through the secretion of soluble factors

Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-24T17:43:58Z No. of bitstreams: 1 Costa-Ferro ZSM Antiepileptic....pdf: 1919637 bytes, checksum: 1a29ba60fca53e173b971686c08d992c (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-11-24T17:44:09Z (GMT) No. of bitstreams: 1 Costa-Ferro ZSM Antiepileptic....pdf: 1919637 bytes, checksum: 1a29ba60fca53e173b971686c08d992c (MD5)Made available in DSpace on 2014-11-24T17:59:13Z (GMT). No. of bitstreams: 1 Costa-Ferro ZSM Antiepileptic....pdf: 1919637 bytes, checksum: 1a29ba60fca53e173b971686c08d992c (MD5) Previous issue date: 2014Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Hemocentro São Lucas. São Paulo, SP, Brasil.CordCell. Umbilical Cord Blood Stem Cell Center. São Paulo, SP, Brasil,CordCell. Umbilical Cord Blood Stem Cell Center. São Paulo, SP, Brasil.Hemocentro São Lucas. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil.Status epilepticus (SE) is a condition of persistent seizure that leads to brain damage and, frequently, to the establishment of chronic epilepsy. Cord blood is an important source of adult stem cells for the treatment of neurological disorders. The present study aimed to evaluate the effects of human umbilical cord blood mononuclear cells (HUCBC) transplanted into rats after induction of SE by the administration of lithium and pilocarpine chloride. Transplantation of HUCBC into epileptic rats protected against neuronal loss in the hippocampal subfields CA1, CA3 and in the hilus of the dentate gyrus, up to 300 days after SE induction. Moreover, transplanted rats had reduced frequency and duration of spontaneous recurrent seizures (SRS) 15, 120 and 300 days after the SE. Our study shows that HUCBC provide prominent antiepileptic and neuroprotective effects in the experimental model of epilepsy and reinforces that early interventions can protect the brain against the establishment of epilepsy