D. M

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Ricardo Arida

Universidade Federal de São Paulo (UNIFESP)

Roberta Cysneiros

Universidade Presbiteriana Mackenzie

Matheus Teixeira Rossignoli

Universidade de São Paulo

Esper Cavalheiro

Universidade Federal de São Paulo (UNIFESP)

Rita Sinigaglia-Coimbra

Universidade Federal de São Paulo (UNIFESP)

Lezio S Bueno-Junior

University of Michigan Medical School

João Leite

Universidade de São Paulo

Maria Da Silva Fernandes

Norberto Garcia-cairasco

Vinícius Rosa Cota

UFSJ - Federal University of São João Del-Rei

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Papers by D. M

Br~lian }oumal of EPilepsy and Cli1ical Sinaptogênese Hipocampal e Epilepsia: Estudo em um Modelo Experimental

by Maria da Graça Naffah-Mazzacoratti, Mayra Mori, and D. M

Resumo A pilocarpina, um agonista colínérgico, administrado em ratos induz crises lírnbicas e sta... more Resumo A pilocarpina, um agonista colínérgico, administrado em ratos induz crises lírnbicas e status epilepticus (SE), (fase aguda), uma normalização comportamental (fase silenciosa) e posteriormente crises espontâneas e recorrentes (fase crônica), mimetizando assim, a epilepsia de lobo temporal observada em humanos. Estas crises são acompanhadas por lesão cerebral e modificações neuroquírnicas, A sinaptcfisina (p38) é uma fosfoprotefna associada à vesícula sináptica, se relacionando à liberação de neurotransmissores e a neo-sinaptogênese, Este trabalho tem como objetivo estudar as modificações na expressão de p38 em sinaptossomas hipocampais nas três fases do modelo de epilepsia induzida por PILO. Ratos machos receberam PILO (350 mg/kg) e foram decapitados após 1 hora de SE, 5 dias após SE e 90 dias após o SE. Os hipocampos foram removidos e submetidos a um fracionamento para obtenção de sinaptossomas e a seguir à técnica de Westem blotting, utilizando anticorpo monoclonal contra p38. A ímunohistoqufrníca realizada no hípocampo destes animais teve como objetivo localizar as alterações na expressão desta proteína. Os resultados do Westem blotting mostram um aumento na concentração de p38 em sinaptossomas hipocampais nas três fases do modelo. A ímunohístoquímíca mostrou que este aumento está concentrado na sub-área de CAJ, no giro denteado e no hílo hipocampal. Estes achados neuroquírnicos podem contribuir para uma melhor compreensão dos mecanismos de reorganização, após um insulto cerebral, mostrando mudanças plásticas permanentes, que podem contribuir para um funcionamento anormal da neurotransmissão hipocarnpal, durante o fenômeno epiléptico. Abstract Pilocarpine (PILO) administered to rats induces limbic seizures and status epiIepcicus (SE), (acute period). A retum to normal behavior is observed (silent period) , whicp is followed bv spontaneous and recurrent seizures (chtonic period) , resenibling the pattem ofhuman temporal lobe epilepsy. Neurochemical changes and cerebral damage accompany these seizures. Synaptophysin (p38), the major synaptic vesicle protein, is associated to neuro-transmitter release and synaptogenesis. The present work was undertaken to study the p38 expression in sínaptoso-mal fractions obtained from hippocampus during ali phases of PILO mode!. Male rats received PILO (350 mg/k.g) and were killed ar 1 hour, 5 days and 90 days after SE induction. The hippocampi were removed and subrnit-Cop,.nghl o Liga Bruilciro de E.pücpci. ted to subcellular fractionating to purify me synaptosomes The synaptosomal samples were submitted to Westem blotting technique, using monoclonal antibody against p38. Immunohistochemistry was also employed to determine p38 dístríbutíon in the hippocampus of these rats. The experimental protocols were approved by the UNI-FESP Ethícs Committee. The results show that híppocam-paI p38 content is increased in ali phases of thís epilepsy mode!. These increased leveis were predominant in CAJ, dentate gyrus and hilus regions ofthe hippocampal formation. Our findings may conrribute to additional understanding of neurotransmitter release mechanisms occuring after cerebral injury, suggesting that a reactive sinapto-genesis can be important in the híppocampal reorganization and could be part of the abnorrnal neurotransmission process, observed during epileptogenesis.

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Melatonin administration after pilocarpine-induced status epilepticus: A new way to prevent or attenuate postlesion epilepsy?

by Francisco R Cabral, Maria da Graça Naffah-Mazzacoratti, and D. M

Epilepsy & Behavior, 2011

Objective: The goal of this study was to verify the effects of treatment with melatonin and N-ace... more Objective: The goal of this study was to verify the effects of treatment with melatonin and N-acetylserotonin on the pilocarpine-induced epilepsy model. Methods: The animals were divided into four groups: (1) animals treated with saline (Saline); (2) animals that received pilocarpine and exhibited SE (SE); (3) animals that exhibited SE and were treated with N-acetylserotonin (30 minutes and 1, 2, 4, 6, 12, 24, 36, and 48 hours) after SE onset (SE + NAS); (4) animals that exhibited SE and were treated with melatonin at the same time the SE + NAS group (SE + MEL). Behavioral (latency to first seizure, frequency of seizures, and mortality) and histological (Nissl and neo-Timm) parameters were analyzed. Results: The animals treated with melatonin (SE + MEL) had a decreased number of spontaneous seizures during the chronic period (P b 0.05), a reduction in mossy fiber sprouting, and less cell damage than the SE group. Animals treated with N-acetylserotonin did not exhibit any kind of significant change. Conclusion: Melatonin exerts an important neuroprotective effect by attenuating SE-induced postlesion and promoting a decrease in the number of seizures in epileptic rats. This suggests, for the first time, that melatonin could be used co-therapeutically in treatment of patients exhibiting SE to minimize associated injuries in these situations.

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Maternal seizures can affect the brain developing of offspring

by Ana Cossa and D. M

Metabolic Brain Disease, 2016

To elucidate the impact of maternal seizures in the developing rat brain, pregnant Wistar rats we... more To elucidate the impact of maternal seizures in the developing rat brain, pregnant Wistar rats were subjected to the pilocarpine-induced seizures and pups from different litters were studied at different ages. In the first 24 h of life, blood glucose and blood gases were analyzed. (14)C-leucine [(14)C-Leu] incorporation was used to analyze protein synthesis at PN1, and Western Blot method was used to analyze protein levels of Bax, Bcl-2 and Poly(ADP-ribose) polymerase-1 (PARP-1) in the hippocampus (PN3-PN21). During the first 22 days of postnatal life, body weight gain, length, skull measures, tooth eruption, eye opening and righting reflex have been assessed. Pups from naive mothers were used as controls. Experimental pups showed a compensated metabolic acidosis and hyperglycemia. At PN1, the [(14)C-Leu] incorporation into different studied areas of experimental pups was lower than in the control pups. During development, the protein levels of Bax, Bcl-2 and PARP-1 in the hippocampus of experimental pups were altered when compared with control pups. A decreased level of pro- and anti-apoptotic proteins was verified in the early postnatal age (PN3), and an increased level of pro-apoptotic proteins concomitant with a reduced level of anti-apoptotic protein was observed at the later stages of the development (PN21). Experimental pups had a delay in postnatal growth and development beyond disturb in protein synthesis and some protein expression during development. These changes can be result from hormonal alterations linked to stress and/or hypoxic events caused by maternal epileptic seizures during pregnancy.

Seizures during pregnancy modify the development of hippocampal interneurons of the offspring

by Ana Cossa, D. M, and Maria Graca Naffah Mazzacoratti

Epilepsy & Behavior, 2010

We investigated the effect of epileptic seizures during pregnancy on hippocampal expression of ca... more We investigated the effect of epileptic seizures during pregnancy on hippocampal expression of calciumbinding proteins in the offspring. Female Wistar rats were submitted to the pilocarpine model and mated during the chronic period. Seizure frequency was monitored over the entire pregnancy. Pups were perfused at postnatal days 6 and 13, and the brains processed for Nissl staining and immunohistochemistry for NeuN, calbindin, calretinin, and parvalbumin. Number of stained cells in the hippocampus was estimated through stereological methods. Our results showed a decrease in epileptic seizure frequency during pregnancy. No differences were observed in NeuN-positive, CR-positive cells, and Nissl-stained hippocampal neurons between the groups. However, there was a significant decrease in calbindin-positive cells (P = 0.005) and a significant increase in parvalbumin-positive cells (P = 0.02) in the experimental group when compared with the control group. These results suggest that seizures during pregnancy affect the development of specific hippocampal interneurons of the offspring.

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Relationship between fluid-attenuated inversion-recovery (FLAIR) signal intensity and inflammatory mediator's levels in the hippocampus of patients with temporal lobe epilepsy and mesial temporal sclerosis

by Esper Cavalheiro and D. M

Arquivos de Neuro-Psiquiatria, 2011

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Cardiovascular protective effect of melatonin in sudden unexpected death in epilepsy: A hypothesis

by Fulvio Scorza, Maria Graca Naffah Mazzacoratti, D. M, and Ricardo Arida

Medical Hypotheses, 2008

Epilepsy is the most common neurological disorder, approximately 1% of the population worldwide h... more Epilepsy is the most common neurological disorder, approximately 1% of the population worldwide have epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, AED number and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. Furthermore, the evidence from the last 10 years suggests that melatonin has an important role in the epileptogenesis process and influences the cardiovascular system as well. The positive effect of melatonin has been demonstrated against different convulsive stimuli in several rodents, including seizures induced by pentylenetetrazole kainate, glutamate, maximal electrical shock and electrically kindled stimulation of amygdala. Clinical studies have also demonstrated a positive role of melatonin on the seizure frequency in children and reduced spiking activity and seizure frequency in patients with intractable epilepsy. In the rat hearts, studies in vivo and in vitro using pharmacological concentrations of melatonin confirmed an anti-arrhythmic effect of this hormone and studies in humans have been shown that chronic heart disease patients have significantly lower melatonin levels in their blood stream than do normal individuals. Thus, caution should be taken in generalization of these findings to epileptic population. Moreover, it is important to note that when dealing with intractable epilepsy that do not respond to any conventional treatment, the additional of melatonin may be evaluated. Taken together, in this paper we suggested a possible relationship between cardiac abnormalities, melatonin and SUDEP.

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Br~lian }oumal of EPilepsy and Cli1ical Sinaptogênese Hipocampal e Epilepsia: Estudo em um Modelo Experimental

by Maria da Graça Naffah-Mazzacoratti, Mayra Mori, and D. M

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Melatonin administration after pilocarpine-induced status epilepticus: A new way to prevent or attenuate postlesion epilepsy?

by Francisco R Cabral, Maria da Graça Naffah-Mazzacoratti, and D. M

Epilepsy & Behavior, 2011

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Maternal seizures can affect the brain developing of offspring

by Ana Cossa and D. M

Metabolic Brain Disease, 2016