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3 results on '"Nesci V"'

1. IL-6 Receptor Blockade by Tocilizumab Has Anti-absence and Anti-epileptogenic Effects in the WAG/Rij Rat Model of Absence Epilepsy.

Author

Leo A, Nesci V, Tallarico M, Amodio N, Gallo Cantafio EM, De Sarro G, Constanti A, Russo E, and Citraro R

Subjects
Animals, Antibodies, Monoclonal, Humanized pharmacology, Dose-Response Relationship, Drug, Epilepsy, Absence genetics, Male, Rats, Rats, Transgenic, Rats, Wistar, Antibodies, Monoclonal, Humanized therapeutic use, Disease Models, Animal, Epilepsy, Absence drug therapy, Epilepsy, Absence metabolism, Receptors, Interleukin-6 antagonists & inhibitors, Receptors, Interleukin-6 metabolism
Abstract

Increased expression of interleukin-6 (IL-6) both in cerebrospinal fluid (CSF) and plasma is closely associated with convulsive epilepsy and symptom severity of depression. By comparison, at present, little is known about the role of this cytokine in childhood (non-convulsive) absence epilepsy. The aim of this work was to investigate the potential effects of acute and chronic treatment with tocilizumab (TCZ, 10 and 30 mg/kg/day), on absence seizures, their development, and related psychiatric comorbidity in WAG/Rij rats. It is known that lipopolysaccharide (LPS)-induced changes in inflammatory processes increase absence epileptic activity. In order to study the central effects of TCZ, we investigated whether administration of this anti-IL-6R antibody could modulate the lipopolysaccharide (LPS) or IL-6-evoked changes in absence epileptic activity in WAG/Rij rats. Our results demonstrate that TCZ, at both doses, significantly reduced the development of absence seizures in adult WAG/Rij rats at 6 months of age (1 month after treatment suspension) compared with untreated controls, thus showing disease-modifying effects. Decreased absence seizure development at 6 months of age was also accompanied by reduced comorbid depressive-like behavior, whereas no effects were observed on anxiety-related behavior. Acute treatment with TCZ, at 30 mg/kg, had anti-absence properties lasting ~25 h. The co-administration TCZ with i.c.v. LPS or IL-6 showed that TCZ inhibited the worsening of absence seizures induced by both proinflammatory agents in the WAG/Rij rats, supporting a central anti-inflammatory-like protective action. These results suggest the possible role of IL-6 and consequent neuroinflammation in the epileptogenic process underlying the development and maintenance of absence seizures in WAG/Rij rats. Accordingly, IL-6 signaling could be a promising pharmacological target in absence epilepsy and depressive-like comorbidity.

Published
2020
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2. First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat

Author

Francesca Lembo, Angela Quirino, Carmen De Caro, Rita Citraro, Antonio Leo, Nadia Marascio, Emilio Russo, Roberto Russo, Valentina Nesci, Mariella Cuomo, Martina Tallarico, Luigi Francesco Iannone, Michelangelo Iannone, Domenico Palumbo, Giovambattista De Sarro, Andrew Constanti, Antonio Calignano, Lorena Coretti, Elisabetta Buommino, Citraro, R., Lembo, F., De Caro, C., Tallarico, M., Coretti, L., Iannone, L. F., Leo, A., Palumbo, D., Cuomo, M., Buommino, E., Nesci, V., Marascio, N., Iannone, M., Quirino, A., Russo, R., Calignano, A., Constanti, A., Russo, E., and De Sarro, G.

Subjects
0301 basic medicine, Physiology, Gut flora, Epilepsy, 0302 clinical medicine, Electroencephalography, Fecal Microbiota Transplantation, Pathophysiology, Anti-Bacterial Agents, Butyrates, Neurology, Anticonvulsants, medicine.symptom, medicine.drug, microbiota–gut–brain axi, DNA, Bacterial, Firmicutes, Colon, Inflammation, Biology, digestive system, DNA, Ribosomal, 03 medical and health sciences, Ileum, Seizures, Genetic model, Proteobacteria, medicine, Animals, Protein Precursors, Rats, Wistar, gut microbiota, Haptoglobins, Bacteroidetes, biology.organism_classification, medicine.disease, Fatty Acids, Volatile, Gastrointestinal Microbiome, Rats, Absence seizure, Disease Models, Animal, 030104 developmental biology, Ethosuximide, Epilepsy, Absence, inflammation, Neurology (clinical), Propionates, Gastrointestinal Motility, 030217 neurology & neurosurgery
Abstract

Objective A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). Methods Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. Results Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. Significance Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

Published
2020

3. Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

Author

Pasquale Striano, Giovambattista De Sarro, Lorenzo Di Cesare Mannelli, Antonio Calignano, Carmen De Caro, Valentina Nesci, Rita Citraro, Emilio Russo, Carmen Avagliano, Andrew Constanti, Carla Ghelardini, Antonio Leo, P. Mainardi, De Caro, C., Leo, A., Nesci, V., Ghelardini, C., di Cesare Mannelli, L., Striano, P., Avagliano, C., Calignano, A., Mainardi, P., Constanti, A., Citraro, R., De Sarro, G., and Russo, E.

Subjects
Male, medicine.medical_treatment, lcsh:Medicine, Convulsants, Pharmacology, Aminosalicylate, Article, Epilepsy, chemistry.chemical_compound, Mice, Mesalazine, medicine, Animals, Colitis, lcsh:Science, Mesalamine, Valproic Acid, Multidisciplinary, Seizure threshold, business.industry, lcsh:R, Anti-Inflammatory Agents, Non-Steroidal, Dextran Sulfate, medicine.disease, Ulcerative colitis, Disease Models, Animal, Epilepsy, intestinal inflammation, Anticonvulsant, chemistry, Pentylenetetrazole, lcsh:Q, Anticonvulsants, business, medicine.drug
Abstract

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.

Published
2018

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