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1. Finding a better drug for epilepsy: Antiinflammatory targets

Author

Dedeurwaerdere, Stefanie, Friedman, Alon, Fabene, Paolo F, Mazarati, Andrèy, Murashima, Yoshiya L, Vezzani, Annamaria, and Baram, Tallie Z

Subjects
Brain Disorders, Neurodegenerative, Epilepsy, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Anti-Inflammatory Agents, Cell Adhesion Molecules, Humans, Inflammation, Brain inflammation, Epileptogenesis, Therapy, Disease-modifying, Clinical Sciences, Neurology & Neurosurgery
Abstract

This monograph summarizes one of the sessions of the XI Workshop on Neurobiology of Epilepsy (WONOEP), and provides a critical review of the current state of the field. Speakers and discussants focused on several broad topics: (1) the coexistence of inflammatory processes encompassing several distinct signal-transduction pathways with the epileptogenic process; (2) evidence for the contribution of specific inflammatory molecules and processes to the onset and progression of epilepsy, as well as to epilepsy-related morbidities including depression; (3) the complexity and intricate cross-talk of the pathways involved in inflammation, and the discrete, often opposite roles of a given mediator in neurons versus other cell types. These complexities highlight the challenges confronting the field as it aims to define inflammatory molecules as promising targets for epilepsy prevention and treatment.

Published
2012

4. Anatomia umana

Author

Seeley, Vanputte, Regan, Russo, Amenta, F., Brunetti, A., Calderan, L., Castaldo, C., Castorina, S., De Luca, A., Di Meglio, F., Fabene, P. F., Ferrandino, I., Guerra, G., Grimaldi, M. C., Macchi, V., Macchiarelli, G., Montagnani, S., Nottola, S. A., Nurzynska, D., Papa, M., Raspanti, M., Rende, M., and Tafuri, D.

Published
2018

5. Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures

Author

Osculati Francesco, Mora Graciela, Merigo Flavia, Rodi Donata, Paradiso Beatrice, Zucchini Silvia, Bovolenta Roberta, Berto Elena, Marconi Peggy, Marzola Andrea, Fabene Paolo F, and Simonato Michele

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Under certain experimental conditions, neurotrophic factors may reduce epileptogenesis. We have previously reported that local, intrahippocampal supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) increases neurogenesis, reduces neuronal loss, and reduces the occurrence of spontaneous seizures in a model of damage-associated epilepsy. Here, we asked if these possibly anti-epileptogenic effects might involve anti-inflammatory mechanisms. Thus, we used a Herpes-based vector to supplement FGF-2 and BDNF in rat hippocampus after pilocarpine-induced status epilepticus that established an epileptogenic lesion. This model causes intense neuroinflammation, especially in the phase that precedes the occurrence of spontaneous seizures. The supplementation of FGF-2 and BDNF attenuated various parameters of inflammation, including astrocytosis, microcytosis and IL-1β expression. The effect appeared to be most prominent on IL-1β, whose expression was almost completely prevented. Further studies will be needed to elucidate the molecular mechanism(s) for these effects, and for that on IL-1β in particular. Nonetheless, the concept that neurotrophic factors affect neuroinflammation in vivo may be highly relevant for the understanding of the epileptogenic process.

Published
2010
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7. Enhancement of GABA(A)-current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

Author

Mazzuferi, M., Eleonora, Palma, Martinello, K., Francesca, Maiolino, Roseti, Cristina, Sergio, Fucile, Fabene, P. F., Schio, F., Pellitteri, M., Sperk, G., Miledi, R., Miledih, R., Fabrizio, Eusebi, and Simonato, M.

Subjects
Male, Xenopus, Fluorescent Antibody Technique, Hippocampus, Biology, Hippocampal formation, Epileptogenesis, Temporal lobe, Rats, Sprague-Dawley, Epilepsy, gaba(a) receptor, GABA receptor, xenopus oocytes, pilocarpine rat, medicine, Animals, Organic Chemicals, Xenopus oocytes, Neurons, Analysis of Variance, Multidisciplinary, Neocortex, GABAA receptor, Pilocarpine, Anatomy, Biological Sciences, Fluoresceins, Receptors, GABA-A, medicine.disease, Immunohistochemistry, Rats, Electrophysiology, medicine.anatomical_structure, Epilepsy, Temporal Lobe, Oocytes, Neuroscience, Signal Transduction
Abstract

Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling mediated by GABA A receptors. In particular, the use-dependent decrease (run-down) of the currents (I GABA ) evoked by the repetitive activation of GABA A receptors is markedly enhanced in hippocampal and cortical neurons of TLE patients. Understanding the role of I GABA run-down in the disease, and its mechanisms, may allow development of medical alternatives to surgical resection, but such mechanistic insights are difficult to pursue in surgical human tissue. Therefore, we have used an animal model (pilocarpine-treated rats) to identify when and where the increase in I GABA run-down occurs in the natural history of epilepsy. We found: ( i ) that the increased run-down occurs in the hippocampus at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made), and then extends to the neocortex and remains constant in the course of the disease; ( ii ) that the phenomenon is strictly correlated with the occurrence of spontaneous seizures, because it is not observed in animals that do not become epileptic. Furthermore, initial exploration of the molecular mechanism disclosed a relative increase in α4-, relative to α1-containing GABA A receptors, occurring at the same time when the increased run-down appears, suggesting that alterations in the molecular composition of the GABA receptors may be responsible for the occurrence of the increased run-down. These observations disclose research opportunities in the field of epileptogenesis that may lead to a better understanding of the mechanism whereby a previously normal tissue becomes epileptic.

Published
2010

17. Cortical development and focal cortical dysplasia

Author

Marina Bentivoglio, Tassi, L., Pech, E., Costa, C., Fabene, P. F., and Spreafico, R.

Subjects
Neurons, Ontogenesis, Epilepsy, Cell Movement, Cerebral cortex, Malformations, Neuronal migration, Humans
Abstract

A brief survey of cortical development is presented, focusing on neuronal migration and its alterations. Corticogenesis is achieved through ordered temporospatial steps, via the formation of transient structures, and successive waves of cell proliferation and migration (followed by cell differentiation and maturation), and apoptotic cell death. The appearance of the proliferative ventricular zone and marginal zone, and of the superficial primordial plexiform layer, is followed by the formation of the prospective layer I, of the subplate, whose neurons are destined to die, and of the cortical plate that will give rise to layers II-VI. Cells arising in the ventricular zone migrate radially using radial glia as a scaffold, and are destined to form pyramidal cells. Cortical interneurons are mainly generated in the ganglionic eminence and migrate along axonal substrates following tangential routes. Disorders of this complex process lead to a wide range of alterations, and focal derangements of cortical organization have been grouped under the term focal cortical dysplasia (FCD). As the result of a neuropathological revision of FCD cases with intractable epilepsy, a novel classification comprising three subgroups of FCD has been introduced, and is supported by electroclinical and neuroimaging data, as well as by the postsurgical outcome of patients: i). architectural dysplasia, characterized by altered cortical lamination; ii). cytoarchitectural dysplasia, with the occurrence of giant neurons besides cortical dyslamination; iii). Taylor-type cortical dysplasia, in which altered cortical lamination is consistently associated with the occurrence of giant, dysmorphic and ectopic neurons, and frequently with the so-called balloon cells.

Published
2003

18. Ongoing Electroencephalographic Activity Associated with Cortical Arousal in Transgenic PDAPP Mice (hAPP V717F)

Author

Del Percio, Claudio, Drinkenburg, Wilhelmus, Lopez, Susanna, Limatola, Cristina, Bastlund, Jesper F., Christensen, Ditte Z., Pedersen, Jan T., Forloni, Gianluigi, Frasca, Angelisa, Noe, Francesco M., Bentivoglio, Marina, Fabene, Paolo F., Bertini, Giuseppe, Colavito, Valeria, Dix, Sophie, Ferri, Raffaele, Bordet, Regis, Richardson, Jill C., and Babiloni, Claudio

Abstract

Background: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). Objective: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer's disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Aβ1-42). Methods: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months ±0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. Results: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. Conclusion: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mice

Published
2018

19. Late-onset Parkinsonism in NF B/c-Rel-deficient mice

Author

Baiguera, C., primary, Alghisi, M., additional, Pinna, A., additional, Bellucci, A., additional, De Luca, M. A., additional, Frau, L., additional, Morelli, M., additional, Ingrassia, R., additional, Benarese, M., additional, Porrini, V., additional, Pellitteri, M., additional, Bertini, G., additional, Fabene, P. F., additional, Sigala, S., additional, Spillantini, M. G., additional, Liou, H.-C., additional, Spano, P. F., additional, and Pizzi, M., additional

Published
2012
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20. In Vivo Phenotyping of the ob/ob Mouse by Magnetic Resonance Imaging and 1H-Magnetic Resonance Spectroscopy*

Author

Calderan, Laura, Marzola, Pasquina, Nicolato, Elena, Fabene, Paolo F., Milanese, Chiara, Bernardi, Paolo, Giordano, Antonio, Cinti, Saverio, and Sbarbati, Andrea

Abstract

AbstractObjective: We studied ob/ob and wild-type (WT) mice to characterize the adipose tissues depots and other visceral organs and to establish an experimental paradigm for in vivo phenotyping.Research Methods and Procedures: An in vivo evaluation was conducted using magnetic resonance imaging and 1H-magnetic resonance spectroscopy (1H-MRS). We used T1-weighted images and three-dimensional spin echo T1-weighted images for the morphological analysis and 1H-MRS spectra on all body mass, as well as 1H-MRS spectra focalized on specific lipid depots [triglyceride (TG) depots] for a molecular analysis.Results: In ob/ob mice, three-dimensional evaluation of the trunk revealed that ∼64% of the volume consists of white adipose tissue, which is 72% subcutaneous and 28% visceral. In vivo 1H-MRS showed that 20.00 ± 6.92% in the WT group and 58.67 ± 6.65% in the ob/ob group of the total proton content is composed of TG protons. In in vivo-localized spectra of ob/ob mice, we found a polyunsaturation degree of 0.5247 in subcutaneous depots. In the liver, we observed that 48.7% of the proton signal is due to water, whereas in the WT group, the water signal amounted to 82.8% of the total proton signal. With the sequences used, the TG amount was not detectable in the brain or kidneys.Discussion: The present study shows that several parameters can be obtained by in vivo examination of ob/ob mice by magnetic resonance imaging and 1H-MRS and that the accumulated white adipose tissue displays low polyunsaturation degree and low hydrolipidic ratio. Relevant anatomical alterations observed in urinary and digestive apparatuses should be considered when ob/ob mice are used in experimental paradigms.

Published
2006
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21. Axon-like processes in type III cells of taste organs

Author

Sbarbati, Andrea, Merigo, Flavia, Benati, Donatella, Bernardi, Paolo, Tizzano, Marco, Fabene, Paolo F., Crescimanno, Caterina, and Osculati, Francesco

Abstract

Type III cells of the taste organs are widely considered to be chemoreceptors. The present study was performed on the frog taste disk and describes an axon-like process in type III cells, which often contains a bundle of densely-packed parallel microfilaments. These processes pass through the basal membrane of the gustatory epithelium, running into the lamina propria (transbasal membrane processes, tBMPs). In their intraepithelial tract, tBMPs contain dense-cored vesicles revealing their origin from type III cells. Type III cells showing both classic nonrigid processes (with vesicles and nerve contacts) and tBMPs are present. The connective tract of a tBMP usually contains dense-cored vesicles only in its proximal portion. In some cases, the connective tract of tBMPs is almost perpendicular to the basal lamina. In other cases, it runs parallel to and below the basal lamina. Some tBMPs contact nerve fibers running in the subepithelial connective tissue; the contact area is rather wide but evident synapse-like junctions were never detected. Contacts between tBMPs and nerve fibers innervating basal cells are also found. In conclusion, the data demonstrate the existence of epithelial cells resembling primitive neurons that display an apical dendrite and axon-like basal processes. Until now, it was not considered possible that epithelial receptor cells extend processes out of the epithelium. © 2006 Wiley-Liss, Inc.

Published
2006
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22. In Vivo MRI in Different Models of Experimental Epilepsy

Author

Fabene, P. F. and Sbarbati, A.

Abstract

In order to investigate epilepsy, that is one of the most common neurological disorders, in the last decades different animal models have been proposed. Prevention, diagnosis, treatment and basic knowledge have been improved by the mean of these models. Numerous animal models have been developed in epilepsy research, both for generalized and for simple / complex partial seizures. Animal models for generalized seizures include sensory (light, noise, movement, etc) or electrical stimulations and genetic models. Models for focal seizures include topical or systemic application of pro-convulsive compounds or electrical stimulation. Baboons, mice, rats, rabbits, and Fayoumi chicken have been extensively used in this regard. Since 1983, when magnetic resonance spectroscopy was used to evaluate for the first time in vivo alterations induced by status epilepticus in rabbit, an increasing interest for the neuroimaging perspective has led to new insights in the study of epileptic disorders. In the early 1990s experimental studies provided evidence for the feasibility of magnetic resonance imaging analysis and detection of tissue damage in kainic acid-induced epilepsy in rat. In the following years a wealth of data has been obtained by the mean of functional MRI and / or by diffusion-weighted images. The studies reported in the literature of the last decades indicate in vivo magnetic resonance of epilepsy model as valuable and extremely informative tool.

Published
2004

23. Cortical development and focal cortical dysplasia

Author

Bentivoglio, Marina, Tassi, Laura, Pech, Emanuel, Costa, Catarina, Fabene, Paolo F, and Spreafico, Roberto

Abstract

A brief survey of cortical development is presented, focusing on neuronal migration and its alterations. Corticogenesis is achieved through ordered temporospatial steps, via the formation of transient structures, and successive waves of cell proliferation and migration (followed by cell differentiation and maturation), and apoptotic cell death. The appearance of the proliferative ventricular zone and marginal zone, and of the superficial primordial plexiform layer, is followed by the formation of the prospective layer I, of the subplate, whose neurons are destined to die, and of the cortical plate that will give rise to layers II‐VI. Cells arising in the ventricular zone migrate radially using radial glia as a scaffold, and are destined to form pyramidal cells. Cortical interneurons are mainly generated in the ganglionic eminence and migrate along axonal substrates following tangential routes. Disorders of this complex process lead to a wide range of alterations, and focal derangements of cortical organization have been grouped under the term focal cortical dysplasia (FCD). As the result of a neuropathological revision of FCD cases with intractable epilepsy, a novel classification comprising three subgroups of FCD has been introduced, and is supported by electroclinical and neuroimaging data, as well as by the postsurgical outcome of patients: i) architectural dysplasia, characterized by altered cortical lamination; ii) cytoarchitectural dysplasia, with the occurrence of giant neurons besides cortical dyslamination; iii) Taylor‐type cortical dysplasia, in which altered cortical lamination is consistently associated with the occurrence of giant, dysmorphic and ectopic neurons, and frequently with the so‐called balloon cells.

Published
2003
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24. Dynamic MRI reveals that the magnitude of the ischemia-related enhancement in skeletal muscle is age-dependent

Author

Sbarbati, Andrea, Marzola, Pasquina, Nicolato, Elena, Farace, Paolo, Asperio, Roberto M., Lunati, Ernesto, Fabene, Paolo F., Marzioni, Daniela, Castellucci, Mario, Capogrossi, Maurizio C., and Osculati, Francesco

Abstract

This study was designed to evaluate the influence of age on the dynamic contrast-enhanced MRI of ischemic tissue. A well-established model of peripheral arterial insufficiency (i.e., the rat hindlimb ischemia after removal of femoral artery) in different age groups (i.e., young, presenescent, and senescent rats) was studied. The analysis of the MR signal demonstrated a marked accumulation of a contrast agent (Gd-DTPA) in the ischemic leg (ischemia-related enhancement, IRE). IRE was an age-related event: 4-month-old rats showed a strong IRE while 12-month-old rats and 20-month old rats showed a significantly reduced IRE in comparison to young animals. Histological analysis of the ischemic muscles revealed that there was no evidence of significant necrosis of the muscle tissue but only a weak interstitial fibrosis; CD31-immunostaining revealed a preserved microcirculatory bed. Magn Reson Med 49:386–390, 2003. © 2003 Wiley-Liss, Inc.

Published
2003
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28. 19th biennial IPEG Meeting

Author

Timofeev, Igor, Kenemans, Leon, Fabene, P. F., Ahnaou, A., Olbrich, Sebastian, Oostenveld, Robert, Arns, Martijn, Boutros, Nash, da Silva, Fernando Lopes, Jensen, Ole, Loo, Sandra K., Landolt, Hans-Peter, Schoffelen, Jan Mathijs, Gouw, Alida A., Hillebrand, Arjan, Demuru, Matteo, Ris, Peterjan, Scheltens, Philip, Stam, Cornelis J., Nissen, Ida A., van Straaten, Ilse E. C. W., Reijneveld, Jaap C., Simpraga, Sonja, Alvarez-Jimenez, Ricardo, Mansvelder, Huibert D., van Gerven, Joop M. A., Groeneveld, Geert Jan, Poil, Simon-Shlomo, Linkenkaer-Hansen, Klaus, van Putten, Michel J. A. M., Tjepkema-Cloostermans, Marleen C., Hofmeijer, Jeannette, Babiloni, Claudio, Triggiani, Antonio Ivano, Lizio, Roberta, Cordone, Susanna, Brunetti, Antonio, Tattoli, Giacomo, Bevilacqua, Vitoantonio, Soricelli, Andrea, Ferri, Raffaele, Nobili, Flavio, Gesualdo, Loreto, Millán-Calenti, José Carlos, Buján, Ana, Tortelli, Rosanna, Cardinali, Valentina, Barulli, Orietta, Giannini, Antonio, Spagnolo, Pantaleo, Armenise, Silvia, Buenza, Grazia, Scianatico, Gaetano, Logroscino, Giancarlo, Frisoni, Giovanni B., Del Percio, Claudio, Hipp, Joerg F., Comley, Robert, Bentley, Darren, Derks, Michael, Garces, Pilar, Knoflach, Frederic, Lennon-Chrimes, Sian, Nave, Stephane, Noldeke, Jana, Seneca, Nick, Trube, Gerhard, Wandel, Christoph, WThomas, Andrew, Hernandez, Maria-Clemancia, Gerrits, Berrie, Vollebregt, Madelon A., Kessels, Roy P. C., Palmer, Donna, Gordon, Evian, Janssen, Tieme W. P., Heslenfeld, Dirk J., van Mourik, Rosa, Geladé, Katleen, Maras, Athanasios, Oosterlaan, Jaap, Brandeis, Daniel, Sander, Christian, Hegerl, Ulrich, Boutros, Nash N., Kirsten, Alexandra, Dohrmann, Anna-Lena, Surova, Galina, Iseger, T. A., Kenemans, J. L., Arns, M., Pawlowski, Marcel A., Adamczyk, Marek, Mikoteit, Thorsten, Steiger, Axel, Kas, Martien J., van Aerde, Karlijn I., van Rijn, Clementina M., Jongsma, Marijtje L. A., van den Broek, Philip L. C., van Egmond, Jan, Walsh, C., Raeymaekers, L., Biermans, R., Manyakov, N. V., Wintmolders, C., Bottelbergs, A., Van Kolen, K., Moechars, D., Kemp, J. A., Drinkenburg, W. H., Marzano, Nicola, Lopez, Susanna, Noce, Giuseppe, Bagnoli, Cristina, Rossini, Paolo Maria, Nobili, Flavio Mariano, Faz, David Bartres, Blin, Olivier, Payoux, Pierre, Bordet, Regis, Mueller, Bernhard, Tsolaki, Magda, Parnetti, Lucilla, Hensch, Tilman, Dukart, Juergen, Bertolino, Alessandro, Forloni, Gianluigi, Frasca, Angelisa, Richardson, Jill, Bastlund, Jesper Frank, Clausen, Bettina, Bentivoglio, Marina, Fabene, Paolo Francesco, Bertini, Giuseppe, Kelley, Jonathan, Drinkenburg, Wilhelmus, Frisoni, Giovanni, Salisbury, Dean F., Coffman, Brian A., Murphy, Timothy, Haigh, Sarah M., Anderer, Peter, Gruber, Georg, Parapatics, Silvia, Saletu-Zyhlarz, Gerda M., Saletu, Bernd, Dorffner, Georg, Jepma, Marieke, Nieuwenhuis, Sander, Schutte, Iris, Heitland, Ivo, Kenemans, J Leon, Sambeth, Anke, Timmermann, Christopher, Kaelen, Mendel, Schenberg, Eduardo, Feilding, Amanda, Leech, Robert, Nutt, David, Carhart-Harris, Robin, Muthukumaraswamy, Suresh, Palenicek, Tomas, Tyls, Filip, Viktorinova, Michaela, Bravermanova, Anna, Androvicova, Renata, Sedlamyerova, Vaclava, Krajca, Vladimir, Brunovsky, Martin, Valle, M, Maqueda, A. E., Romero, S., Mañanas, M. A., Barker, S., Riba, J., Horacek, Jiri, Sos, Peter, Höschl, Cyril, Perenboom, Matthijs J. L., Yang, Yuan, van der Helm, Frans C. T., Ferrari, Michel D., Schouten, Alfred C., Tolner, Else A., Rosipal, Roman, Trejo, Leonardo Jose, Wallerius, John, Apparies, Ross, Cimrova, Barbora, Miller, James, Zobeiri, Mehrnoush, Chaudhary, Rahul, Lütjohann, Annika, Meuth, Patrick, Pape, Hans-Christian, Chetkovich, Dane M., van Luijtelaar, Gilles, Budde, Thomas, Jacob, S., Tahon, K., Balschun, D., Koprivova, J., Saifutdinova, E., Nekovarova, T., Raszka, M., Prasko, J., Bonanni, L., Franciotti, R., Falasca, N. W., Nobili, F., Arnaldi, D., Onofrj, M., Donse, Lana, Sack, Alexander T., Fitzgerald, Paul B., Thiebes, Stephanie, Leicht, Gregor, Curic, Stjepan, Steinmann, Saskia, Polomac, Nenad, Eichler, Iris, Eichler, Lars, Zöllner, Christian, Gallinat, Jürgen, Hanganu-Opatz, Ileana, Mulert, Christoph, Swatzyna, Ronald J., Tarnow, Jay D., Turner, Robert P., Roark, Alexandra J., MacInerney, Erin K., Kozlowski, Gerald P, Perescis, Martin F. J., de Bruin, Natasja, Heijink, Liesbeth, Kruse, Chris, Vinogradova, Lyudmila, Lüttjohann, Annika, Ranzi, Paolo, Freund, Jan A., Thiel, Christiane M., Herrmann, Christoph S., Huysmans, H., Azadi, Parissa, Hollup, Stig, Korcak, Jakub, Koudelka, Vlastimil, Bares, Martin, Czarik, Eléonore, Caci, Hervé, Laurent, Jean-Paul, Deepeshwar, S., Manjunath, N. K., Avinash, M., Dimpfel, Wilfried, Dupont, Caroline, Parsons, Brendan, Brisebois, Hélène, Szabo, Andrea, Duveau, V., Pouyatos, B., Maury, R., Mandé-Nidergang, B., Bouyssières, C., Roucard, C., Roche, Y., Ferger, Boris, Voehringer, Patrizia, Griskova-Bulanova, Inga, Melynyte, Sigita, Dapsys, Kastytis, Voicikas, Aleksandras, Iseger, Tabitha, Tylš, Filip, Vejmola, Čestmír, Kadeřábek, Lukáš, Piorecká, Václava, Novák, Tomáš, Brunovský, Martin, Páleníček, Tomáš, Kruiper, Caitlyn, Sommer, Iris E., Oranje, Bob, Kozlowski, Gerald P., Menolascino, Shelly M., Belgin, Mitchell, Izzo, Genevieve N., Fisher, Lillian E., Meyer, Torsten, Brühl, Annette, Mohammed, Haitham S., Mourad, Iman M., Noor, Neveen A., Ezz, Heba S. Aboul, Khadrawy, Yasser A., Navid, Muhammad Samran, Lelic, Dina, Niazi, Imran Khan, Holt, Kelly, Mark, Esben Bolvig, Drewes, Asbjørn Mohr, Haavik, Heidi, Krajča, Vladimír, de la Salle, Sara, Choueiry, Joelle, Impey, Danielle, Smith, Dylan, Aidelbaum, Robert, Baddeley, Ashley, Hyde, Molly, Duncan, Brittany, Piché, Justin, Rahmani, Noreen, Ilivitsky, Vadim, Knott, Verner, Swart, Jennifer C., Määttä, Jessica I., Cools, Roshan, den Ouden, Hanneke E. M., Jackson, D. A., Veselcic, Peter, Mollon, Jennifer, Spanakis, Emmanouil, Vasileva, Maria, Wicke, Karsten, Novak, Tomas, van der Vinne, Nikita, Vlcek, Premysl, Kohutova, Barbora, Polak, Jakub, Wang, Grace Y., Tiffany, Lin, Hamid, Nazimah, and Sumich, Alex

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29. Translational spectral electroencephalographic markers in the European PharmaCog project: a new resource for drug discovery for Alzheimer's disease.

Author

Babiloni, C., Infarinato, F., Bastlund, J. F., Clausen, B., Forloni, G., Frasca, A., Bentivoglio, M., Fabene, P. F., Bertini, G., Kelley, J., Dix, S., Richardson, J. C., Drinkenburg, W., and Del Percio, C.

Subjects
ELECTROENCEPHALOGRAPHY, AROUSAL (Physiology), MILD cognitive impairment
Abstract

In the IMI PharmaCog project (2010-2014) we showed that the electroencephalographic (EEG) rhythms related to eyes opening as a condition of cortical arousal are abnormal in patients with mild cognitive impairment and Alzheimer's disease (AD; Babiloni et al., 2010, JAD). Towards a back-translation we evaluated whether EEG rhythms related to motor activity change across physiological aging in wild type (WT) mice, as well as in Tg models of AD such as PDAPP and TASTPM mice. For the physiological aging, EEG data were recorded in 19 young (4.5-6 months), 12 middle age (12-14 months), and 15 old (24 months) male WT mice. For the pathological aging, EEG data were recorded in 15 WT vs. 10 PDAPP male mice (24 months), as well as in 14 WT mice (12-14 months) vs. 15 TASTPM mice (12-14 months). Artifact-free EEG segments during wake active state (gross movements, exploratory movements or locomotor activity) and passive state (no sleep) were used as an input for EEG power density analysis. Results showed that (1) 1-2 and 2-4 Hz power density during the passive state was greater in old WT than in young and middle age WT mice (p<0.05); (2) 6-8 Hz power density during the active state was greater in these old mice (p<0.05); (3) 8-10 Hz power density during the active state was greater in young than in middle age mice (p<0.05); (4) 2-4 and 4-6 Hz power density during the passive state was lower in PDAPP compared to WT mice (p<0.05); (5) 8-10 Hz power density during the active state was lower in PDAPP compared to WT mice (p<0.05); (6) 2-4 and 4-6 Hz power density during the passive state was lower in TASTPM compared to WT mice (p<0.05); and (7) 10-12 Hz power density during the active state was lower in TASTPM compared to WT mice (p<0.05). The present results suggest that the EEG markers of motor activity are useful to unveil neurophysiological mechanisms of cortical neural synchronization characterizing the physiological aging in WT mice, as well as the pathological cortical neural synchronization in Tg mice. [ABSTRACT FROM AUTHOR]

Published
2013

30. Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Author

Lisann Pelzl, Gabriela Constantin, Pietro Pucci, Emilia Turco, Immacolata Andolfo, Enrica Caterina Pietronigro, Francesca Garello, Kevin Peikert, Giuseppe Bertini, Enrica Federti, Maria Chiara Monti, Elena Tibaldi, Seth L. Alper, Mario Rosario Buffelli, Erika Lorenzetto, Flora Cozzolino, Angela Amoresano, Andreas Hermann, Alessandro Matte, Carlo Zancanaro, Anna Maria Brunati, Paola Defilippi, Massimiliano Bonifacio, Rainer Ordemann, Enzo Terreno, Adrian Danek, Lucia De Franceschi, Katja Akgün, Angela Siciliano, Federico Del Gallo, Hannes Glaß, Achille Iolascon, Paolo F. Fabene, Tjalf Ziemssen, Anna Illiano, Ruth H. Walker, Florian Lang, Peikert, K., Federti, E., Matte, A., Constantin, G., Pietronigro, E. C., Fabene, P. F., Defilippi, P., Turco, E., Del Gallo, F., Pucci, P., Amoresano, A., Illiano, A., Cozzolino, F., Monti, M., Garello, F., Terreno, E., Alper, S. L., Glass, H., Pelzl, L., Akgun, K., Ziemssen, T., Ordemann, R., Lang, F., Brunati, A. M., Tibaldi, E., Andolfo, I., Iolascon, A., Bertini, G., Buffelli, M., Zancanaro, C., Lorenzetto, E., Siciliano, A., Bonifacio, M., Danek, A., Walker, R. H., Hermann, A., and De Franceschi, L.

Subjects
Male, Cell signaling, Dasatinib, Vesicular Transport Proteins, Mice, Drug Delivery Systems, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Chorea acanthocytosis, Mice, Knockout, 0303 health sciences, Neurodegeneration, Neuroacanthocytosi, 3. Good health, src-Family Kinases, Basal ganglia, Female, Tyrosine kinase, Neuroacanthocytosis, medicine.drug, Protein Kinase Inhibitor, Chorein, Lyn, Cell signaling, Basal ganglia, Neurodegeneration, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Vesicular Transport Protein, LYN, Animals, RC346-429, Lyn, Protein Kinase Inhibitors, Neuroinflammation, 030304 developmental biology, Animal, business.industry, Chorein, Research, Autophagy, medicine.disease, Mice, Inbred C57BL, Pyrimidines, Pyrimidine, Nilotinib, Cancer research, Neurology. Diseases of the nervous system, Neurology (clinical), business, Drug Delivery System, 030217 neurology & neurosurgery
Abstract

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a−/− mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a−/− basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a−/− Lyn−/− showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a−/− hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

Published
2021

31. Cerebral perfusion alterations in epileptic patients during peri-ictal and post-ictal phase: PASL vs DSC-MRI

Author

Giuseppe Bertini, Paolo F. Fabene, Xavier Golay, Giada Zoccatelli, Paolo Manganotti, Francesca B. Pizzini, Paolo Farace, Luigi Giuseppe Bongiovanni, Alberto Beltramello, Antonio Marco Maria Osculati, Pizzini, F. B., Farace, P., Manganotti, Paolo, Zoccatelli, G., Bongiovanni, L. G., Golay, X., Beltramello, A., Osculati, A., Bertini, G., and Fabene, P. F.

Subjects
Adult, Male, medicine.medical_specialty, Arterial spin labeling, Magnetic resonance imaging, Epilepsy, Hyperperfusion, Hypoperfusion, Peri, Biomedical Engineering, Biophysics, Perfusion scanning, Sensitivity and Specificity, Young Adult, Internal medicine, Image Interpretation, Computer-Assisted, medicine, Humans, Radiology, Nuclear Medicine and imaging, Ictal, Cerebral perfusion pressure, Brain Mapping, medicine.diagnostic_test, business.industry, Reproducibility of Results, Middle Aged, medicine.disease, Image Enhancement, Anesthesia, Cerebrovascular Circulation, Cardiology, Female, business, Perfusion, Blood Flow Velocity, Magnetic Resonance Angiography
Abstract

Non-invasive pulsed arterial spin labeling (PASL) MRI is a method to study brain perfusion that does not require the administration of a contrast agent, which makes it a valuable diagnostic tool as it reduces cost and side effects. The purpose of the present study was to establish the viability of PASL as an alternative to dynamic susceptibility contrast (DSC-MRI) and other perfusion imaging methods in characterizing changes in perfusion patterns caused by seizures in epileptic patients. We evaluated 19 patients with PASL. Of these, the 9 affected by high-frequency seizures were observed during the peri-ictal period (within 5 hours since the last seizure), while the 10 patients affected by low-frequency seizures were observed in the post-ictal period. For comparison, 17/19 patients were also evaluated with DSC-MRI and CBF/CBV. PASL imaging showed focal vascular changes, which allowed the classification of patients in three categories: 8 patients characterized by increased perfusion, 4 patients with normal perfusion and 7 patients with decreased perfusion. PASL perfusion imaging findings were comparable to those obtained by DSC-MRI. Since PASL is a) sensitive to vascular alterations induced by epileptic seizures, b) comparable to DSC-MRI for detecting perfusion asymmetries, c) potentially capable of detecting time-related perfusion changes, it can be recommended for repeated evaluations, to identify the epileptic focus, and in follow-up and/or therapy-response assessment.

Published
2012

32. Early onset of age-related changes on neural processing in rats.

Author

Navarro-Mora G, Fabene PF, and van Luijtelaar G

Subjects
Acoustic Stimulation, Animals, Electroencephalography methods, Male, Rats, Rats, Wistar, Aging physiology, Brain growth & development, Brain physiology, Brain Waves physiology, Evoked Potentials, Auditory physiology
Abstract

Altered perceptual and emotional processing might bind impaired cognitive mechanisms during aging; however the nature of these sensory perception modifications is still unknown. In the present experiment we analyzed in rats, from early to mature life (2 to 11 months old), the response to unattended auditory evoked stimulation (Auditory evoked potential, AEP) and the power spectrum of spontaneous electroencephalogram (EEG), with the aim of unraveling the onset and target functional effects of aging. Somatosensory and cingulate cortex, mediodorsal thalamus and CA3 hippocampus were chosen for examination based on their involvement in sensory processing and age-related deficits. The main finding of this study is the early onset of age-related changes in adult rats as can be established with both AEP's and frequency analyses, and its diversity between brain regions during normal aging., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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33. Drug resistance and hippocampal damage after delayed treatment of pilocarpine-induced epilepsy in the rat.

Author

Chakir A, Fabene PF, Ouazzani R, and Bentivoglio M

Subjects
Animals, Brain Damage, Chronic physiopathology, Brain Damage, Chronic prevention & control, Carbamazepine pharmacology, Convulsants pharmacology, Disease Models, Animal, Down-Regulation drug effects, Down-Regulation physiology, Drug Administration Schedule, Drug Resistance drug effects, Epilepsy complications, Epilepsy drug therapy, Epilepsy physiopathology, Epilepsy, Temporal Lobe physiopathology, Gliosis etiology, Gliosis physiopathology, Gliosis prevention & control, Hippocampus drug effects, Hippocampus pathology, Male, Nerve Degeneration etiology, Nerve Degeneration physiopathology, Nerve Degeneration prevention & control, Neurons drug effects, Neurons metabolism, Neurons pathology, Parvalbumins metabolism, Pilocarpine pharmacology, Rats, Status Epilepticus complications, Status Epilepticus drug therapy, Status Epilepticus physiopathology, Time Factors, Anticonvulsants administration & dosage, Brain Damage, Chronic etiology, Drug Resistance physiology, Epilepsy, Temporal Lobe complications, Epilepsy, Temporal Lobe drug therapy, Hippocampus physiopathology
Abstract

Temporal lobe epilepsy (TLE) is the most common and pharmacoresistant form of epilepsy. Problems that cause pharmacoresistance may include delayed therapy due to late consultation, especially in developing countries. Our study aimed at unraveling consequences of delayed drug treatment using a rat model of TLE. Following pilocarpine-induced status epilepticus interrupted after 4h, rats were continuously videorecorded for onset and recurrence of spontaneous convulsive seizures. The animals were then treated for 50 days with carbamazepine (CBZ; first-line drug in TLE and effective also in rats), starting at seizure onset (27.22+/-3.38 days after status epilepticus) or 50 days later, and compared with epileptic untreated rats and non-epileptic CBZ-treated ones. Convulsive seizure frequency and duration, and hippocampal cell changes were evaluated. In particular, parvalbumin-containing hippocampal interneurons, astrocytes and microglia were characterized with immunohistochemistry and quantitative analyses. Prompt administration of CBZ suppressed seizures; delayed treatment only decreased frequency of convulsive seizures, which were also relatively prolonged. In hippocampal regions, histopathological damage, parvalbumin immunoreactivity loss, and glial activation were very marked after delayed treatment, and were reduced only slightly compared to untreated epilepsy, but enhanced compared to early treatment. The data on high frequency and duration of convulsive seizures in late-therapy rats indicate that delayed CBZ administration caused a high degree of drug resistance. This condition was subserved by severe damage in the hippocampus, presumably consequent to long-term seizure recurrence. Overall the data indicate that the paradigm of delayed treatment of limbic epilepsy could provide a model of drug-refractory TLE with hippocampal sclerosis.

Published
2006
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34. Structural and functional MRI following 4-aminopyridine-induced seizures: a comparative imaging and anatomical study.

Author

Fabene PF, Weiczner R, Marzola P, Nicolato E, Calderan L, Andrioli A, Farkas E, Süle Z, Mihaly A, and Sbarbati A

Subjects
Amygdala pathology, Amygdala physiopathology, Animals, Astrocytes pathology, Astrocytes ultrastructure, Brain physiopathology, Brain Mapping, Diffusion Magnetic Resonance Imaging methods, Epilepsy chemically induced, Epilepsy physiopathology, Hippocampus pathology, Hippocampus physiopathology, Male, Microscopy, Electron, Parietal Lobe pathology, Parietal Lobe physiopathology, Pyramidal Cells pathology, Pyramidal Cells ultrastructure, Rats, Rats, Wistar, Temporal Lobe pathology, Temporal Lobe physiopathology, Thalamus pathology, Thalamus physiopathology, 4-Aminopyridine, Brain pathology, Epilepsy pathology, Magnetic Resonance Imaging methods, Potassium Channel Blockers
Abstract

Structural and functional MRI was used in conjunction with computerized electron microscopy morphometry to study changes 2 h, 24 h and 3 days after 4-aminopyridine-induced seizures lasting 2 h in rats. T2 (relaxation time) values showed changes throughout the cerebral cortex, hippocampus, amygdala and medial thalamus, with a different temporal progression, showing a complete recovery only after 3 days. Two hours after seizures, the apparent diffusion coefficient was decreased throughout the brain compared to control animals, and a further decrease was evident 24 h after seizures. This was followed by a complete recovery at 3 days post-seizures. Functional MRI was performed using regional cerebral blood volume (rCBV) maps. The rCBV was increased shortly after convulsions (2 h) in all structures investigated, with a significant return to baseline values in the parietal cortex and hippocampus, but not in the medial thalamic nuclei, 24 h after seizure onset. No rCBV alterations were detected 3 days after seizures. Electron microscopy of tissue samples of parietal neocortex and hippocampus revealed prominent astrocytic swelling 2 h post-convulsions which decreased thereafter gradually. In conclusion, this experiment reports for the first time structural and functional brain alterations, lasting several hours, in 4-aminopyridine-treated rats after seizure onset. MRI approach combined with histological and ultrastructural analysis provided a clarification of the mechanisms involved in the brain acute response to ictal activity.

Published
2006
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35. Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum.

Author

van Luijtelaar G, Fabene PF, de Bruin N, Jongema C, Ellenbroek BA, and Veening JG

Subjects
Animals, Electroencephalography, Female, Hippocampus physiology, Rats, Rats, Wistar, Acoustic Stimulation methods, Conditioning, Psychological physiology, Evoked Potentials, Auditory physiology, Neurons physiology, Proto-Oncogene Proteins c-fos metabolism, Septal Nuclei physiology
Abstract

In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.

Published
2001
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