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1. Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo — in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Author

C. M. Drion, J. van Scheppingen, A. Arena, K. W. Geijtenbeek, L. Kooijman, E. A. van Vliet, E. Aronica, and J. A. Gorter

Subjects
Rapamycin, Curcumin, Inflammation, Oxidative stress, Temporal lobe epilepsy, mTOR, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin. Methods To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)—induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE). Results Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE. Conclusions These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo.

Published
2018
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2. Innate and adaptive immunity in amyotrophic lateral sclerosis: Evidence of complement activation

Author

M. Sta, R.M.R. Sylva-Steenland, M. Casula, J.M.B.V. de Jong, D. Troost, E. Aronica, and F. Baas

Subjects
Neuroinflammation, Complement system, Amyotrophic Lateral Sclerosis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Increasing evidence suggests a role for the immune system in amyotrophic lateral sclerosis (ALS). To determine the extent of the immune activation in ALS we analyzed the expression and cellular distribution of components of innate and adaptive immunity in spinal cord (SC) and motor cortex (MCx) from patients with rapid and slow sporadic ALS and controls. High levels of mRNA and protein of classical complement pathway, C1q and C4, as well as the downstream complement components C3 and C5b-9 were found in all ALS samples. Furthermore, we found higher numbers of activated microglia, reactive astrocytes, dendritic cells (DCs) and CD8+ T-cells in ALS than in control tissue. Rapid ALS cases had more dendritic cells than slow ALS cases, whereas slow ALS cases had more activated microglia than rapid cases.Our findings demonstrate a persistent and prominent activation of both innate and adaptive immunity in ALS. We propose a complement-driven immune response which may contribute to the progression of the inflammation and ultimately lead to even more motor neuron injury.

Published
2011
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3. Expression and localization of voltage dependent potassium channel Kv4.2 in epilepsy associated focal lesions

Author

E. Aronica, K. Boer, K.J. Doorn, E. Zurolo, W.G.M. Spliet, P.C. van Rijen, J.C. Baayen, J.A. Gorter, and A. Jeromin

Subjects
Hippocampal sclerosis, Focal cortical dysplasia, Cortical tubers, Ganglioglioma, Immunocytochemistry, Epilepsy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

An increasing number of observations suggest an important role for voltage-gated potassium (Kv) channels in epilepsy. We studied the cell-specific distribution of Kv4.2, phosphorylated (p) Kv4.2 and the Kv4.2 interacting protein NCS-1 using immunocytochemistry in different epilepsy-associated focal lesions. In hippocampal sclerosis (HS), Kv4.2 and pKv4.2 immunoreactivity (IR) was reduced in the neuropil in regions with prominent neuronal cell loss. In both HS and malformations of cortical development (MCD), intense labeling was found in neuronal somata, but not in dendrites. Strong NCS-1 IR was observed in neurons in all lesion types. Western blot analysis demonstrated an increase of total Kv4.2 in all lesions and activation of the ERK pathway in HS and ganglioglioma. These findings indicate that Kv4.2 is expressed in both neuronal and glial cells and its regulation may involve potassium channel interacting proteins, alterations in the subcellular localization of the channel, as well as phosphorylation-mediated posttranslational modifications.

Published
2009
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4. Complement activation in experimental and human temporal lobe epilepsy

Author

E. Aronica, K. Boer, E.A. van Vliet, S. Redeker, J.C. Baayen, W.G.M. Spliet, P.C. van Rijen, D. Troost, F.H. Lopes da Silva, W.J. Wadman, and J.A. Gorter

Subjects
Human, Rat, Hippocampus, Astrocytes, Neurons, Microglia, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

We investigated the involvement of the complement cascade during epileptogenesis in a rat model of temporal lobe epilepsy (TLE), and in the chronic epileptic phase in both experimental as well as human TLE. Previous rat gene expression analysis using microarrays indicated prominent activation of the classical complement pathway which peaked at 1 week after SE in CA3 and entorhinal cortex. Increased expression of C1q, C3 and C4 was confirmed in CA3 tissue using quantitative PCR at 1 day, 1 week and 3–4 months after status epilepticus (SE). Upregulation of C1q and C3d protein expression was confirmed mainly to be present in microglia and in a few hippocampal neurons. In human TLE with hippocampal sclerosis, astroglial, microglial and neuronal (5/8 cases) expression of C1q, C3c and C3d was observed particularly within regions where neuronal cell loss occurs. The membrane attack protein complex (C5b-C9) was predominantly detected in activated microglial cells. The persistence of complement activation could contribute to a sustained inflammatory response and could destabilize neuronal networks involved.

Published
2007
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5. The IL-1β system in epilepsy-associated malformations of cortical development

Author

T. Ravizza, K. Boer, S. Redeker, W.G.M. Spliet, P.C. van Rijen, D. Troost, A. Vezzani, and E. Aronica

Subjects
Focal cortical dysplasia, Glioneuronal tumors, Astrocytes, Microglia, Dysmorphic neurons, Pediatric epilepsy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Focal cortical dysplasia (FCD) and glioneuronal tumors (GNT) are recognized causes of chronic intractable epilepsy. The cellular mechanism(s) underlying their epileptogenicity remain largely unknown. Compelling evidence in experimental models of seizures indicates an important role of interleukin (IL)-1β in the mechanisms of hyperexcitability leading to the occurrence of seizures. We immunocytochemically investigated the brain expression and cellular distribution pattern of IL-1β, IL-1 receptor (IL-1R) types I and II and IL-1R antagonist (IL-1Ra) in FCD and GNT specimens, and we correlate these parameters with the clinical history of epilepsy in patients with medically intractable seizures.In normal control cortex, and in perilesional regions with histologically normal cortex, IL-1β, IL-1Rs and IL-1Ra expression was undetectable. In all FCD and GNT specimens, IL-1β and its signalling receptor IL-1RI were highly expressed by more than 30% of neurons and glia whereas the decoy receptor IL-RII and IL-Ra were expressed to a lesser extent by ∼10% and 20% of cells, respectively.These findings show a high expression of IL-1β and its functional receptor (IL-1RI) in FCD and GNT specimens together with a relative paucity of mechanisms (IL-1RII and IL-1Ra) apt to inactivate IL-1β actions. Moreover, the number of IL-1β- and IL-1RI-positive neurons was positively correlated with the frequency of seizures, whereas the number of IL-1Ra-positive neurons and astroglial cells was negatively correlated with the duration of epilepsy prior to surgery.The expression of IL-1β family members in these developmental lesions may contribute to their intrinsic and high epileptogenicity, thus possibly representing a novel target for antiepileptic strategies.

Published
2006
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7. Author response for 'MicroRNA‐34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis'

Author

null A. Korotkov, null N.S. Sim, null M.J. Luinenburg, null J.J. Anink, null J. van Scheppingen, null T.S. Zimmer, null A. Bongaarts, null D.W.M. Broekaart, null C. Mijnsbergen, null F.E. Jansen, null W. Van Hecke, null W.G.M. Spliet, null P.C. van Rijen, null M. Feucht, null J.A. Hainfellner, null P. Krsek, null J. Zamecnik, null P.B. Crino, null K. Kotulska, null L. Lagae, null A.C. Jansen, null D.J. Kwiatkowski, null S. Jozwiak, null P. Curatolo, null A. Mühlebner, null J.H. Lee, null J.D. Mills, null E.A. van Vliet, and null E. Aronica

Published
2021
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8. The control of diabetes and other Non-communicable Diseases is an urgent health priority in Africa: Grenoble declaration

Author

S. Wackernie, E. Giros, Philippe Touraine, Stéphane Besançon, S. Genay Diliautas, C. Mary, G. Duriez, C. Paquet, E. Aronica, I. Quick, C. Waterlot, Cynthia Fleury, C. Giron, Maryvette Balcou-Debussche, Assa Traoré Sidibé, O. Chabre, E. Comte, J. Bernasconi, Xavier Debussche, O. Toure, Joseph Drabo, A. Fontbonne, B. Burgalat, H. Du-Boullay, Naby Balde, G. Raymond, C. Debeaufort, M. de Kerdanet, L. Delisle, P. Micheletti, O. Weil, Malek Batal, P. Chancel, David Beran, J.F. Delfraissy, A.L. Coulon, D. Hacquin, P. Salignon, T. Shojaei, F. Mohadji, S. Olejas, Hôpital Donka, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie (GRENOBLE - Endocrino), CHU Grenoble, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Département international et tropical (INVS), Institut national de veille sanitaire, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Sols et Environnement (LSE), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), and Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Health Priorities, Public Health, Environmental and Occupational Health, Health Promotion, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Infectious Diseases, Political science, Africa, Diabetes Mellitus, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Noncommunicable Diseases, Delivery of Health Care, Humanities, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018
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9. EPENDYMOMA

Author

L. M. Hoffman, A. M. Donson, I. Nakachi, A. M. Griesinger, D. K. Birks, V. Amani, M. S. Hemenway, A. K. Liu, M. Wang, T. C. Hankinson, M. H. Handler, N. K. Foreman, M. Zakrzewska, K. Zakrzewski, W. Fendler, L. Stefanczyk, P. P. Liberski, M. Massimino, L. Gandola, P. Ferroli, L. Valentini, V. Biassoni, M. L. Garre, I. Sardi, L. Genitori, C. Giussani, L. Massimi, D. Bertin, A. Mussano, E. Viscardi, P. Modena, A. Mastronuzzi, S. Barra, G. Scarzello, G. Cinalli, P. Peretta, F. Giangaspero, L. Boschetti, E. Schiavello, G. Calareso, M. Antonelli, E. Pecori, F. Di Meco, R. Migliorati, A. Taborelli, H. Witt, M. Sill, K. Wani, S. C. Mack, D. Capper, K. Pajtler, S. Lambert, T. Tzaridis, T. Milde, P. A. Northcott, A. E. Kulozik, O. Witt, V. P. Collins, D. W. Ellison, M. D. Taylor, M. Kool, D. T. W. Jones, A. Korshunov, A. Ken, S. M. Pfister, K. Makino, H. Nakamura, J.-i. Kuroda, J.-i. Kuratsu, H. Toledano, Y. Margolin, A. Ohali, S. Michowiz, P. Johann, U. Tabori, E. Walker, C. Hawkins, M. Taylor, I. Yaniv, S. Avigad, L. Hoffman, S. R. Plimpton, N. V. Stence, R. Vibhakar, A. Lourdusamy, R. Rahman, J. Ward, H. Rogers, R. Grundy, C. Punchihewa, R. Lee, T. Lin, W. Orisme, J. Dalton, E. Aronica, A. Smith, A. Gajjar, A. Onar, S. Pounds, R. Tatevossian, T. Merchant, D. Ellison, M. Parker, K. Mohankumar, R. Weinlich, T. Phoenix, R. Thiruvenkatam, E. White, K. Gupta, F. Boop, L. Ding, E. Mardis, R. Wilson, J. Downing, R. Gilbertson, D. Speed, T. Gould, t. I. E. Consortium, A. Griesinger, A. Donson, D. Birks, N. Ohe, H. Yano, N. Nakayama, T. Iwama, K. Wright, T. Hassall, D. C. Bowers, J. Crawford, A. Bendel, P. G. Fisher, P. Klimo, G. Armstrong, I. Qaddoumi, G. Robinson, C. Wetmore, A. Broniscer, R. Chapman, C. Mayne, H. Duane, J.-P. Kilday, B. Coyle, A. Graul-Conroy, W. Hartsell, T. Bragg, S. Goldman, S. Rebsamen, D. Puccetti, S. Salamat, N. J. Patel, A. Gomi, H. Oguma, T. Hayase, Y. Kawahara, M. Yagi, A. Morimoto, C. Wilbur, C. Dunham, D. Mabbott, A.-S. Carret, L. Lafay-Cousin, P. D. McNeely, D. Eisenstat, B. Wilson, D. Johnston, J. Hukin, M. Mynarek, R. D. Kortmann, P. Kaatsch, T. Pietsch, B. Timmermann, G. Fleischhack, M. Benesch, C. Friedrich, A. O. von Bueren, N. U. Gerber, K. Muller, S. Tippelt, M. Warmuth-Metz, S. Rutkowski, K. von Hoff, M. K. Murugesan, H. Poppleton, S. Currle, T. Kranenburg, C. Eden, N. Boulos, J. Dapper, Y. Patel, B. Freeman, A. Shelat, C. Stewart, R. Guy, J. Adamski, A. Huang, U. Bartels, V. Ramaswamy, R. Krishnatry, N. Laperriere, E. Bouffet, A. Araki, M. Chocholous, J. Gojo, C. Dorfer, T. Czech, K. Dieckmann, I. Slavc, C. Haberler, E. Doerner, A. z. Muehlen, R. Kortmann, A. von Buehren, H. Ottensmeier, A. Resch, R. Kwiecien, A. Faldum, J. Kuehl, D. Sabnis, L. Storer, L. Simmonds, S. Blackburn, J. Lowe, I. Kerr, I. Wohlers, T. Goschzik, V. Dreschmann, D. Denkhaus, S. Rahmann, L. Klein-Hitpass, M. J. L. Iglesias, F. G. Riet, F. D. Dhermain, S. Canale, C. Dufour, C. S. Rose, S. Puget, J. Grill, S. Bolle, J. Parkes, A. Davidson, A. Figaji, K. Pillay, T. Kilborn, L. Padayachy, M. Hendricks, A. Van Eyssen, E. Piccinin, E. Lorenzetto, M. Brenca, K. Aldape, Y.-J. Cho, W. Weiss, J. Phillips, N. Jabado, J. Mora, X. Fan, S. Jung, J. Y. Lee, K. Zitterbart, P. French, J. M. Kros, P. Hauser, C. Faria, and S. Pfister

Subjects
Abstracts, Cancer Research, Tumor grade, Oncology, Expression pattern, business.industry, microRNA, Cancer research, Medicine, Neurology (clinical), business
Published
2014
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10. PATHOLOGY

Author

J.-i. Adachi, K. Totake, M. Shirahata, K. Mishima, T. Suzuki, T. Yanagisawa, K. Fukuoka, R. Nishikawa, A. Arimappamagan, N. Manoj, A. Mahadevan, D. Bhat, H. Arvinda, B. Indiradevi, S. Somanna, B. Chandramouli, S. A. Petterson, S. K. Hermansen, R. H. Dahlrot, S. Hansen, B. W. Kristensen, F. Carvalho, S. Jalali, S. Singh, S. Croul, K. Aldape, G. Zadeh, J. Choi, S.-H. Park, S. K. Khang, Y.-L. Suh, S. P. Kim, Y. S. Lee, S. H. Kim, S. Coberly, K. Samayoa, Y. Liu, P. Kiaei, J. Hill, S. Patterson, M. Damore, S. Dahiya, R. Emnett, J. Phillips, D. Haydon, J. Leonard, A. Perry, D. Gutmann, S. Epari, S. Ahmed, M. Gurav, S. Raikar, A. Moiyadi, P. Shetty, T. Gupta, R. Jalali, J. Georges, A. Zehri, E. Carlson, N. Martirosyan, A. Elhadi, J. Nichols, L. Ighaffari, J. Eschbacher, B. Feuerstein, T. Anderson, M. Preul, K. Jensen, P. Nakaji, H. Girardi, F. Monville, S. Carpentier, M. Giry, J. Voss, R. Jenkins, B. Boisselier, V. Frayssinet, C. Poggionovo, A. Catteau, K. Mokhtari, M. Sanson, H. Peyro-Saint-Paul, C. Giannini, T. Hide, H. Nakamura, K. Makino, S. Yano, S. Anai, N. Shinojima, J.-i. Kuroda, T. Takezaki, J.-i. Kuratsu, F. Higuchi, H. Matsuda, K. Iwata, K. Ueki, P. Kim, J. Kong, L. Cooper, F. Wang, J. Gao, G. Teodoro, L. Scarpace, T. Mikkelsen, M. Schniederjan, C. Moreno, J. Saltz, D. Brat, U. Cho, Y.-K. Hong, R. Lober, L. Lu, M. H. Gephart, P. Fisher, M. Miyazaki, H. Nishihara, T. Itoh, M. Kato, S. Fujimoto, T. Kimura, M. Tanino, S. Tanaka, N. Nguyen, G. Moes, J. L. Villano, H. Kanno, Y. Kato, T. Ohnishi, H. Harada, S. Ohue, S. Kouno, A. Inoue, D. Yamashita, S. Okamoto, M. Nitta, Y. Muragaki, T. Maruyama, T. Sawada, T. Komori, T. Saito, Y. Okada, S. B. Omay, J. M. Gunel, V. E. Clark, J. Li, E. Z. E. Omay, A. Serin, L. E. Kolb, R. M. Hebert, K. Bilguvar, K. Ozduman, M. N. Pamir, T. Kilic, J. Baehring, J. M. Piepmeier, C. W. Brennan, J. Huse, P. H. Gutin, K. Yasuno, A. Vortmeyer, M. Gunel, S. Pugh, C. L. Rogers, D. Brachman, W. McMillan, J. Jenrette, I. Barani, D. Shrieve, A. Sloan, M. Mehta, A. Prabowo, A. Iyer, T. Veersema, J. Anink, A. S.-v. Meeteren, W. Spliet, P. van Rijen, T. Ferrier, D. Capper, M. Thom, E. Aronica, T. Chharchhodawala, M. Sable, M. C. Sharma, C. Sarkar, V. Suri, M. Singh, V. Santosh, B. Thota, M. Srividya, K. Sravani, S. Shwetha, A. Arivazhagan, K. Thennarasu, A. Hegde, P. Kondaiah, K. Somasundaram, M. Rao, V. P. Kumar, A. Shastry, R. Narayan, S. Naz, S. Venneti, M. Garimella, L. Sullivan, D. Martinez, A. Heguy, M. Santi, C. Thompson, A. Judkins, Z. Voronovich, L. Chen, K. Clark, M. Walsh, J. Mannas, C. Horbinski, B. Wiestler, T. Holland-Letz, A. Korshunov, A. von Deimling, S. M. Pfister, M. Platten, M. Weller, W. Wick, G. Zieman, C. Dardis, and L. Ashby

Subjects
Abstracts, Cancer Research, Oncology, Neurology (clinical)
Published
2013
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11. OMICS AND PROGNSTIC MARKERS

Author

K. Adachi, H. Sasaki, S. Nagahisa, K. Yoshida, N. Hattori, Y. Nishiyama, T. Kawase, M. Hasegawa, M. Abe, Y. Hirose, A. Alentorn, Y. Marie, S. Poggioli, H. Alshehhi, B. Boisselier, C. Carpentier, K. Mokhtari, L. Capelle, D. Figarella-Branger, K. Hoang-Xuan, M. Sanson, J.-Y. Delattre, A. Idbaih, S. Yust-Katz, M. Anderson, A. Olar, A. Eterovic, N. Ezzeddine, K. Chen, H. Zhao, G. Fuller, K. Aldape, J. de Groot, N. Andor, J. Harness, S. G. Lopez, T. L. Fung, H. W. Mewes, C. Petritsch, A. Arivazhagan, K. Somasundaram, K. Thennarasu, P. Pandey, B. Anandh, V. Santosh, B. Chandramouli, A. Hegde, P. Kondaiah, M. Rao, R. Bell, R. Kang, C. Hong, J. Song, J. Costello, R. Nagarajan, B. Zhang, A. Diaz, T. Wang, L. Bie, Y. Li, H. Liu, W. F. C. Luyo, M. H. Carnero, M. E. P. Iruegas, A. R. Morell, M. C. Figueiras, R. L. Lopez, C. F. Valverde, A. K.-Y. Chan, J. C.-S. Pang, N. Y.-F. Chung, K. K.-W. Li, W. S. Poon, D. T.-M. Chan, Y. Wang, H.-a. K. Ng, M. Chaumeil, P. Larson, H. Yoshihara, D. Vigneron, S. Nelson, R. Pieper, J. Phillips, S. Ronen, V. Clark, Z. E. Omay, A. Serin, J. Gunel, B. Omay, C. Grady, M. Youngblood, K. Bilguvar, J. Baehring, J. Piepmeier, P. Gutin, A. Vortmeyer, C. Brennan, M. N. Pamir, T. Kilic, B. Krischek, M. Simon, K. Yasuno, M. Gunel, A. L. Cohen, M. Sato, K. D. Aldape, C. Mason, K. Diefes, L. Heathcock, L. Abegglen, D. Shrieve, W. Couldwell, J. D. Schiffman, H. Colman, Q. G. D'Alessandris, T. Cenci, M. Martini, L. Ricci-Vitiani, R. De Maria, L. M. Larocca, R. Pallini, B. Theeler, F. Lang, G. Rao, M. Gilbert, E. Sulman, R. Luthra, K. Eterovic, M. Routbort, R. Verhaak, G. Mills, J. Mendelsohn, F. Meric-Bernstam, A. Yung, K. MacArthur, S. Hahn, G. Kao, R. Lustig, M. Alonso-Basanta, S. Chandrasekaran, E. P. Wileyto, E. Reyes, J. Dorsey, K. Fujii, K. Kurozumi, T. Ichikawa, M. Onishi, J. Ishida, Y. Shimazu, B. Kaur, E. A. Chiocca, I. Date, C. Geisenberger, A. Mock, R. Warta, C. Schwager, C. Hartmann, A. von Deimling, A. Abdollahi, C. Herold-Mende, O. Gevaert, A. Achrol, S. Gholamin, S. Mitra, E. Westbroek, J. Loya, L. Mitchell, S. Chang, G. Steinberg, S. Plevritis, S. Cheshier, J. Xu, S. Napel, G. Zaharchuk, G. Harsh, D. Gutman, C. Holder, R. Colen, W. Dunn, R. Jain, L. Cooper, S. Hwang, A. Flanders, D. Brat, J. Hayes, A. Droop, H. Thygesen, M. Boissinot, D. Westhead, S. Short, S. Lawler, P. Bady, S. Kurscheid, M. Delorenzi, M. E. Hegi, C. Crosby, C. Faulkner, T. Smye-Rumsby, K. Kurian, M. Williams, K. Hopkins, A. Palmer, H. Williams, C. Wragg, H. R. Haynes, K. M. Kurian, P. White, T. Oka, L. Jalbert, A. Elkhaled, R. Jensen, K. Salzman, M. Schabel, D. Gillespie, M. Mumert, B. Johnson, T. Mazor, M. Barnes, S. Yamamoto, H. Ueda, K. Tatsuno, K. Aihara, A. Bollen, M. Hirst, M. Marra, A. Mukasa, N. Saito, H. Aburatani, M. Berger, B. Taylor, S. Popov, A. Mackay, W. Ingram, A. Burford, A. Jury, M. Vinci, C. Jones, D. T. W. Jones, V. Hovestadt, S. Picelli, W. Wang, P. A. Northcott, M. Kool, G. Reifenberger, T. Pietsch, M. Sultan, H. Lehrach, M.-L. Yaspo, A. Borkhardt, P. Landgraf, R. Eils, A. Korshunov, M. Zapatka, B. Radlwimmer, S. M. Pfister, P. Lichter, A. Joy, I. Smirnov, M. Reiser, W. Shapiro, S. Kim, B. Feuerstein, C. Jungk, S. Friauf, A. Unterberg, T. A. Juratli, J. McElroy, W. Meng, A. Huebner, K. D. Geiger, D. Krex, G. Schackert, A. Chakravarti, T. Lautenschlaeger, B. Y. Kim, W. Jiang, J. Beiko, S. Prabhu, F. DeMonte, R. Sawaya, D. Cahill, I. McCutcheon, C. Lau, L. Wang, K. Terashima, S. Yamaguchi, M. Burstein, J. Sun, T. Suzuki, R. Nishikawa, H. Nakamura, A. Natsume, S. Terasaka, H.-K. Ng, D. Muzny, R. Gibbs, D. Wheeler, X.-q. Zhang, S. Sun, K.-f. Lam, K. M. Y. Kiang, J. K. S. Pu, A. S. W. Ho, G. K. K. Leung, F. Loebel, W. T. Curry, F. G. Barker, N. Lelic, A. S. Chi, D. P. Cahill, D. Lu, J. Yin, C. Teo, K. McDonald, A. Madhankumar, C. Weston, B. Slagle-Webb, J. Sheehan, A. Patel, M. Glantz, J. Connor, C. Maire, J. Francis, C.-Z. Zhang, J. Jung, V. Manzo, V. Adalsteinsson, H. Homer, B. Blumenstiel, C. S. Pedamallu, E. Nickerson, A. Ligon, C. Love, M. Meyerson, K. Ligon, L. E. Jalbert, S. J. Nelson, A. W. Bollen, I. V. Smirnov, J. S. Song, A. B. Olshen, M. S. Berger, S. M. Chang, B. S. Taylor, J. F. Costello, S. Mehta, B. Armstrong, S. Peng, A. Bapat, M. Berens, B. Melendez, M. Mollejo, P. Mur, T. Hernandez-Iglesias, C. Fiano, J. Ruiz, J. A. Rey, V. Stadler, A. Schulte, K. Lamszus, C. Schichor, M. Westphal, J.-C. Tonn, O. Morozova, S. Katzman, M. Grifford, S. Salama, D. Haussler, A. Olshen, S. Fouse, S. Nakamizo, T. Sasayama, H. Tanaka, K. Tanaka, K. Mizukawa, M. Yoshida, E. Kohmura, P. Northcott, D. Jones, S. Pfister, R. Otani, S. Takayanagi, K. Saito, S. Tanaka, M. Shin, T. Ozawa, M. Riester, Y.-K. Cheng, J. Huse, K. Helmy, N. Charles, M. Squatrito, F. Michor, E. Holland, M. Perrech, L. Dreher, G. Rohn, R. Goldbrunner, M. Timmer, B. Pollo, V. Palumbo, C. Calatozzolo, M. Patane, R. Nunziata, M. Farinotti, A. Silvani, S. Lodrini, G. Finocchiaro, E. Lopez, A. Rioscovian, R. Ruiz, G. Siordia, A. P. de Leon, C. Rostomily, R. Rostomily, D. Silbergeld, D. Kolstoe, M. Chamberlain, J. Silber, P. Roth, A. Keller, J. Hoheisel, P. Codo, A. Bauer, C. Backes, P. Leidinger, E. Meese, E. Thiel, A. Korfel, M. Weller, G. Nagae, M. Nagane, J. Z. Sanborn, T. Mikkelsen, S. Jhanwar, L. Chin, M. Nishihara, M. Schliesser, C. Grimm, E. Weiss, R. Claus, D. Weichenhan, M. Weiler, T. Hielscher, F. Sahm, B. Wiestler, A.-C. Klein, J. Blaes, C. Plass, W. Wick, G. Stragliotto, A. Rahbar, C. Soderberg-Naucler, M. Won, R. Ezhilarasan, P. Sun, D. Blumenthal, M. Vogelbaum, R. Jenkins, R. Jeraj, P. Brown, K. Jaeckle, D. Schiff, J. Dignam, J. Atkins, D. Brachman, M. Werner-Wasik, M. Mehta, J. Shen, J. Luan, A. Yu, M. Matsutani, Y. Liang, T.-K. Man, A. Trister, M. Tokita, S. Mikheeva, A. Mikheev, S. Friend, M. van den Bent, L. Erdem, T. Gorlia, M. Taphoorn, J. Kros, P. Wesseling, H. Dubbink, A. Ibdaih, P. French, H. van Thuijl, J. Heimans, B. Ylstra, J. Reijneveld, A. Prabowo, I. Scheinin, H. van Essen, W. Spliet, C. Ferrier, P. van Rijen, T. Veersema, M. Thom, A. S.-v. Meeteren, E. Aronica, H. Kim, S. Zheng, D. J. Brat, S. Virk, S. Amini, C. Sougnez, J. Barnholtz-Sloan, R. G. W. Verhaak, C. Watts, A. Sottoriva, I. Spiteri, S. Piccirillo, A. Touloumis, P. Collins, J. Marioni, C. Curtis, S. Tavare, B. Tews, T. P. C. Yeung, B. Al-Khazraji, L. Morrison, L. Hoffman, D. Jackson, T.-Y. Lee, S. Yartsev, G. Bauman, J. Fu, R. Vegesna, Y. Mao, L. E. Heathcock, W. Torres-Garcia, S. Wang, A. McKenna, C. W. Brennan, W. K. A. Yung, J. N. Weinstein, E. P. Sulman, and D. Koul

Subjects
Abstracts, Cancer Research, Text mining, Oncology, business.industry, Neurology (clinical), Computational biology, Biology, Omics, business
Published
2013
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12. BIOLOGY

Author

J. H. Kim, H. B. Song, D. H. Kim, K. D. Park, B. J. Lee, S. Khatua, E. Kalkan, R. Brown, M. Pearlman, T. Vats, L. Abela, G. Fiaschetti, T. Shalaby, E. Grunder, M. Ma, J. Grahlert, M. Baumgartner, U. Siler, N. Nonoguchi, H. Ohgaki, M. Grotzer, J.-i. Adachi, T. Suzuki, K. Fukuoka, T. Yanagisawa, K. Mishima, T. Koga, M. Matsutani, R. Nishikawa, I. Sardi, L. Giunti, C. Bresci, S. Cardellicchio, M. Da Ros, A. M. Buccoliero, S. Farina, M. Arico, L. Genitori, M. Massimino, L. Filippi, A. Erdreich-Epstein, H. Zhou, X. Ren, M. Schur, T. B. Davidson, L. Ji, R. Sposto, S. Asgharzadeh, Y. Tong, E. White, M. Murugesan, B. Nimmervoll, M. Wang, D. Marino, D. Ellison, D. Finkelstein, S. Pounds, D. Malkin, R. Gilbertson, C. Eden, B. Ju, T. Phoenix, H. Poppleton, C. Lessman, M. Taylor, G. la Marca, S. Malvagia, V. Fratoni, M. G. Giovannini, F. Giangaspero, M. Badiali, V. Gleize, S. Paris, L. Moi, S. Elhouadani, A. Arcella, R. Morace, M. Antonelli, F. Buttarelli, K. Mokhtari, M. Sanson, S. Smith, J. Ward, M. Wilson, C. Rahman, F. Rose, A. Peet, D. Macarthur, R. Grundy, R. Rahman, S. Venkatraman, D. Birks, I. Balakrishnan, I. Alimova, P. Harris, P. Patel, N. Foreman, R. Vibhakar, H. Wu, Q. Zhou, D. Wang, G. Wang, D. Dang, E. Pencreach, A. Nguyen, E. Guerin, C. Lasthaus, D. Guenot, N. Entz-Werle, R. Unland, S. Schlosser, N. Farwick, T. Plagemann, G. Richter, H. Juergens, M. Fruehwald, C.-L. Chien, Y.-H. Lee, C.-I. Lin, J.-Y. Hsieh, S.-C. Lin, T.-T. Wong, D. M.-T. Ho, H.-W. Wang, S. Lagah, I.-L. Tan, S. Malcolm, Y. Majani, D. G. van Vuurden, E. Aronica, L. E. Wedekind, E. Hulleman, D. Biesmans, M. Bugiani, W. P. Vandertop, G. J. L. Kaspers, T. Wurdinger, D. P. Noske, P. M. Van der Stoop, S. Shukla, G. K. Kuipers, B. J. Slotman, J. Cloos, T. Sun, N. Warrington, J. Luo, S. Ganzhorn, U. Tabori, T. Druley, D. Gutmann, J. Rubin, P. Castelo-Branco, S. Choufani, S. Mack, D. Galagher, C. Zhang, T. Lipman, N. Zhukova, D. Martin, D. Merino, J. Wasserman, C. Samuel, N. Alon, J. Hitzler, J. C. Y. Wang, G. Keller, P. B. Dirks, S. Pfister, M. D. Taylor, R. Weksberg, P. Leblond, S. Meignan, A. Dewitte, F. Le Tinier, N. Wattez, E. Lartigau, A. Lansiaux, R. Hanson, I. Gordon, S. Zhao, K. Camphausen, K. Warren, N. M. Warrington, D. H. Gutmann, J. B. Rubin, M. Jaillet, Z. Kovacs, E. Martin-Fiori, M. Bernasconi, B. Werner, C. Dyberg, N. Baryawno, J. Milosevic, M. Wickstrom, P. A. Northcott, M. Kool, P. Kogner, J. I. Johnsen, G. Reynolds, N. Davies, T. Arvanitis, A. Zoghbi, M. Meisterernst, M. C. Fruehwald, K. Kerl, B. Orr, M. Haffner, W. Nelson, S. Yegnasubramanian, C. Eberhart, A. Fotovati, S. Abu-Ali, P.-S. Wang, L. Deleyrolle, C. Lee, J. Triscott, J. Chen, S. Franciosi, Y. Nakamura, Y. Sugita, T. Uchiumi, M. Kuwano, B. Leavitt, S. Singh, A. Jury, C. Jones, H. Wakimoto, B. Reynolds, C. Pallen, S. Dunn, S. Fletcher, J. Levine, M. Li, N. Kagawa, R. Hirayama, Y. Chiba, N. Kijima, H. Arita, M. Kinoshita, N. Hashimoto, S. Izumoto, M. Maruno, and T. Yoshimine

Subjects
Abstracts, Cancer Research, Oncology, Neurology (clinical)
Published
2012
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13. Ongoing Clinical Trials

Author

J. L. Clarke, M. M. Ennis, K. R. Lamborn, M. D. Prados, V. K. Puduvalli, M. Penas-Prado, M. R. Gilbert, M. D. Groves, K. R. Hess, V. A. Levin, J. de Groot, H. Colman, C. A. Conrad, M. E. Loghin, K. Hunter, W. K. Yung, C. Chen, D. Damek, A. Liu, L. E. Gaspar, A. Waziri, K. Lillehei, B. Kavanagh, J. L. Finlay, K. Haley, G. Dhall, S. Gardner, J. Allen, A. Cornelius, R. Olshefski, J. Garvin, K. Pradhan, M. Etzl, S. Goldman, M. Atlas, S. Thompson, A. Hirt, J. Hukin, M. Comito, S. Bertolone, J. Torkildson, M. Joyce, C. Moertel, J. Letterio, G. Kennedy, A. Walter, L. Ji, R. Sposto, K. Dorris, L. Wagner, T. Hummel, R. Drissi, L. Miles, J. Leach, L. Chow, R. Turner, M. N. Gragert, D. Pruitt, M. Sutton, J. Breneman, K. Crone, M. Fouladi, B. B. Friday, J. Buckner, S. K. Anderson, C. Giannini, J. Kugler, M. Mazurczac, P. Flynn, H. Gross, E. Pajon, K. Jaeckle, E. Galanis, M. A. Badruddoja, M. A. Pazzi, B. Stea, P. Lefferts, N. Contreras, M. Bishop, J. Seeger, R. Carmody, N. Rance, M. Marsella, K. Schroeder, A. Sanan, L. J. Swinnen, C. Rankin, E. J. Rushing, L. F. Hutchins, D. M. Damek, G. R. Barger, A. D. Norden, G. Lesser, S. N. Hammond, J. Drappatz, C. E. Fadul, T. T. Batchelor, E. C. Quant, R. Beroukhim, A. Ciampa, L. Doherty, D. LaFrankie, S. Ruland, C. Bochacki, P. Phan, E. Faroh, B. McNamara, K. David, M. R. Rosenfeld, P. Y. Wen, S. Phuphanich, D. Reardon, E. T. Wong, S. R. Plotkin, A. Mintz, J. J. Raizer, T. J. Kaley, K. H. Smith, M. C. Chamberlain, C. Graham, M. Mrugala, S. Johnston, T. N. Kreisl, P. Smith, F. Iwamoto, J. Sul, J. A. Butman, H. A. Fine, M. Westphal, O. Heese, M. Warmuth-Metz, T. Pietsch, U. Schlegel, J.-C. Tonn, J. Schramm, G. Schackert, A. Melms, H. M. Mehdorn, V. Seifert, K. Geletneky, D. Reuter, F. Bach, M. Khasraw, L. E. Abrey, A. B. Lassman, A. Hormigo, C. Nolan, I. T. Gavrilovic, I. K. Mellinghoff, A. S. Reiner, L. DeAngelis, A. M. Omuro, S. R. Burzynski, R. A. Weaver, T. J. Janicki, G. S. Burzynski, B. Szymkowski, S. S. Acelar, L. L. Mechtler, P. C. O'Connor, H.-A. Kroon, T. Vora, P. Kurkure, B. Arora, T. Gupta, V. Dhamankar, S. Banavali, A. Moiyadi, S. Epari, N. Merchant, R. Jalali, S. Moller, K. Grunnet, S. Hansen, H. Schultz, M. Holmberg, M. M. Sorensen, H. S. Poulsen, U. Lassen, D. A. Reardon, J. J. Vredenburgh, A. Desjardins, D. E. Janney, K. Peters, J. Sampson, S. Gururangan, H. S. Friedman, S. Jeyapalan, M. Constantinou, D. Evans, H. Elinzano, B. O'Connor, M. Y. Puthawala, M. Goldman, A. Oyelese, D. Cielo, T. Dipetrillo, H. Safran, M. Anan, M. Seyed Sadr, J. Alshami, C. Sabau, E. Seyed Sadr, V. Siu, M.-C. Guiot, A. Samani, R. Del Maestro, U. Bogdahn, G. Stockhammer, A. K. Mahapatra, N. K. Venkataramana, V. E. Oliushine, V. E. Parfenov, I. E. Poverennova, P. Hau, P. Jachimczak, H. Heinrichs, K.-H. Schlingensiepen, S. Shibui, T. Kayama, T. Wakabayashi, R. Nishikawa, M. de Groot, E. Aronica, C. J. Vecht, S. T. Toering, J. J. Heimans, J. C. Reijneveld, T. Batchelor, P. Mulholland, B. Neyns, L. B. Nabors, M. Campone, A. Wick, W. Mason, T. Mikkelsen, L. S. Ashby, J. F. DeGroot, H. R. Gattamaneni, L. M. Cher, M. A. Rosenthal, F. Payer, J. Xu, Q. Liu, M. van den Bent, B. Nabors, K. Fink, M. Chan, J. Trusheim, S. Raval, C. Hicking, J. Henslee-Downey, M. Picard, D. Schiff, S. Karimi, L. M. DeAngelis, C. P. Nolan, A. Omuro, I. Gavrilovic, A. Norden, B. W. Purow, F. S. Lieberman, S. Hariharan, J. G. Perez-Larraya, J. Honnorat, O. Chinot, I. Catry-Thomas, L. Taillandier, J. S. Guillamo, C. Campello, A. Monjour, M. L. Tanguy, J. Y. Delattre, D. N. Franz, D. A. Krueger, M. M. Care, K. Holland-Bouley, K. Agricola, C. Tudor, P. Mangeshkar, A. W. Byars, T. Sahmoud, M. Alonso-Basanta, R. A. Lustig, J. F. Dorsey, R. K. Lai, L. D. Recht, N. Paleologos, M. Groves, S. Meech, T. Davis, D. Pavlov, M. A. Marshall, M. Slot, S. M. Peerdeman, P. D. Beauchesne, G. Faure, G. Noel, T. Schmitt, C. Kerr, E. Jadaud, L. Martin, C. Carnin, K. B. Peters, J. E. Herndon, J. P. Kirkpatrick, L. Nayak, K. S. Panageas, and L. M. Deangelis

Subjects
Clinical trial, Cancer Research, medicine.medical_specialty, Oncology, business.industry, medicine, Alternative medicine, Medical encyclopedia, Neurology (clinical), Health information, Intensive care medicine, business
Published
2010
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14. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures

Author

J, van Scheppingen, A M, Iyer, A S, Prabowo, A, Mühlebner, J J, Anink, T, Scholl, M, Feucht, F E, Jansen, W G, Spliet, P, Krsek, J, Zamecnik, A M, Buccoliero, F, Giordano, L, Genitori, K, Kotulska, S, Jozwiak, J, Jaworski, E, Liszewska, E A, van Vliet, and E, Aronica

Subjects
Adult, Neurons, Adolescent, Cell Culture Techniques, Brain, Infant, Astrocytoma, Middle Aged, MicroRNAs, Young Adult, Tuberous Sclerosis, Astrocytes, Child, Preschool, Humans, Child, Cells, Cultured, Signal Transduction
Abstract

Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate.

Published
2016

15. Additional file 2: Figure S2. of Dysregulation of the (immuno)proteasome pathway in malformations of cortical development

Author

J. Van Scheppingen, D. Broekaart, T. Scholl, M. Zuidberg, J. Anink, W. Spliet, P. Van Rijen, T. Czech, J. Hainfellner, M. Feucht, A. MĂźhlebner, E. Van Vliet, and E. Aronica

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, hemic and lymphatic diseases, embryonic structures, neoplasms, nervous system diseases
Abstract

β1i and β5i intensity signal in control, mMCD, FCDII, and TSC. FCD: focal cortical dysplasia; TSC: tuberous sclerosis complex; mMCD: mild malformations of cortical development. (PPTX 61 kb)

Published
2016
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17. Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review

Author

L J, Schipper, J, Raaphorst, E, Aronica, F, Baas, R, de Haan, M, de Visser, and D, Troost

Subjects
Adult, Aged, 80 and over, Inclusion Bodies, Male, DNA Repeat Expansion, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Brain, RNA-Binding Proteins, Middle Aged, DNA-Binding Proteins, Spinal Cord, Frontotemporal Dementia, Humans, Female, Aged
Abstract

The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists.We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD.In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%).The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.

Published
2014

18. Expression of neurodegenerative disease-related proteins and caspase-3 in glioneuronal tumours

Author

A S, Prabowo, A M, Iyer, T J, Veersema, J J, Anink, A Y N, Schouten-van Meeteren, W G M, Spliet, P C, van Rijen, C H, Ferrier, M, Thom, and E, Aronica

Subjects
Adult, Male, Epilepsy, Adolescent, Caspase 3, Nerve Degeneration, Biomarkers, Tumor, Humans, Neuroectodermal Tumors, Primitive, Female, Child, Immunohistochemistry, Ganglioglioma
Abstract

Recent evidence supports the activation of mechanisms underlying cellular ageing and neurodegeneration in developmental lesions associated with epilepsy. The present study examined the ongoing cell injury and vulnerability to neuronal degeneration in glioneuronal tumours (GNT).We evaluated a series of GNT (n = 31 gangliogliomas, GG and n = 30 dysembryoplastic neuroepithelial tumours, DNT). Sections were processed for immunohistochemistry using markers for the evaluation of caspase-3 and neurodegeneration-related proteins/pathways and their expression was correlated with the tumour features and the clinical history of epilepsy.Both GG and DNT specimens contained caspase-3-positive cells. In GG, expression of activated caspase-3 was negatively correlated the with the BRAF V600E mutation status. We also observed an abnormal expression of death receptor-6 and β-amyloid precursor protein (APP). Moreover, dysplastic neurones expressed p62, phosphorylated (p)TDP43 and pTau. Double labelling experiments showed colocalization of phosphorylated S6 (marker of mammalian target of rapamycin, mTOR, pathway activation) with pTau and p62. In GG, neuronal p62 expression was positively correlated with pS6. The immunoreactivity score (IRS) of caspase-3, APP, DR6, p62 and pTDP43 were found to be significantly higher in GG than in DNT. Expression of APP, DR6, pTau (in GG and DNT) and caspase-3 (in GG) positively correlated with duration of epilepsy. In GG, the expression of neuronal caspase-3, DR6 and glial p62 was associated with a worse postoperative seizure outcome.Our observations in GNT provide evidence of premature activation of mechanisms of neurodegeneration which are associated with the clinical course of epilepsy in patient with GG.

Published
2014

19. Pharmacological activation of group II metabotropic glutamate receptors enhances the production of glial cell line-derived neurotrophic factor in the mouse brain

Author

G. BATTAGLIA, G. MOLINARO, B. RIOZZI, P. SPINSANTI, T. DE VITA, E. ARONICA, F. NICOLETTI, TRAFICANTE, Alessandro, MUDO', Giuseppa, BONOMO, Alessandra, BRUNO, Vittorio, BELLUARDO, Natale, G BATTAGLIA, G MOLINARO, B RIOZZI, A TRAFICANTE, P SPINSANTI, T DE VITA, MUDO' G, A BONOMO, E ARONICA, F NICOLETTI, V BRUNO, and N BELLUARDO

Published
2007

20. Assessing fluvial flood risk in urban environments: A case study

Author

Longo, E. Aronica, G. T. Di Baldassarre, G. Mukolwe, M. and Longo, E. Aronica, G. T. Di Baldassarre, G. Mukolwe, M.

Abstract

Nowadays, floods are among the most impactful calamities regarding costs. Looking at the natural hazards damage data collected in the International Disaster Database (EM-DAT), it is observable a significant increase over the past four decades of both frequency of floods and associated costs. Similarly, dramatic trends are also found by analyzing other types of flood losses, such as the number of people affected by floods, homeless, injured or killed.To deal with the aforementioned rise of flood risk, more and more efforts are being made to promote integrated flood risk management, for example, the Flood Directive 2007/60/EC. The main goals of this research are the estimation of flood damages using the KULTURisk methodology and the comparing of the projected costs with the observed one. The case study is the 2002 flood in Eilenburg. According to KULTURisk methodology, two major classes of data are considered to evaluate flood risk damage: hydraulic data as regards Hazard and economic information to assess Exposure and Vulnerability This study shows the possibility to extend the lesson learned with the Eilenburg case study in other similar contexts.

Published
2016
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22. Review: immune-mediated necrotizing myopathies--a heterogeneous group of diseases with specific myopathological features

Author

W, Stenzel, H-H, Goebel, and E, Aronica

Subjects
Necrosis, Muscular Diseases, Animals, Humans, Hydroxymethylglutaryl CoA Reductases, Muscle, Skeletal, Autoantibodies, Autoimmune Diseases
Abstract

Immune-mediated necrotizing myopathies (IMNMs) are now well recognized among the so-called idiopathic inflammatory myopathies (IIMs), which also comprise dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (sIBM) and non-specific myositis. All of these conditions are defined on the basis of distinct clinical symptoms, in combination with results derived from muscle biopsy and additional data, such as measurement of the serum creatine kinase (CK) level as well as myositis-associated and myositis-specific autoantibodies, electromyography (EMG) and modern imaging techniques. Importantly, diagnosis of one of the above mentioned myositis forms implies a specific clinical syndrome or a distinct disease. However, there is considerable clinical heterogeneity, and overlap requiring further diagnostic precision. Classification and subclassification of IIMs are highly debated and the subjects of intense research, especially as clinical trials with anti-inflammatory agents should follow universally defined and accepted criteria. This review focuses on the description of the spectrum of immune-mediated necrotizing myopathies with an emphasis on their myopathological features.

Published
2012

23. Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

Author

W O, Rohof, E, Aronica, H, Beaumont, D, Troost, and G E, Boeckxstaens

Subjects
Aged, 80 and over, Male, Muscle Relaxation, Receptor, Metabotropic Glutamate 5, Myenteric Plexus, Vagus Nerve, Middle Aged, Receptors, GABA-A, Receptors, Metabotropic Glutamate, Immunohistochemistry, Esophageal Sphincter, Lower, Receptors, GABA-B, Neural Pathways, Reflex, Gastroesophageal Reflux, Humans, Female, Nodose Ganglion, Receptors, Cannabinoid, Aged, Brain Stem
Abstract

Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABA(B)), γ-aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. Using immunohistochemistry, we investigated the distribution of mGluR5, GABA(A), GABA(B), CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. MGluR5, GABA(B), CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA(A) receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

Published
2012

26. Immunohistochemical localization of vascular endothelial growth factor receptors-1, -2 and -3 in human spinal cord: altered expression in amyotrophic lateral sclerosis

Author

W G M, Spliet, E, Aronica, M, Ramkema, A N, Witmer, R O, Schlingemann, J M B V, de Jong, and D, Troost

Subjects
Adult, Aged, 80 and over, Male, Paraffin Embedding, Vascular Endothelial Growth Factor Receptor-1, Amyotrophic Lateral Sclerosis, Middle Aged, Vascular Endothelial Growth Factor Receptor-3, Immunohistochemistry, Vascular Endothelial Growth Factor Receptor-2, Spinal Cord, Blood Vessels, Humans, Female, Neuroglia, Aged
Abstract

Vascular endothelial growth factor (VEGF) has recently been implicated in several neurological disorders. Apart from its prominent role in angiogenesis, VEGF has been shown to have direct effects on neuronal and glial cells through activation of different VEGF receptor (VEGFR) types. In the present study the expression patterns of VEGFR-1, -2 and -3 were investigated in the spinal cord of control and both sporadic and familial amyotrophic lateral sclerosis (ALS) patients. Immunocytochemical analysis of control human spinal cord demonstrated that VEGFR-1, but not VEGFR-2 or -3 was found to be present in blood vessels of both white and grey matter. All three VGEFRs were not detectable in resting glial cells of control tissue. Diffuse neuropil staining was observed in the control spinal cord grey matter for VEGFR-3. Regional differences in VEGFRs immunoreactivity (IR) were apparent in ALS compared to controls. In particular, VEGFR-1 expression was increased in reactive astroglial cells in both grey (ventral horn) and white matter of ALS spinal cord. In addition to the astroglial labelling, increased expression of VEGFR-1 and, to a less extent also of VEGFR-2, was observed in blood vessels of the ALS spinal cord. No changes in VEGFR-3 IR were detected in blood vessels or reactive astroglial cells, whereas VEGFR-3 neuropil expression was reduced and paralleled the distribution of neuronal loss in the ventral horn of ALS spinal cord. These findings indicate that VEGFRs have specific distribution patterns, suggesting different physiological functions in human spinal cord. Moreover, the altered expression observed in ALS supports a role for these receptors in the complex reactive processes that are associated with the progression of spinal cord damage.

Published
2004

28. Cystatin C, a cysteine protease inhibitor, is persistently up-regulated in neurons and glia in a rat model for mesial temporal lobe epilepsy

Author

E, Aronica, E A, van Vliet, E, Hendriksen, D, Troost, F H, Lopes da Silva, and J A, Gorter

Subjects
Male, Calbindins, Blotting, Western, Hippocampus, Avian Proteins, Rats, Sprague-Dawley, S100 Calcium Binding Protein G, Antigens, CD, Antigens, Neoplasm, Glial Fibrillary Acidic Protein, Animals, Entorhinal Cortex, Vimentin, Cystatin C, Neurons, Membrane Glycoproteins, Pyramidal Cells, Blood Proteins, Cystatins, Immunohistochemistry, Rats, Up-Regulation, Cysteine Endopeptidases, Disease Models, Animal, Parvalbumins, Epilepsy, Temporal Lobe, Astrocytes, Antigens, Surface, Dentate Gyrus, Basigin, Microglia, Neuroglia
Abstract

Cystatin C (CSTC), a cysteine protease inhibitor, has been implicated in the processes of neuronal degeneration and repair of the nervous system. Using serial analysis of gene expression (SAGE), we recently identified CSTC as one of the genes that are overexpressed after electrically induced status epilepticus (SE). In the present study, Western blot analysis extended the SAGE results, showing increased CSTC protein in the hippocampus and entorhinal cortex. Immunocytochemistry revealed an increase in CSTC expression in glial cells, which was first apparent 24 h after onset of SE, and persisted for at least 3 months. Double immunolabelling confirmed that both reactive astrocytes, and activated microglia were CSTC immunopositive. Within the hippocampus, up-regulation was also observed in neuronal cells within one day after SE. Up-regulation was still present in hippocampal pyramidal cells and surviving interneurons of chronic epileptic rats (3-8 months post-SE). This study demonstrates that status epilepticus leads to a widespread and persistent up-regulation of CSTC in the hippocampus and entorhinal cortex, which may represent an intrinsic neuroprotective mechanism in the course of epileptogenesis that may counteract progression of the disease.

Published
2001

29. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy

Author

E, Aronica, B, Yankaya, G H, Jansen, S, Leenstra, C W, van Veelen, J A, Gorter, and D, Troost

Subjects
Adult, Male, Epilepsy, Adolescent, Brain Neoplasms, Teratoma, Receptors, Metabotropic Glutamate, Immunohistochemistry, Neoplasms, Neuroepithelial, Receptors, Glutamate, Humans, Female, Child, Ganglioglioma
Abstract

Glioneuronal tumours are an increasingly recognized cause of chronic pharmaco-resistant epilepsy. In the present study the immunocytochemical expression of various glutamate receptor (GluR) subtypes was investigated in 41 gangliogliomas (GG) and 16 dysembryoplastic neuroepithelial tumours (DNT) from patients with intractable epilepsy. Immunocytochemistry with antibodies specific for ionotropic NR1, NR2A/B (NMDA) GluR1, GluR2 (AMPA), GluR5-7 (kainate), and metabotropic mGluR1, mGluR2-3, mGluR5, mGluR7a subtypes demonstrated in both GG and DNT the presence of an highly differentiated neuronal population, containing subunits from each receptor class. More than 50% of tumours contained a high percentage of neuronal cells immunolabelled for NMDA, AMPA and kainate receptor subunits. A high percentage of neurones showed strong expression of NR2A-B, which co-localized with NR1. Group I mGluRs (mGluR1 and mGluR5) were highly represented in the neuronal component of the tumours. Immunolabelling for several GluRs was also present in the glial component. Increased expression of mGluR2-3, mGluR5 and GluR5-7 was observed in reactive astrocytes in the perilesional zone compared to normal cortex. The neurochemical profile of glioneuronal tumours, with high expression of specific GluR subtypes, supports the central role of glutamatergic transmission in the mechanisms underlying the intrinsic and high epileptogenicity of these lesions.

Published
2001

30. Induction of neonatal sodium channel II and III alpha-isoform mRNAs in neurons and microglia after status epilepticus in the rat hippocampus

Author

E, Aronica, B, Yankaya, D, Troost, E A, van Vliet, F H, Lopes da Silva, and J A, Gorter

Subjects
Male, Neurons, Hippocampus, Sodium Channels, Rats, Rats, Sprague-Dawley, Status Epilepticus, Animals, Newborn, Reference Values, Dentate Gyrus, Animals, Protein Isoforms, Tissue Distribution, Microglia, RNA, Messenger
Abstract

Sodium channels (NaChs) regulate neuronal excitability in both physiological and pathological conditions, including epilepsy and are therefore an important target for antiepileptic drugs. In the present study, we examined the distribution of mRNAs encoding neonatal NaChs II and III alpha-isoforms in control rat hippocampus and after electrically-induced status epilepticus (SE), using nonradioactive in situ hybridization (ISH). Only weak expression of neonatal NaCh II and III mRNAs was observed in control hippocampus. By contrast, increased expression of neonatal NaCh II and III mRNAs was observed 4 h after the induction of SE in neurons of CA1-CA3 and the dentate granule cell layer. These changes were detected only in rats in which SE was successfully induced and persisted, although less intense, for up to 3 months, when rats display spontaneous seizures. Strong expression of neonatal NaCh alpha-isoforms was observed 1 week after SE in microglial cells, as confirmed by double labelling, combining ISH with immunocytochemistry for microglia markers. The increased expression of neonatal isoforms of the NaCh in both neurons and microglial cells may represent a critical mechanism for modulation of neuronal excitability, glial function and pharmacological response to antiepileptic drugs in the course of epileptogenesis.

Published
2001

31. Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons

Author

J A, Gorter, E A, van Vliet, E, Aronica, and F H, Lopes da Silva

Subjects
Male, Neurons, Cell Death, Electroencephalography, Nerve Tissue Proteins, Hippocampus, Electric Stimulation, Electrodes, Implanted, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Parvalbumins, Status Epilepticus, Epilepsy, Temporal Lobe, Recurrence, Seizures, Mossy Fibers, Hippocampal, Disease Progression, Neurites, Animals, Somatostatin
Abstract

The development of spontaneous limbic seizures was investigated in a rat model in which electrical tetanic stimulation of the angular bundle was applied for up to 90 min. This stimulation produced behavioural and electrographic seizures that led to a status epilepticus (SE) in most rats (71%). Long-term EEG monitoring showed that the majority of the rats (67%) that underwent SE, displayed a progressive increase of seizure activity once the first seizure was recorded after a latent period of about 1 week. The other SE rats (33%) did not show this progression of seizure activity. We investigated whether these different patterns of evolution of spontaneous seizures could be related to differences in cellular or structural changes in the hippocampus. This was the case regarding the following changes. (i) Cell loss in the hilar region: in progressive SE rats this was extensive and bilateral whereas in nonprogressive SE rats it was mainly unilateral. (ii) Parvalbumin and somatostatin-immunoreactive neurons: in the hilar region these were almost completely eliminated in progressive SE rats but were still largely present unilaterally in nonprogressive SE rats. (iii) Mossy fibre sprouting: in progressive SE rats, extensive mossy fibre sprouting was prominent in the inner molecular layer. In nonprogressive SE rats, mossy fibre sprouting was also present but less prominent than in progressive SE rats. Although mossy fibre sprouting has been proposed to be a prerequisite for chronic seizure activity in experimental temporal lobe epilepsy, the extent of hilar cell death also appears to be an important factor that differentiates between whether or not seizure progression will occur.

Published
2001

32. Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy

Author

E, Aronica, E A, van Vliet, O A, Mayboroda, D, Troost, F H, da Silva, and J A, Gorter

Subjects
Male, Receptor, Metabotropic Glutamate 5, Electroencephalography, Receptors, Metabotropic Glutamate, Antibodies, Rats, Up-Regulation, Rats, Sprague-Dawley, Disease Models, Animal, Status Epilepticus, Epilepsy, Temporal Lobe, Transforming Growth Factor beta, Astrocytes, Animals, Vimentin, Gliosis
Abstract

Reactive gliosis is a prominent morphological feature of mesial temporal lobe epilepsy. Because astrocytes express glutamate receptors, we examined changes in metabotropic glutamate receptor (mGluR) 2/3, mGluR5 and transforming growth factor (TGF)-beta in glial cells of the hippocampal regions in an experimental rat model of spontaneous seizures. Rats that exhibited behavioural status epilepticus (SE) directly after 1 h of electrical angular bundle stimulation, displayed chronic spontaneous seizures after a latent period of 1-2 weeks as observed using continuous electrographic monitoring. SE resulted in hypertrophy of astrocytes and microglia activation throughout the hippocampus as revealed by immunolabelling studies. A dramatic, seizure intensity-dependent increase in vimentin immunoreactivity (a marker for reactive astrocytes) was revealed in CA3 and hilar regions where prominent neuronal loss occurs. Increased vimentin labelling was first apparent 24 h after onset of SE and persisted up to 3 months. mGluR2/3 and mGluR5 protein expression increased markedly in glial cells of CA3 and hilus by 1 week after SE, and persisted up to 3 months after SE. Double immunolabelling of brain sections with vimentin confirmed co-localization with glial fibrillary acidic protein (GFAP), mGluR2/3 and mGluR5 in reactive astrocytes. TGF-beta, a cytokine implicated in mGluR3-mediated neuroprotection, was also upregulated during the first 3 weeks after SE throughout the hippocampus. This study demonstrates seizure-induced upregulation of two mGluR subtypes in reactive astrocytes, which - together with the increased production of TGF-beta - may represent a novel mechanism for modulation of glial function and for changes in glial-neuronal communication in the course of epileptogenesis.

Published
2000

33. Reciprocal influences of nigral cells and striatal patch neurons in dissociated co-cultures

Author

E, Aronica, L C, Costantini, and A, Snyder-Keller

Subjects
Neostriatum, Rats, Sprague-Dawley, Substantia Nigra, Bromodeoxyuridine, Tyrosine 3-Monooxygenase, Dopamine, Animals, Cell Count, Cell Communication, Immunohistochemistry, Coculture Techniques, Rats
Abstract

Our previous work has shown that the functional efficacy of nigral tissue transplants into dopamine (DA)-depleted rats is increased when embryonic striatal tissue is included (Costantini et al.: Exp Neurol 127:219-231, 1994). To examine further the influence of striatal patch neurons in this regard, we employed co-cultures of dissociated nigral and striatal cells taken from embryos at different ages. Striatal patch neurons were labeled by in vivo bromodeoxyuridine (BrdU) on embryonic day (E)13 and E14. The percentage of striatal cells that were BrdU labeled was greater in E14 striatal cultures (51.0%) compared with E16 (33.9%) and E20 (3.5%) striatal cultures at 1 day in vitro (DIV). The proportion of surviving BrdU-labeled cells in striatal cultures decreased over time. The inclusion of E14 nigral cells attenuated this decline. Similarly, the number of dopaminergic [tyrosine hydroxylase (TH)-immunoreactive] neurons in pure nigral cultures decreased with time in vitro (8.2% at 1 DIV to 3.5% at 12-15 DIV). The inclusion of E14 striatal tissue increased the number of TH-immunoreactive neurons at all time points, whereas E16 and E20 striatal tissue was somewhat less effective. Thus, the survival of nigral DA neurons and striatal patch neurons in culture appears to be enhanced in the presence of the other. These reciprocal influences on neuronal survival may be relevant to the in vivo development of the nigrostriatal system as well as the enhanced function of cells in co-transplants.

Published
1996

34. The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration

Author

M V, Bennett, D E, Pellegrini-Giampietro, J A, Gorter, E, Aronica, J A, Connor, and R S, Zukin

Subjects
Status Epilepticus, Gene Expression Regulation, Receptors, Glutamate, Nerve Degeneration, Animals, Humans, Calcium, Receptors, AMPA, Gerbillinae, Brain Ischemia, Rats
Abstract

Increased glutamate-receptor-mediated Ca++ influx is considered an important factor underlying delayed neurodegeneration following ischemia or seizures. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca(++)-permeable. It is now well established that glutamate receptors of the AMPA type, encoded by a gene family designated GluR1-GluR4, exist in both Ca(++)-permeable and Ca(++)-impermeable forms, depending on their subunit composition and degree of RNA editing. Recombinant channels assembled without GluR2 are permeable to Ca++; channels assembled with (edited) GluR2 are Ca(++)-impermeable. AMPA receptors in most adult neurons are hetero-oligomers containing GluR2 subunits, but some neurons have GluR2-less, Ca(++)-permeable receptors. The "GluR2 hypothesis" predicts that a relative reduction in the expression of GluR2 results in enhanced Ca++ influx through newly synthesized AMPA receptors, thereby increasing neurotoxicity of endogenous glutamate. Recent observations indicate reduction in GluR2 expression and predict formation of Ca(++)-permeable AMPA receptors following global ischemia and kainate-induced status epilepticus; these changes are likely to be a major factor contributing to the delayed neurodegeneration that follows these pathological events. The delayed neurodegeneration appears to be primarily apoptotic. Thus, there are at least three strategies for neuroprotection: block of formation of GluR2-less receptors, which may be possible at several levels; block of the GluR2-less receptors themselves; and block of the subsequent apoptosis.

Published
1996

35. Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

Author

Wout O. Rohof, Guy E. Boeckxstaens, E. Aronica, H. Beaumont, and D. Troost

Subjects
medicine.medical_specialty, Endocrine and Autonomic Systems, Physiology, GABAA receptor, Chemistry, Gastroenterology, Nodose Ganglion, GABAB receptor, GABAA-rho receptor, Endocrinology, Dorsal motor nucleus, nervous system, Internal medicine, mental disorders, medicine, Cannabinoid receptor type 2, Receptor, Myenteric plexus
Abstract

Background Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABAB), γ-aminobutyric acid type A (GABAA), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. Methods Using immunohistochemistry, we investigated the distribution of mGluR5, GABAA, GABAB, CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. Key Results MGluR5, GABAB, CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABAA receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. Conclusions & Inferences Human mGluR5, GABAA,B, and CB1,2 receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABAB receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

Published
2012
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36. Ionotropic and metabotropic glutamate receptor gene expression following transient focal cerebral ischemia

Author

M. Globus, O.F. Alonso, R.S. Zukin, Linda K. Friedman, Myron D. Ginsberg, and E. Aronica

Subjects
Pharmacology, Cellular and Molecular Neuroscience, Metabotropic glutamate receptor 8, Chemistry, Metabotropic glutamate receptor, Metabotropic glutamate receptor 5, Metabotropic glutamate receptor 4, Metabotropic glutamate receptor 7, Metabotropic glutamate receptor 6, Metabotropic glutamate receptor 1, Metabotropic glutamate receptor 3
Published
1996
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37. Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy.

Author

E. A. van Vliet, S. da Costa Araújo, S. Redeker, R. van Schaik, E. Aronica, and J. A. Gorter

Subjects
TEMPORAL lobe epilepsy, IMMUNOCYTOCHEMISTRY, RATS, MICROGLIA
Abstract

Leakage of the blood–brain barrier (BBB) is associated with various neurological disorders, including temporal lobe epilepsy (TLE). However, it is not known whether alterations of the BBB occur during epileptogenesis and whether this can affect progression of epilepsy. We used both human and rat epileptic brain tissue and determined BBB permeability using various tracers and albumin immunocytochemistry. In addition, we studied the possible consequences of BBB opening in the rat for the subsequent progression of TLE. Albumin extravasation in human was prominent after status epilepticus (SE) in astrocytes and neurons, and also in hippocampus of TLE patients. Similarly, albumin and tracers were found in microglia, astrocytes and neurons of the rat. The BBB was permeable in rat limbic brain regions shortly after SE, but also in the latent and chronic epileptic phase. BBB permeability was positively correlated to seizure frequency in chronic epileptic rats. Artificial opening of the BBB by mannitol in the chronic epileptic phase induced a persistent increase in the number of seizures in the majority of rats. These findings indicate that BBB leakage occurs during epileptogenesis and the chronic epileptic phase and suggest that this can contribute to the progression of epilepsy. [ABSTRACT FROM AUTHOR]

Published
2007
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43. Additional file 2: of Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo â in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Author

C. Drion, J. Van Scheppingen, A. Arena, K. Geijtenbeek, L. Kooijman, E. Van Vliet, E. Aronica, and J. Gorter

Subjects
body regions, nervous system, fungi, 3. Good health
Abstract

Figure S1. Effects of IL-1β, rapamycin, and curcumin on the viability of astrocyte cell cultures. (PDF 1690 kb)

44. GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.

Author

Cocozza G, Busdraghi LM, Chece G, Menini A, Ceccanti M, Libonati L, Cambieri C, Fiorentino F, Rotili D, Scavizzi F, Raspa M, Aronica E, Inghilleri M, Garofalo S, and Limatola C

Abstract

Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1 G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1 G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1 G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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45. Vigabatrin-associated brain magnetic resonance imaging abnormalities and clinical symptoms in infants with tuberous sclerosis complex.

Author

Stevering C, Lequin M, Szczepaniak K, Sadowski K, Ishrat S, De Luca A, Leemans A, Otte W, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Feucht M, Krsek P, Nabbout R, Jansen A, Wojdan K, Sijko K, Glowacka-Walas J, Borkowska J, Domanska-Pakiela D, Moavero R, Hertzberg C, Hulshof H, Scholl T, Petrák B, Maminak M, Aronica E, De Ridder J, Lagae L, Jozwiak S, Kotulska K, Braun K, and Jansen F

Abstract

Objective: Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants., Methods: The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated., Results: Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77)., Significance: VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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46. Somatic variant analysis of resected brain tissue in epilepsy surgery patients.

Author

Sanders MWCB, Koeleman BPC, Brilstra EH, Jansen FE, Baldassari S, Chipaux M, Sim NS, Ko A, Kang HC, Blümcke I, Lal D, Baulac S, Lee JH, Aronica E, and Braun KPJ

Subjects
Humans, Male, Female, Adolescent, Adult, Malformations of Cortical Development genetics, Malformations of Cortical Development surgery, Malformations of Cortical Development complications, Child, Young Adult, Mosaicism, Child, Preschool, Hemimegalencephaly genetics, Hemimegalencephaly surgery, Genetic Variation genetics, Cohort Studies, Neurosurgical Procedures methods, Malformations of Cortical Development, Group I genetics, Malformations of Cortical Development, Group I surgery, Epilepsy genetics, Epilepsy surgery, Brain pathology, Brain surgery
Abstract

We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations of cortical development (MCD) who underwent surgery between 2015 and 2020 at University Medical Center Utrecht (the Netherlands) and pooled our data with four previously published cohort studies. Tissue analysis yielded a pathogenic variant in 203 of 663 (31%) combined cases. In 126 of 379 (33%) focal cortical dysplasia (FCD) type II cases and 23 of 37 (62%) hemimegalencephaly cases, a pathogenic variant was identified, mostly involving the mTOR signaling pathway. Pathogenic variants in 10 focal epilepsy genes were found in 48 of 178 (27%) FCDI/mild MCD/mMCD with oligodendroglial hyperplasia and epilepsy cases; 36 of these (75%) were SLC35A2 variants. Six of 69 (9%) patients without a histopathological lesion had a pathogenic variant in SLC35A2 (n = 5) or DEPDC5 (n = 1). A germline variant in blood DNA was confirmed in all cases with a pathogenic variant in tissue, with a variant allele frequency (VAF) of ~50%. In seven of 114 patients (6%) with a somatic variant in tissue, mosaicism in blood was detected. More than half of pathogenic somatic variants had a VAF < 5%. Further analysis of the correlation between genetic variants and surgical outcomes will improve patient counseling and may guide postoperative treatment decisions., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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47. Big data research is everyone's research-Making epilepsy data science accessible to the global community: Report of the ILAE big data commission.

Author

Josephson CB, Aronica E, Beniczky S, Boyce D, Cavalleri G, Denaxas S, French J, Jehi L, Koh H, Kwan P, McDonald C, Mitchell JW, Rampp S, Sadleir L, Sisodiya SM, Wang I, Wiebe S, Yasuda C, and Youngerman B

Subjects
Humans, Artificial Intelligence, Epilepsy therapy, Epilepsy diagnosis, Big Data, Data Science
Abstract

Epilepsy care generates multiple sources of high-dimensional data, including clinical, imaging, electroencephalographic, genomic, and neuropsychological information, that are collected routinely to establish the diagnosis and guide management. Thanks to high-performance computing, sophisticated graphics processing units, and advanced analytics, we are now on the cusp of being able to use these data to significantly improve individualized care for people with epilepsy. Despite this, many clinicians, health care providers, and people with epilepsy are apprehensive about implementing Big Data and accompanying technologies such as artificial intelligence (AI). Practical, ethical, privacy, and climate issues represent real and enduring concerns that have yet to be completely resolved. Similarly, Big Data and AI-related biases have the potential to exacerbate local and global disparities. These are highly germane concerns to the field of epilepsy, given its high burden in developing nations and areas of socioeconomic deprivation. This educational paper from the International League Against Epilepsy's (ILAE) Big Data Commission aims to help clinicians caring for people with epilepsy become familiar with how Big Data is collected and processed, how they are applied to studies using AI, and outline the immense potential positive impact Big Data can have on diagnosis and management., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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48. Selective modulation of epileptic tissue by an adenosine A 3 receptor-activating drug.

Author

Ghosh A, Ribeiro-Rodrigues L, Ruffolo G, Alfano V, Domingos C, Rei N, Tosh DK, Rombo DM, Morais TP, Valente CA, Xapelli S, Bordadágua B, Rainha-Campos A, Bentes C, Aronica E, Diógenes MJ, Vaz SH, Ribeiro JA, Palma E, Jacobson KA, and Sebastião AM

Subjects
Humans, Animals, Male, Rats, gamma-Aminobutyric Acid metabolism, Female, Rats, Sprague-Dawley, Mice, Adenosine pharmacology, Adenosine analogs & derivatives, Excitatory Postsynaptic Potentials drug effects, GABA Plasma Membrane Transport Proteins metabolism, Hippocampus drug effects, Hippocampus metabolism, Receptor, Adenosine A3 metabolism, Epilepsy drug therapy, Epilepsy metabolism, Adenosine A3 Receptor Agonists pharmacology, Anticonvulsants pharmacology
Abstract

Background and Purpose: Adenosine, through the A 1 receptor (A 1 R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A 1 R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A 1 R and/or through a disease-specific mechanism, we assessed the effect of MRS5474 on the hippocampus., Experimental Approach: Excitatory synaptic currents, field potentials, spontaneous activity, [ 3 H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A 3 receptor (A 3 R) density in human tissue were assessed by Western blot., Key Results: MRS5474 (50-500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT-1)-mediated γ-aminobutyric acid (GABA) uptake, an action not blocked by an A 1 R antagonist but blocked by an A 3 R antagonist and mimicked by an A 3 R agonist. A 3 R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration-dependent potentiation of GABA-evoked currents in oocytes micro-transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non-epileptic tissue, an action blocked by an A 3 R antagonist., Conclusion and Implications: We identified a drug that activates A 3 R and has selective actions on epileptic hippocampal tissue. This underscores A 3 R as a promising target for the development of antiseizure medications., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2024
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49. mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.

Author

Zwakenberg S, Westland D, van Es RM, Rehmann H, Anink J, Ciapaite J, Bosma M, Stelloo E, Liv N, Sobrevals Alcaraz P, Verhoeven-Duif NM, Jans JJM, Vos HR, Aronica E, and Zwartkruis FJT

Subjects
Humans, HEK293 Cells, Phosphorylation, Signal Transduction, Cell Nucleus metabolism, Neuropeptides metabolism, Neuropeptides genetics, Active Transport, Cell Nucleus, Mutation, Lysosomes metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 1 genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, TOR Serine-Threonine Kinases metabolism, TOR Serine-Threonine Kinases genetics, Ras Homolog Enriched in Brain Protein metabolism, Ras Homolog Enriched in Brain Protein genetics, Monomeric GTP-Binding Proteins metabolism, Monomeric GTP-Binding Proteins genetics, Multiprotein Complexes metabolism, Multiprotein Complexes genetics
Abstract

To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC)., Competing Interests: Declaration of interests E.A. has served on the scientific advisory boards of UCB and Nutricia., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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50. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives.

Author

Specchio N, Trivisano M, Aronica E, Balestrini S, Arzimanoglou A, Colasante G, Cross JH, Jozwiak S, Wilmshurst JM, Vigevano F, Auvin S, Nabbout R, and Curatolo P

Subjects
Humans, Genetic Testing, Genetic Therapy, Epilepsy genetics
Abstract

Recent advances in genetic testing technologies have revolutionised the identification of genetic abnormalities in early onset developmental and epileptic encephalopathies (DEEs). In this Review, we provide an update on the expanding landscape of genetic factors contributing to DEEs, encompassing over 800 reported genes. We focus on the cellular and molecular mechanisms driving epileptogenesis, with an emphasis on emerging therapeutic strategies and effective treatment options. We explore noteworthy, novel genes linked to DEE phenotypes, such as gBRAT-1 and GNAO1, and gene families such as GRIN and HCN. Understanding the network-level effects of gene variants will pave the way for potential gene therapy applications. Given the diverse comorbidities associated with DEEs, a multidisciplinary team approach is essential. Despite ongoing efforts and improved genetic testing, DEEs lack a cure, and treatment complexities persist. This Review underscores the necessity for larger international prospective studies focusing on both seizure outcomes and developmental trajectories., Competing Interests: Declaration of interests NS has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Eisai, BioMarin, Livanova, Sanofi; and has served as an investigator for Zogenix, Marinus, BioMarin, Union Chimique Belge (UCB), and Roche. MT has served on advisory boards for BioMarin and Biocodex; has received speaker honoraria from BioMarin, Biocodex, and Orion; and has served as an investigator for Zogenix, Marinus, BioMarin, UCB, and Roche. SB has served on advisory boards for Biocodex and has received speaker and consultant honoraria from Angelini, Biocodex, and Jazz Pharmaceutics. AA has received speaker and consultant honoraria from Biocodex, EISAI, Jazz Pharmaceutics, Sanofi, and UCB and is co-director of the European Consortium for Epilepsy Trials. JHC has received grants from Stoke Therapeutics, Ultragenyx, UCB, the National Institute for Health and Care Research, Great Ormond Street Hospital Children's Charity, LifeARC, the Waterloo Foundation, and Action Medical Research. JHC has also received honoraria payments from Biocodex, Nutricia, Jazz Pharmaceuticals, Nutricia, Takeda, and UCB, all of which have been paid to University College London. JMW is associate editor of Epilepsia and chief editor of the Paediatric Neurology subsection of Frontiers in Neurology and has served on advisory boards for Sanofi and Novartis. FV has received speaker fees from Zogenix, Neuraxpharm, Angelini, and Eisai and has served on advisory boards for Zogenix, Neuraxpharm, Angelini, and Eisai. SA has received honoraria for lectures from Biocodex, BioMarin, Eisai, Jazz Pharmaceuticals, Neuraxpharm, Nutricia, Stoke, UCB, and Zogenix; has been paid as a consultant for lectures by Biocodex, Encoded, Grintherapeutics, Jazz Pharmaceuticals, Neuraxpharm, Nutricia, Orion, Proveca, Supernus, Stoke, Takeda, UCB, and Xenon; and has been an investigator for clinical trials for Eisai, Proveca, Takeda, and UCB. RN has served as principal investigator in clinical trials for Novartis, Nutricia, Eisai, UCB, GW Pharma, and Livanova; has received consulting and lecturer honoraria from BioGene, BioMarin, Praxis, GW Pharma, Zogenix, Novartis, Nutricia, Stoke, Ionis, Targeon, Neuraxpharma, Takeda, Nutricia, Biocodex, Advicennes, and Eisai; and has received unrestricted research grants from Eisai, UCB, Livanova, and GW Pharma and academic research grants from the European Joint Programme on Rare Diseases (Horizons 2020). PC has served on a scientific advisory board for Novartis, has received speaker honoraria from Jazz Pharmaceuticals and ItalFarmaco, and has served as investigator for clinical trials for Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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