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1. Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols

Author

Irina Serbanescu, Mary Ann Ryan, Ruchika Shukla, Miguel A. Cortez, O. Carter Snead, III, and Stephen C. Cunnane

Subjects
AY-9944, BM 15.766, brain cholesterol, cholesterol, epilepsy, seizures, Biochemistry, QD415-436
Abstract

AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by

Published
2004
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2. Finite element model of ocular injury in abusive head trauma

Author

Jamie Ho, Matthew Rusinek, Alex V. Levin, Sarath Babu Kamalakkannan, Vikas Hasija, Carole Jenny, N. Rangarajan, Irina Serbanescu, and Tariq Shams

Subjects
Angular acceleration, medicine.medical_specialty, genetic structures, Finite Element Analysis, Posterior pole, Poison control, Retina, Viscoelasticity, Eye injuries, Stress (mechanics), Eye Injuries, Stress, Physiological, Newtonian fluid, Humans, Medicine, Computer Simulation, business.industry, Infant, Retinal Hemorrhage, Mechanics, Shaken Baby Syndrome, medicine.disease, eye diseases, Sclera, Surgery, Vitreous Body, Ophthalmology, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, sense organs, business
Abstract

Purpose To develop a finite element analysis of the eye and orbit that can be subjected to virtual shaking forces. Methods LS-DYNA computer software was used to design a finite element model of the human infant eye, including orbit, fat, sclera, retina, vitreous, and muscles. The orbit was modeled as a rigid solid; the sclera and retina as elastic shells; the vitreous as viscoelastic solid or Newtonian fluid; and fat as elastic or viscoelastic solid. Muscles were modeled as spring-damper systems. Orbit-fat, fat-sclera, sclera-retina, and vitreous nodes-retina interfaces were defined with the use of the tied surface-surface function in LS-DYNA. The model was subjected to angular acceleration pulses obtained from shaking tests of a biofidelic doll (Aprica 2.5 kg dummy). Parametric studies were conducted to evaluate the effect of varying the material properties of vitreous/fat on maximum stress and stress distribution. Results With the vitreous modeled as a Newtonian fluid, the repeated acceleration-deceleration oscillatory motion characteristic of abusive head trauma (AHT) causes cumulative increases in the forces experienced at the vitreoretinal interface. Under these vitreous conditions, retinal stress maximums occur at the posterior pole and peripheral retina, where AHT retinal hemorrhage is most often found. Conclusions Our model offers an improvement on dummy and animal models in allowing analysis of the effect of shaking on ocular tissues. It can be used under certain material conditions to demonstrate progressive "stacking" of intraocular stresses in locations corresponding to typical AHT injury patterns, allowing a better understanding of the mechanisms of retinal hemorrhage patterns.

Published
2009
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3. Refractory atypical absence seizures in rat: a two hit model

Author

O. Carter Snead, Irina Serbanescu, Colin McKerlie, and Miguel A. Cortez

Subjects
medicine.medical_specialty, Methylazoxymethanol Acetate, Atypical absence seizures, Drug Resistance, trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride, Epilepsy, chemistry.chemical_compound, Atrophy, Pregnancy, Internal medicine, medicine, Animals, Rats, Long-Evans, Protein Synthesis Inhibitors, Methylazoxymethanol acetate, business.industry, Anticholesteremic Agents, Brain, Electroencephalography, Carbamazepine, Human brain, medicine.disease, Rats, Disease Models, Animal, Endocrinology, Neuronal migration disorder, medicine.anatomical_structure, Ethosuximide, Epilepsy, Absence, Neurology, chemistry, Prenatal Exposure Delayed Effects, Female, Neurology (clinical), business, medicine.drug
Abstract

Medically refractory seizure disorders in children usually have malignant neurodevelopmental outcomes and often are associated with the presence of congenital cortical dysplasias in the brain. To date, there are no animal models of these disorders by which to test hypotheses of pathogenesis or to screen novel drugs for antiepileptic activity. In rats, treatment with the antimitotic agent methylazoxymethanol acetate (MAM) on gestational day (G) 15 produces a neuronal migration disorder similar to the cortical dysplasias seen in human brain. We sought to produce chronic, recurrent, medically refractory seizures by administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during postnatal development in rats exposed prenatally to MAM. Prenatal MAM and postnatal AY treatments resulted in spontaneous, recurrent atypical absence seizures that were characterized by bilaterally synchronous slow spike-and-wave discharges (SWD) with a frequency of 6 Hz. The MAM-AY-induced seizures were refractory to ethosuximide, sodium valproate, and the GABABR antagonist CGP 35348, and were exacerbated by carbamazepine. Histological examination of brains from MAM-treated rats showed hippocampal heterotopias, in addition to atrophy and abnormalities of cortical lamination. The MAM-AY-treated rat represents a reproducible model of refractory atypical absence seizures in children with brain dysgenesis.

Published
2004
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4. Natural animal shaking: a model for non-accidental head injury in children?

Author

Sandra M. Brown, Irina Serbanescu, Alex V. Levin, and D. Ramsay

Subjects
Child abuse, medicine.medical_specialty, Eye disease, Poison control, Head trauma, Diagnosis, Differential, Injury prevention, medicine, Animals, Craniocerebral Trauma, Humans, Child Abuse, Child, business.industry, Head injury, Retinal Hemorrhage, Shaken Baby Syndrome, Hares, medicine.disease, Surgery, Ophthalmology, Accidental, Anesthesia, Models, Animal, Cats, business, Retinal haemorrhage
Abstract

Background: Non-accidental head injury (NAHI) is a form of child abuse where a perpetrator may violently subject an infant to repeated acceleration-deceleration forces with or without head impact, producing injuries including retinal haemorrhages in most cases. Animal models have included laboratory shaking of mice and rats, but only a small fraction develop retinal haemorrhages presumably due to the small eyes, which would require unattainable force levels to mimic that sustained by the infant eye. Animal models are also problematic due to ethical issues raised by subjecting even anaesthetized animals to abusive injury. Methods: We investigated a naturally occurring event, where three animal victims were shaken by a canine. The eyes were harvested and examined histologically. Results: The victims' eyes showed no haemorrhage or retinoschisis. Conclusions: Our model may not be a complete NAHI mimic. The discrepancies may ensue from anatomical and mechanical differences in the injury mechanism. Other models must be sought to further study this form of abusive eye injury. Language: en

Published
2008
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5. List of Contributors

Author

Juan-Carlos Abad, Mark B Abelson, David H Abramson, Martin A Acquadro, Anthony P Adamis, Wesley H Adams, Natalie A Afshari, Everett Ai, Lloyd M Aiello, Lloyd P Aiello, Levent Akduman, Marissa L Albano, Daniel M. Albert, Terry J Alexandrou, Eduardo C Alfonso, Jorge L Alié, Hassan Alizadeh, Ibrahim A Al Jadaan, Sabah Al-Jastaneiah, Calliope E Allen, David Allen, Robert C Allen, Albert Alm, Samar Al-Swailem, Abigail K Alt, Michael M Altaweel, Russell Anderson, Christopher M Andreoli, Sofia Androudi, Leonard PK Ang, Fahd Anzaar, David J Apple, Claudia A Arrigg, Pablo Artal, Penny Asbell, George K Asdourian, Neal Atebara, Pelin Atmaca-Sonmez, Isabelle Audo, Gerd U Auffarth, Robin K Avery, Dimitri T Azar, Ann S Baker, Mark Balles, Scott D Barnes, Donald M Barnett, Neal P Barney, Fina C Barouch, George B Bartley, Jason JS Barton, Irmgard Behlau, Jose I Belda, Jeffrey L Bennett, Timothy J Bennett, Gregg J Berdy, Carlo Roberto Bernardino, Vitaliano Bernardino, Eliot L Berson, Amitabh Bharadwaj, Robert Bhisitkul, Ravinder D Bhui, Jurij Bilyk, Valérie Biousse, Alan C Bird, Norman Paul Blair, Barbara A Blodi, Mark S Blumenkranz, H Culver Boldt, Mark S Borchert, Luigi Borrillo, Gary E Borodic, S Arthur Boruchoff, Swaraj Bose, Michael E Boulton, RW Bowman, Elizabeth A Bradley, Periklis D Brazitikos, Robert Breeze, Neil M Bressler, Susan B Bressler, Alfred Brini, Donald L Budenz, Angela N Buffenn, Scott E Burk, Salim Butrus, David Callanan, J Douglas Cameron, Louis B Cantor, William A Cantore, Jorge Cantu-Dibildox, Victoria Casas, Miriam Casper, Robin J Casten, Yara P Catoira, Jerry Cavallerano, Samantha J Chai, Maria R Chalita, Sherman M Chamberlain, Audrey S Chan, Chi-Chao Chan, Paul Chan, Matthew J Chapin, Karen L Chapman, Eric Chen, Joe Chen, Julie A Chen, Teresa C Chen, Zhou Chen, Patricia Chévez-Barrios, Emily Y Chew, Mark Chiang, James Chodosh, Eva-Marie Chong, Denise Chun, Leo T Chylack, Antonio P Ciardella, Mortimer Civan, Liane Clamen, John I Clark, Glenn Cockerham, Andre Cohen, Elisabeth J Cohen, Kathryn A Colby, Anne L Coleman, Hanna R Coleman, Joseph Colin, J Michael Collier, Grant M Comer, M Ronan Conlon, Kim E Cooper, James J Corbett, Miguel C Coma, Marshall N Cyrlin, Linda R Dagi, Matthew A Dahlgren, Timothy J Daley, Andrea P Da Mata, Bertil Damato, Donald J D'Amico, Reza Dana, Aude Danan-Husson, Helen B Danesh-Meyer, Ronald P Danis, Jason K Darlington, Stefanie L Davidson, Janet L Davis, Elizabeth A Davis, Jose J de la Cruz, Adam G de la Garza, Margaret M DeAngelis, Sheri L DeMartelaere, Joseph L Demer, Avninder Dhaliwal, J Paul Dieckert, Diana V Do, Marshall G Doane, Christopher Dodds, Claes H Dohlman, Guy Donati, Eric D Donnenfeld, Arlene Drack, Thaddeus P Dryja, David Dueker, Jay S Duker, Jennifer A Dunbar, James P Dunn, William J Dupps, Marlene L Durand, Jonathan J Dutton, Chiara M Eandi, Deepak P Edward, Robert A Egan, David A Eichenbaum, Susan E Eklund, Elizabeth C Engle, Kristine Erickson, Bita Esmaeli, Aaron Fay, Leonard Feiner, Sharon Fekrat, Frederick L Ferris, Howard F Fine, Donald C Fletcher, Paul Flikier, Richard P Floyd, Harry W Flynn, Donald S Fong, Ramon L Font, Brian JR Forbes, Rod Foroozan, Bradley S Foster, C Stephen Foster, Jill A Foster, Gary N Foulks, Tamara R Fountain, Gregory M Fox, Thomas F Freddo, Sharon F Freedman, K Bailey Freund, Thomas R Friberg, Alan H Friedman, David Friedman, Deborah I Friedman, Ephraim Friedman, Arthur D Fu, Anne B Fulton, Ahmed Galal, Steven Galetta, Mark Gallardo, Brenda Gallie, Alec Garner, James A Garrity, Damien Gatinel, Steven J Gedde, Craig E Geist, Steve Gerber, Ramon C Ghanem, Jon P Gieser, Michael S Gilmore, Howard V Gimbel, Ilene K Gipson, Tyrone Glover, Robert A Goldberg, Mordechai Goldenfeld, Scott M Goldstein, Cintia F Gomi, Haiyan Gong, John A Gonzales, John Goosey, Justin L Gottlieb, Joshua Gould, Evangelos S Gragoudas, David B Granet, Michael J Greaney, Daniel G Green, Franz Grehn, Jack V Greiner, Craig M Greven, Gregory J Griepentrog, Carl Groenewald, Cynthia L Grosskreutz, Lori Latowski Grover, Vamsi K Gullapalli, Padma Gulur, Jonathan Gunther, Manish Gupta, Mayank Gupta, David R Guyer, Darin R Haivala, Julia A Haller, GM Halmagyi, Lawrence S Halperin, Islam M Hamdi, Steven R Hamilton, Kristin M Hammersmith, Dennis P Han, Ronald M Hansen, J William Harbour, Seenu M Hariprasad, Mona Harissi-Dagher, Shirin E. Hassan, Mark P Hatton, Pamela Hawley, Yasutaka Hayashida, John R Heckenlively, Thomas R Hedges, Alfred D Heggie, Katrinka L Heher, Jeffrey S Heier, J Fielding Hejtmancik, Bonnie A Henderson, Peter S Hersh, Ahmed A Hidayat, Eva Juliet Higginbotham, Tatsuo Hirose, Allen C Ho, ThucAnh T Ho, R Nick Hogan, David E Holck, Nancy M Holekamp, Peter G Hovland, Thomas C Hsu, William C Hsu, Andrew JW Huang, Mark S Hughes, Jennifer Hui, David G Hunter, Laryssa A Huryn, Deeba Husain, Robert A Hyndiuk, Michael Ip, Brian J Jacobs, Frederick A Jakobiec, Lee M Jampol, Harold G Jensen, Fei Ji, David L Johnson, Douglas H Johnson, Mark W Johnson, R Paul Johnson, Robert N Johnson, Karen M Joos, Nancy C Joyce, J Michael Jumper, Ula V. Jurkunas, Alon Kahana, Malik Y Kahook, Elliott Kanner, Kevin Kalwerisky, Henry J Kaplan, Ekaterini C Karatza, Randy Kardon, James A Katowitz, William R Katowitz, Melanie Kazlas, Kelly S Keefe, Lara Kelley, Charles J Kent, Kenneth R Kenyon, Bilal F Khan, Jemshed A Khan, Naheed W Khan, Peng Tee Khaw, Femida Kherani, Eva C Kim, Hee Joon Kim, Ivana K Kim, Jonathan W Kim, Rosa Y Kim, Stella K Kim, Tae-Im Kim, Christina M Klais, Stephen R Klapper, Barbara EK Klein, Guy Kleinmann, Thomas Klink, Dino D Klisovic, Stephen D Klyce, Tolga Kocaturk, Thomas Kohnen, Takeshi Kojima, Tobias Koller, David A Kostick, Joel A Kraut, Chandrasekharan Krishnan, Ronald R Krueger, Joseph H Krug, Sara Krupsky, Rachel W Kuchtey, Ramsay S Kurban, Paul A Kurz, JR Kuszak, Young H Kwon, Thad A Labbe, Deborah L Lam, Jeffrey C Lamkin, Kathleen A Lamping, Anne Marie Lane, Katherine A Lane, Keith J Lane, Jonathan H Lass, Mary G Lawrence, Andrew G Lee, Carol M Lee, Michael S Lee, Paul P Lee, William B Lee, Igal Leibovitch, Bradley N Lemke, Craig A Lemley, Andrea Leonardi, Simmons Lessell, Leonard A Levin, Grace A Levy-Clarke, Julie C Lew, Craig Lewis, Wei Li, Laurence S Lim, Lyndell L Lim, Wee-Kiak Lim, Grant T Liu, John I Loewenstein, McGregor N Lott, Jonathan C Lowry, David B Lyon, Robert E Lytle, Mathew MacCumber, Bonnie T Mackool, Nalini A Madiwale, Francis Mah, Martin A Mainster, Michael H Manning, Steven L Mansberger, Robert E Marc, Mellone Marchong, Dennis M Marcus, Julie A Mares, Brian P Marr, Carlos E Martinez, Robert W Massof, Yukihiro Matsumoto, Cynthia Mattox, Marlon Maus, Cathleen M McCabe, Steven A McCormick, Michael McCrakken, James P McCulley, John A McDermott, H Richard McDonald, Marguerite B McDonald, Peter J McDonnell, Robert McGillivray, Craig A McKeown, James McLaughlin, W Wynn McMullen, Shlomo Melamed, George Meligonis, Efstratios Mendrinos, Dale R Meyer, Catherine B Meyerle, William F Mieler, Michael Migliori, Martin C Mihm, Darlene Miller, David Miller, Joan W Miller, Neil R Miller, David M Mills, Monte D Mills, Tatyana Milman, Lylas Mogk, Marja Mogk, Jordi Monés, Robert Montes-Micó, Christie L Morse, Asa D Morton, Anne Moskowitz, Shizuo Mukai, A Linn Murphree, Robert P Murphy, Timothy G Murray, Philip I Murray, Karina Nagao, Jay Neitz, Maureen Neitz, Peter A Netland, Arthur H Neufeld, Nancy J Newman, Eugene WM Ng, Quan Dong Nguyen, Jerry Y Niederkorn, Robert J Noecker, Robert B Nussenblatt, Joan M O'Brien, Paul D O'Brien, Terrence P O'Brien, Denis O'Day, R Joseph Olk, Karl R Olsen, Sumru Onal, Yen Hoong Ooi, E Mitchel Opremcak, George Ousler, Randall R Ozment, Samuel Packer, Millicent L Palmer, George N Papaliodis, DJ John Park, David W Parke, Cameron F Parsa, M Andrew Parsons, Louis R Pasquale, Neha N Patel, Sayjal J Patel, Thomas D Patrianakos, James R Patrinely, Deborah Pavan-Langston, Eli Peli, Susan M Pepin, Victor L Perez, Juan J Pérez-Santonja, John R Perfect, Henry D Perry, Joram Piatigorsky, Dante Pieramici, Eric A Pierce, Roberto Pineda, Misha L Pless, Howard D Pomeranz, Constantin J Pournaras, William Power, Manvi Prakash, Anita G Prasad, Valerie Purvin, David A Quillen, Graham E Quinn, Melvin D Rabena, James L Rae, Michael B Raizman, Alessandro Randazzo, Narsing A Rao, Christopher J Rapuano, Sherman W Reeves, Carl D Regillo, Elias Reichel, Martin H Reinke, Douglas Rhee, Claudia U Richter, Joseph F Rizzo, Richard M Robb, Anja C Roden, I Rand Rodgers, Merlyn M Rodrigues, Yonina Ron, Geoffrey E Rose, Emanuel S Rosen, James T Rosenbaum, Perry Rosenthal, Strutha C Rouse, Barry W Rovner, Malgorzata Rozanowska, Michael P Rubin, Peter AD Rubin, Shimon Rumelt, Anil K Rustgi, Tina Rutar, Mark S Ruttum, Allan R Rutzen, Edward T Ryan, Alfredo A Sadun, José-Alain Sahel, Leorey Saligan, Sarwat Salim, John F Salmon, Diva R Salomão, David Sami, Michael A Sandberg, Virender S Sangwan, Maria A Saornil, Joseph W Sassani, Rony R Sayegh, Andrew P Schachat, Wiley A Schell, Amy C Schefler, Tina Scheufele, Vivian Schiedler, Gretchen Schneider, Alison Schroeder, Ronald A Schuchard, Joel S Schuman, Ivan R Schwab, Adrienne Scott, Ingrid U Scott, Marvin L Sears, Johanna M Seddon, Theo Seiler, Robert P Selkin, Richard D Semba, Irina Serbanescu, Briar Sexton, Tarek M Shaarawy, Peter Shah, Aron Shapiro, Savitri Sharma, Jean Shein, Debra J Shetlar, M Bruce Shields, Carol L Shields, Jerry A Shields, Bradford J Shingleton, John W Shore, Lesya M Shuba, Guy J Ben Simon, Richard J Simmons, Michael Simpson, Arun D Singh, Omah S Singh, Karen Sisley, Arthur J Sit, David Smerdon, William E Smiddy, Ronald E Smith, Terry J Smith, Neal G Snebold, Lucia Sobrin, John A Sorenson, Sarkis H Soukiasian, George L Spaeth, Richard F Spaide, Monika Srivastava, Sunil K Srivastava, Alexandros N Stangos, Tomy Starck, Walter J Stark, Joshua D Stein, Roger F Steinert, Leon Strauss, Barbara W Streeten, J Wayne Streilein, James D Strong, Ilene K Sugino, Eric B Suhler, Timothy J Sullivan, Jennifer K Sun, Janet S Sunness, Francis C Sutula, Nasreen A Syed, Christopher N Ta, Hidehiro Takei, Jonathan H Talamo, Richard R Tamesis, Madhura Tamhankar, Kristen J Tarbet, Michelle Tarver-Carr, Mark A Terry, Joseph M Thomas, Vance Thompson, Jennifer E Thorne, Matthew J Thurtell, David P Tingey, King W To, Faisal M Tobaigy, Michael J Tolentino, Melissa G Tong, Gail Torkildsen, Cynthia A Toth, Elias I Traboulsi, Michele Trucksis, James C Tsai, Julie H Tsai, David T Tse, Scheffer CG Tseng, Elmer Y Tu, Ira J Udell, Alejandra A Valenzuela, Russell N Van Gelder, Gregory P Van Stavern, Deborah K Vander Veen, Demetrios Vavvas, David H Verity, Paolo Vinciguerra, Paul F Vinger, Nicholas J Volpe, Werner Wackernagel, Sonal Desai Wadhwa, Michael D Wagoner, Nadia K Waheed, David S Walton, Martin Wand, Jie Jin Wang, Scott M Warden, Lennox Webb, David Weber, Daniel Wee, Corey B Westerfeld, Christopher T Westfall, Scott M Whitcup, Valerie A White, William L White, Jason Wickens, Janey L Wiggs, Jacob T Wilensky, Charles P Wilkinson, Patrick D Williams, David J Wilson, M Roy Wilson, Steven E Wilson, Jules Winokur, William J Wirostko, Gadi Wollstein, Albert Chak Ming Wong, Tien Y Wong, John J Woog, Michael Wride, Carolyn S Wu, Darrell WuDunn, Jean Yang, Lawrence A Yannuzzi, Michael J Yaremchuk, R Patrick Yeatts, Richard W Yee, Steven Yeh, Lucy HY Young, Jenny Y Yu, Beatrice YJT Yue, Charles M Zacks, Bruce M Zagelbaum, Maryam Zamani, Marco Zarbin, Leonidas Zografos, and Christopher I Zoumalan

Published
2008
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7. Daily rhythms of seizure activity and behavior in a model of atypical absence epilepsy

Author

Vasan Persad, Niraj Mistry, Eduard Bercovici, Ruchica Shukla, O. Carter Snead, Miguel A. Cortez, Lee S. Stewart, and Irina Serbanescu

Subjects
Male, medicine.medical_specialty, Atypical absence seizures, Movement, Hippocampus, trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride, Behavioral Neuroscience, Epilepsy, Mice, Rhythm, Seizures, Internal medicine, medicine, Animals, Rats, Long-Evans, Seizure activity, Cerebral Cortex, Chronobiology, Mice, Inbred C3H, Neocortex, Behavior, Animal, Anticholesteremic Agents, Electroencephalography, medicine.disease, Circadian Rhythm, Rats, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Neurology, Epilepsy, Absence, Neurology (clinical), Serotonin, Psychology, Neuroscience
Abstract

We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY) during early postnatal development. Chronic atypical absence seizures were verified in the AY-treated animals by the presence of spontaneous 5- to 6-Hz slow spike–wave discharges (SSWDs) in the neocortex. General behavioral activity, as measured by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), and rotational behavior (TURNS), were continuously recorded under a 12-hour light:12-hour dark photocycle. The average SSWD duration in AY-treated rats varied daily, with two peaks occurring at approximately dark phase and light phase onset. Mice treated with AY exhibited significant increases in all behavioral measures during the light and dark phases, with the exception of light-phase CT, which did not differ from that of controls. Consequently, the daily rhythm of total behavioral activity (TM) exhibited a significantly higher mean oscillation (mesor) and amplitude without evidence of phase shift compared with the TM rhythm of controls. The occurrence of SSWD activity in the AY model appears to be subject to regulation by biological timing mechanisms and, furthermore, associated with motor hyperactivity that does not alter the timing of behavioral rhythmicity.

Published
2006

8. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet

Author

Sergei S. Likhodii, Irina Serbanescu, O. Carter Snead, Patricia Murphy, Miguel A. Cortez, and W. McIntyre Burnham

Subjects
Male, Ketone, medicine.medical_treatment, Atypical absence seizures, Convulsants, Pharmacology, trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride, Acetone, chemistry.chemical_compound, Epilepsy, Epilepsy, Complex Partial, Ketogenesis, medicine, Diabetes Mellitus, Kindling, Neurologic, Animals, Rats, Wistar, chemistry.chemical_classification, Brain Chemistry, Electroshock, Dose-Response Relationship, Drug, Kindling, business.industry, medicine.disease, Amygdala, Diet, Rats, Anticonvulsant, Neurology, chemistry, Epilepsy, Absence, Anesthesia, Pentylenetetrazole, Anticonvulsants, Ataxia, Neurology (clinical), Epilepsy, Tonic-Clonic, business, Ketogenic diet
Abstract

The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.

Published
2003

9. An in vivo selection system for homing endonuclease activity

Author

Mathias Gruen, Kathy Chang, Irina Serbanescu, and David R. Liu

Subjects
Genetics, Binding Sites, Endodeoxyribonucleases, biology, Mutant, DNA, Homing endonuclease, Cell biology, Substrate Specificity, Endonuclease, chemistry.chemical_compound, Plasmid, chemistry, Mutation, biology.protein, Escherichia coli, Flap endonuclease, NAR Methods Online, Cell Division, Homing (hematopoietic), Plasmids
Abstract

Homing endonucleases are enzymes that catalyze the highly sequence-specific cleavage of DNA. We have developed an in vivo selection in Escherichia coli that links cell survival with homing endonuclease-mediated DNA cleavage activity and sequence specificity. Using this selection, wild-type and mutant variants of three homing endonucleases were characterized without requiring protein purification and in vitro analysis. This selection system may facilitate the study of sequence-specific DNA cleaving enzymes, and selections based on this work may enable the evolution of homing endonucleases with novel activities or specificities.

Published
2002

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