Professor, The Saul R. Korey Department of Neurology
Associate Professor, Dominick P. Purpura Department of Neuroscience
ROLE OF GABAA SIGNALING AND THE mTOR PATHWAY IN EPILEPTOGENESIS AND BRAIN DEVELOPMENT
EFFECTS OF EARLY LIFE SEIZURES ON BRAIN DEVELOPMENT
MODELS OF INFANTILE SPASMS AND EARLY LIFE EPILEPSY
PATHOPHYSIOLOGY OF RETT SYNDROME
The maturation of GABAA receptor-mediated signaling from depolarizing to inhibitory is an age-related process controlled by cation chloride cotransporters, such as KCC2. As a result, GABA exerts dual functions, being an important neurotrophic factor during early development and the principal inhibitory neurotransmitter of the mature central nervous system. In our laboratory we have been investigating the age and gender specific mechanisms through which early life stressors and seizures may disrupt the normal patterns of brain development, by disrupting the neurotrophic effects of GABA. We are also studying methods to reverse these adverse processes. Furthermore, we are very interested in understanding how epileptogenesis proceeds in the developing brain and what is the specific role of GABAA receptors in this process.
To better understand the pathophysiology and design better methods to treat catastrophic early life epilepsies, we are developing and studying new models of early life epilepsy. These include models of symptomatic infantile spasms that recapitulate most of the features of the human condition. Several projects are under way to (a) elucidate the pathophysiology of infantile spasms, and (b) conduct preclinical trials to find better treatments for spasms and the associated comorbidities. Our studies have provided preclinical evidence for new potential treatments with disease modifying properties for these early life epileptic encephalopathies, such as mTOR inhibitor, carisbamate and a new vigabatrin analog.
Rett syndrome is one of the major causes of mental retardation and epilepsy. Most of these patients have mutations in the MeCP2 gene and also manifest abnormal stereotypic movements and autonomic dysfunction. Despite the devastating course of the disease, two independent laboratories have recently demonstrated that, in mice, phenotypic reversal can be achieved by restoring the normal function of MeCP2. We are using a mouse model of Rett syndrome to determine how pathogenic mutations of MeCP2 may interfere with the function and physiology of structures involved in the control of motor system and seizures, like the substantia nigra and how these processes may be reversed by appropriate therapeutic interventions.
Students interested in these projects will gain exposure to a variety of in vivo and in vitro techniques that combine molecular biology, in vivo and in vitro electrophysiology, histological, and behavioral studies and will be involved in projects with direct translational relevance to the clinical practice, i.e. identification of novel therapies.
Akman O, Moshé SL, Galanopoulou AS. Sex-specific consequences of early life seizures. Neurobiol Dis. (2014) (in press) http://www.ncbi.nlm.nih.gov/pubmed/24874547
Giorgi FS, Galanopoulou AS, Moshé SL. Sex dimorphism in seizure-controlling networks. Neurobiol Dis. (2014) (in press) http://www.ncbi.nlm.nih.gov/pubmed/24851800
Pardo CA, Nabbout R, Galanopoulou AS. Mechanisms of epileptogenesis in pediatric epileptic syndromes: Rasmussen encephalitis, infantile spasms, and febrile infection-related epilepsy syndrome (FIRES). Neurotherapeutics (2014) 11(2):297-310. http://www.ncbi.nlm.nih.gov/pubmed/24639375
Briggs SW, Mowrey W, Hall CB, Galanopoulou AS. CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms. Epilepsia (2014) (in press). http://www.ncbi.nlm.nih.gov/pubmed/24321005
Jequier Gygax M, Klein BD, White HS, Kim M, Galanopoulou AS. Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms. Epilepsy Res (2014) 108: 98-108.http://www.ncbi.nlm.nih.gov/pubmed/24252685
Brooks-Kayal AR, Bath KG, Berg AT, Galanopoulou AS,Holmes GL, Jensen FE, Kanner AM, O'Brien TJ, Whittemore VH, Winawer MR, Patel M, Scharfman HE. Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia (2013) 54 (Suppl 4): 44-60. http://www.ncbi.nlm.nih.gov/pubmed/23909853
Pitkänen A, Nehlig A, Brooks-Kayal AR, Dudek FE, Friedman D, Galanopoulou AS, Jensen FE, Kaminski RM, Kapur J, Klitgaard H, Löscher W, Mody I, Schmidt D. Issues related to development of antiepileptogenic therapies. Epilepsia (2013) 54 (Suppl 4): 35-43. http://www.ncbi.nlm.nih.gov/pubmed/23909852
Galanopoulou AS, Kokaia M, Loeb JA, Nehlig A, Pitkänen A, Rogawski MA, Staley KJ, Whittemore VH, Dudek FE. Epilepsy therapy development: technical and methodologic issues in studies with animal models. Epilepsia (2013) 54 (Suppl 4): 13-23.http://www.ncbi.nlm.nih.gov/pubmed/23909850
Galanopoulou AS, Simonato M, French JA, O'Brien TJ. Joint AES/ILAE translational workshop to optimize preclinical epilepsy research. Epilepsia (2013) 54 (Suppl 4) : 1-2. http://www.ncbi.nlm.nih.gov/pubmed/23909848
Galanopoulou AS. Basic mechanisms of catastrophic epilepsy - Overview from animal models. Brain & Development 2013 (in press). http://www.ncbi.nlm.nih.gov/pubmed/23312951
Galanopoulou AS, Simonato M, French JA, O’Brien TJ. “Joint AES / ILAE Translational Workshop to Optimize Preclinical Epilepsy Research”. Epilepsia (2013) 54 (Suppl. 4): 1-2.
Galanopoulou AS, Kokaia M, Loeb JA, Nehlig A, Pitkanen A, Rogawski MA, Staley KJ, Whittemore VH, Dudek EF. “Epilepsy therapy development: technical and methodological issues in studies with animal models.” Epilepsia (2013) 54 (Suppl. 4): 13-23.
Brooks-Kayal A, Bath KG, Berg AT, Galanopoulou AS, Holmes GL, Jensen FE, Kanner AM, O’Brien TJ, Whittemore VH, Winawer MR, Patel M, Scharfman HE. “Issues related to symptomatic and disease modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy.” Epilepsia (2013) 54 (Suppl. 4): 44-60.
Pitkanen A, Nehlig A, Brooks-Kayal A, Dudek FE, Friedman D, Galanopoulou AS, Jensen FE, Kaminski RM, Kapur J, Klitgaard H, Löscher W, Mody I, Schmidt D. “Issues related to development of antiepileptogenic therapies.” Epilepsia (2013) 54 (Suppl. 4): 35-43.
Simonato M, French JA, Galanopoulou AS, O’Brien TJ: “Issues for new antiepilepsy drug development” (2013) Curr Opin Neurol 26: 195-200. http://www.ncbi.nlm.nih.gov/pubmed/23406913
Galanopoulou AS, Gorter JA, Cepeda C; Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 2012; 53(7): 1119-30. http://www.ncbi.nlm.nih.gov/pubmed/22578218
Galanopoulou AS, Buckmaster PS, Staley KJ, Moshé SL, Perucca E, Engel J Jr, Löscher W, Noebels JL, Pitkänen A, Stables J, White HS, O'Brien TJ, Simonato M; American Epilepsy Society Basic Science Committee And The International League Against Epilepsy Working Group On Recommendations For Preclinical Epilepsy Drug Discovery: Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 2012; 53(3): 571-82. http://www.ncbi.nlm.nih.gov/pubmed/22292566
Galanopoulou AS, Moshé SL (2011). In search of biomarkers in the immature brain: goals, challenges, strategies. Future Medicine 5(5): 615-628. http://www.ncbi.nlm.nih.gov/pubmed/22003910
Ono T, Moshé SL, Galanopoulou AS.: Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms. Epilepsia 2011; 52(9): 1678-84. http://www.ncbi.nlm.nih.gov/pubmed/21770922
Briggs SW, Galanopoulou AS: “Altered GABA signaling in early life epilepsies” Neural Plasticity 2011: 527605 (2011). http://www.ncbi.nlm.nih.gov/pubmed/21826277
Raffo E, Coppola A, Ono T, Briggs SW, Galanopoulou AS: A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol. Dis. 2011; 43(2): 322-9. http://www.ncbi.nlm.nih.gov/pubmed/21504792
Chudomelova L., Scantlebury MH, Raffo E, Coppola A, Betancourth D, Galanopoulou AS. Modeling new therapies for infantile spasms. Epilepsia: 2010; 51(Suppl. 3):27-33. http://www.ncbi.nlm.nih.gov/pubmed/20618396
Galanopoulou AS: “Mutations affecting GABAergic signaling in seizures and epilepsy”: Pflugers Arch 460(2): 505-23: (2010). http://www.ncbi.nlm.nih.gov/pubmed/20352446
Chudomel O, Herman H, Nair K, Moshé SL, Galanopoulou AS. Age- and gender-related differences in GABA(A) receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat. Neuroscience: 2009; 163(1): 155-67. http://www.ncbi.nlm.nih.gov/pubmed/19531372
Galanopoulou AS. Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABAA receptors. J Neurosci. 2008; vol 28 (7): 1557-67. http://www.ncbi.nlm.nih.gov/pubmed/18272677
Galanopoulou AS: Sexually Dimorphic expression of KCC2 and GABA function. Epilepsy Res. 2008; 80(2-3):99-113. http://www.ncbi.nlm.nih.gov/pubmed/18524541
Galanopoulou AS. Sex and cell type specific patterns of GABA(A) receptor and estradiol mediated signaling in the immature rat substantia nigra. Eur J Neurosci 23(9):2423-30 (2006). http://www.ncbi.nlm.nih.gov/pubmed/16706849
Kyrozis, A, Chudomel, O, Moshé SL, Galanopoulou AS. Sex-dependent maturation of GABA(A) receptor mediated synaptic events in rat substantia nigra reticulata. Neurosci Lett 398(1-2):1-5 (2006). http://www.ncbi.nlm.nih.gov/pubmed/16540244
Galanopoulou AS, Kyrozis A, Claudio OI, Stanton PK, Moshé SL (2003). “Sex-specific KCC2 expression and GABAA receptor function in rat substantia nigra” Exp Neurol, 183: 628-637, (2003). http://www.ncbi.nlm.nih.gov/pubmed/14552904
Galanopoulou AS, Moshé SL: “Role of sex hormones in the sexually dimorphic expression of KCC2 in rat substantia nigra” Exp Neurol, 184(2): 1003-1009, (2003). http://www.ncbi.nlm.nih.gov/pubmed/14769394
More Information About Dr. Aristea Galanopoulou
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Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South , Room 306
Bronx, NY 10461