H. STEVE WHITE
e-mail: steve.white@hsc.utah.edu |
Professor of Pharmacology and Toxicology Neurobiology of Disease Molecular Neuroscience |
RESEARCH:
Neuropharmacology; anticonvulsant drug mechanisms; genetics of audiogenic seizures
Dr. White is the principal investigator and scientific director of the NIH-sponsored Anticonvulsant Drug Development Program that was established in 1975 to identify novel anticonvulsant drugs using established animal seizure and epilepsy models. Over the years, the efforts of this program have contributed to the successful development of nine new antiepileptic drugs for the treatment of refractory partial epilepsy. Dr. White's research is focused on understanding the factors which contribute to the initiation, propagation, and amelioration of seizure activity. Dr. White's laboratory utilizes a variety of in vivo and in vitro model systems to identify and characterize the anticonvulsant profile and potential mechanism of action of established and new antiepileptic drugs. In addition, ongoing investigations in Dr. White's laboratory are focused on understanding the pathophysiology and genetics of sound-induced seizures in the audiogenic seizure-susceptible Frings mouse and the influence of genetics on seizure-susceptibility and antiepileptic drug pharmacology. In addition to their efforts at identifying new therapies for the symptomatic treatment of partial epilepsy, Dr. White's laboratory is conducting research that may aid in the identification of disease modifying therapies that halt, slow, or prevent the development of epilepsy in susceptible individuals. To this end, work in Dr. White's laboratory has focused on the development of models of therapy resistant epilepsy and models of acquired and genetic epilepsy that can be utilized for new therapy development.
Students working in Dr. White's laboratory have multiple opportunities to contribute to a broad-based research program aimed at gaining a further understanding of the factors that contribute to the expression and prevention of seizure activity. The results obtained from these investigations are likely to lead to the design and development of more efficacious and less toxic therapies for the prevention and treatment of epilepsy.
Selected Publications:
Green, B.R., White, K.L., McDougle, D.R., Zhang, L., Klein, B., Scholl, E.A., Pruess, T.H., White, H.S., and Bulaj, G. (2010) Introduction of lipidization-cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities. J Pept Sci, 2010, Jul 19. PubMed ID: 20645434
Libbey, J.E., Kirkman, N.J., Wilcox, K.S., White, H.S., and Fujinami, R.S. (2010) Role for complement in the development of seizures following acute viral infection. J Virol, Jul; 84(13):6452-6460, Apr 2010.
Robertson, C.R., Scholl, E.A., Pruess, T.H., Green, B.R., White, H.S., and Bulaj, G. (2010) Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and dxhibit anticonvulsant activity following systemic delivery. J. Med. Chem., (in press).
Bialer, M., and White, H.S. (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat. Rev. Drug Discov., 9(1):68-82.
Kirkman, N.J.*, Libbey, J.E.*, Wilcox, K.S., White, H.S., and Fujinami, R.S. (2010) Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia, 51(3)454-464. * equal contribution Cover art.
Stewart, K.-A.A., Wilcox, K.S., Fujinami, R.S., and White, H.S. Theiler's virus infection chronically alters seizure susceptibility. Epilepsia, epub ahead of print (12-1-09).
Madsen, K.K., White, H.S., and Schousboe, A. (2010) Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther, Mar;125(3):394-401. Epub 2009 Dec 22. PMID: 20026354
Bialer, M., and White, H.S. (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov, 9(1):68-82.
Lee, H.K., Smith, M.D., Smith, B.J., Grussendorf, J., Xu, L., Gillies, R.J., White, H.S., and Bulaj, G. (2009) Anticonvulsant Met-enkephalin analogues containing backbone spacers reveal alternative non-opioid signaling in the brain. ACS Chem. Biol., 4(8):659-671.
Singh, N.A., Pappas, C., Dahle, E.J., Claes, L.R., Pruess, T.H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H.S., Filloux, F., and Leppert, M.F. (2009) A role of SCH9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet, 5(9): e1000649.
Singh, N.A., Otto, J.F., Jill Dahle, E., Pappas, C., Leslie, J.D., Vilaythong, A., Noebels, J.L., White, H.S., Wilcox, K.S., and Leppert, M.F. (2008) Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. J Physiol., Jul 15;586(Pt 14):3405-3423. Epub 2008 May 15.
Libbey, J.E., Kirkman, N.J., Smith, M.C., Tanaka, T., Wilcox, K.S., White, H.S., and Fujinami, R.S. (2008) Seizures following picornavirus infection. Epilepsia, Jun;49(6):1066-74. Epub 2008 Mar 6. PMID: 18325012 [PubMed - indexed for MEDLINE]
Stohr, T., Kupferberg, H.J., Stables, J.P., Choi, D., Harris, R.H., Kohn, H., Walton, N., and White, H.S. (2007) Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy. Epilepsy Res., May;74(2-3):147-54. Epub 2007 Apr 12.
White, H.S., Smith, M.D., and Wilcox, K.S. (2007) Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol., 81:85-110. Review.
Sobol, E., Yagen, B., Lamb, J.G., White, H.S., Wlodarczyk, B.J., Finnell, R.H., and Bialer, M. (2007) Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug,N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide. Epilepsy Res., Jan;73(1):75-84. Epub 2006 Sep 25.
Smith, M., Wilcox, K.S., and White, H.S. (2007) Discovery of antiepileptic drugs. Neurotherapeutics, Jan;4(1):12-7. Review.
Simeone, T.A., Otto, J.F., Wilcox, K.S., and White, H.S. (2006) Felbamate is a subunit selective modulator of recombinant gamma-aminobutyric acid type A receptors expressed in Xenopus oocytes. Eur J Pharmacol., Dec 15;552(1-3):31-5. Epub 2006 Sep 16.
White, H.S. (2005) Molecular pharmacology of topiramate: managing seizures and preventing migraine. Headache, Apr;45 Suppl 1:S48-56.
Layer, R.T., Wagstaff, J.D., and White, H.S. (2004) Conantokins: peptide antagonists of NMDA receptors. Curr Med Chem.,Dec;11(23):3073-3084. Review.
Klein, B.D., Fu, Y-H., Ptacek, L.J., and White, H.S. (2004) c-Fos immunohistochemical mapping of the audiogenic seizure network and tonotopic neuronal hyperexcitability in the inferior colliculus of the Frings mouse. Epilepsy Res., 62:13-25.
Schousboe, A., Sarup, A., Larsson, O.M., and White, H.S. (2004) GABA transporters as drug targets for modulation of GABAergic activity. Biochem. Pharmacol., 68:1557-1563.
Schousboe, A., Larsson, O.M., Sarup, A., and White, H.S. (2004) Role of the betaine/GABA transporter (BGT-1/GAT2) for the control of epilepsy. Eur. J. Pharmacol., 500:281-287.
Bialer, M., Twyman, R.E., and White, H.S. (2004) Correlation analysis between anticonvulsant ED50 values of antiepileptic drugs in mice and rats and their therapeutic doses and plasma levels. Epilepsy & Behavior, 5:866-872.
Yang, Y., Beyer, B.M., Otto, J.F., O'Brien, T.P., Letts, V.A., White, H.S., and Frankel, W.N. (2003) Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold. Hum. Mol. Genet., 12(9):975-984.
White, H.S. (2002) Animal models of epileptogenesis. Neurology, 59:S7-S14.
White, H.S., Sarup, A., Bolvig, T., Kristensen, A.S., Petersen, G., Nelson, N., Pickering, D.S., Larsson, O.M., Frolund, B., Krogsgaard-Larsen, P., and Schousboe, A. (2002) Correlation between anticonvulsant activity and inhibitory action on glial GABA uptake of the highly selective mouse GAT1 inhibitor 3-hydroxy-r-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and its N-aklylated analogs. J. Pharmacol. Exp. Ther., 302:636-644.
Jimenez, E.C., Donevan, S., Walker, C., Zhou, L-M., Nielsen, J., Cruz, L.J., Armstrong, H., White, H.S., and Olivera, B.M. (2002) Conantokin-L, a new NMDA receptor antagonist: determinants for anticonvulsant potency. Epilepsy Res., 51:73-80.
Walker, M.C., White, H.S., and Sander, J.W.A.S. (2002) Disease modification in partial epilepsy. Brain, 125:1937-1950.
Barton, M.E., Klein, B.D., Wolf, H.H., and White, H.S. (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res., 47:217-227.
Skradski, S.L., Clark, A.M., Jiang, H., White, H.S., Fu, Y-H., and Ptacek, L.J. (2001) A novel gene causing a Mendelian audiogenic mouse epilepsy. Neuron, 31:537-544.
Salvati, P., Maj, R., Caccia, C., Cervini, M.A., Fornaretto, M.G., Lamberti, E., Pevarello, P., Skeen, G.A., White, H.S., Wolf, H.H., Faravelli, L., Mazzanti, M., Mancinelli, E., Varasi, M., and Fariello, R.G. (1999) Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J. Pharmacol. Exp. Ther., 288(3):1151-1159.
Rogers, S.W., Gahring, L.C., and White, H.S. (1998) Glutamate receptor GluR1 expression is altered selectively by chronic audiogenic seizures in the Frings mouse brain. J. Neurobiol., 35:209-216.
Skradski, S.L., White, H.S., and Ptacek, L.J. (1998) Genetic mapping of a locus (mass1) causing audiogenic seizures in mice. Genomics, 49:188-192.
White, H.S., Wolf, H.H., Woodhead, J.H., and Kupferberg, H.J. (1998) The National Institutes of Health Anticonvulsant Drug Development Program: screening for efficacy. In: Antiepileptic Drug Development. Advances in Neurology, Vol. 76, edited by J. French, I. Leppik, and M. A. Dichter, pp. 29-39, Lippincott-Raven Publishers, Philadelphia.
Carter, R.B., Wood, P.L., Wieland, S., Hawkinson, J.E., Belelli, D., Lambert, J.J., Mirsadeghi, S., Tahir, H., Bolger, M.B., Lan, N.C., White, H.S., Wolf, H.H., and Gee, K.W. (1997) Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3a-hydroxy-3b-methyl-5a-gregnan-20-one), a selective high-affinity neurosteroid modulator of the GABAA receptor. JPET, 280:1284-1295.
Gahring, L.C., White, H.S., Skradski, S.L., Carlson, N.G., and Rogers, S.W. (1997) Interleukin-1a in the brain is induced by audiogenic seizure. Neurobiol. Disease, 3(4):263-269.
White, H.S. (1997) Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia, 38(Suppl.):S9-S17.
White. H.S. (1997) Mechanisms of Antiepileptic Drugs. In Epilepsies II, edited by R. Porter and D. Chadwick, Butterworth-Heinemann Publ., Boston, MA. pp. 1-30.
Rostock, A., Tober, C., Rundfeldt, C., Bartsch, R., Engel, J., Polymeropoulos, E.E., Kutscher, B., Loscher, W., Honack, D., White, H.S., and Wolf, H.H. (1996) D-2319: A new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res., 23(3):211-223.
