Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

Journal of Neuroscience - Tập 24 Số 18 - Trang 4412-4420 - 2004
Pamela L. Follett1, Wenbin Deng2, Weimin Dai2, Delia M. Talos2, Leon J. Massillon2, Paul A. Rosenberg2, Joseph J. Volpe2, Frances E. Jensen2
1Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
2Harvard University

Tóm tắt

Periventricular leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insultin vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes eitherin vivoorin vitro. Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.

Từ khóa


Tài liệu tham khảo

10.1016/0165-3806(91)90214-4

1998, J Neurosci, 18, 6241, 10.1523/JNEUROSCI.18-16-06241.1998

2001, J Neurosci, 21, 1302, 10.1523/JNEUROSCI.21-04-01302.2001

2002, J Neurosci, 22, 455, 10.1523/JNEUROSCI.22-02-00455.2002

10.1111/j.1471-4159.1984.tb05396.x

10.1126/science.1317970

10.1002/neu.480230915

10.1097/00007691-200110000-00006

Crawley JN (2000) What's wrong with my mouse? Behavioral phenotyping of transgenic and knock-out mice. New York: Wiley.

10.1038/sj.bjp.0703993

10.1177/088307388900400408

10.1073/pnas.1136624100

2000, Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop, 20, 34

2000, J Neurosci, 20, 9235, 10.1523/JNEUROSCI.20-24-09235.2000

10.1016/S0165-6147(00)01494-2

10.1002/glia.440110204

1996, J Neurosci, 16, 2659, 10.1523/JNEUROSCI.16-08-02659.1996

10.1016/0896-6273(90)90216-3

2000, Epilepsia, 41, S10

10.1002/ana.410020108

10.1097/00005072-199705000-00002

2003, J Neurosci, 23, 7069, 10.1523/JNEUROSCI.23-18-07069.2003

10.1001/archpedi.154.7.725

1992, Dev Pharmacol Exp Ther, 18, 139, 10.1159/000480613

10.1159/000056616

10.1016/0887-8994(95)00192-1

10.1126/science.1058827

10.1002/1531-8249(199911)46:5<755::AID-ANA11>3.0.CO;2-0

10.1046/j.1471-4159.2002.00866.x

10.1016/S1071-9091(98)80033-8

10.1002/ana.1122

10.1046/j.1471-4159.2002.00981.x

10.1038/35016083

10.1097/00007691-200206000-00007

10.1002/ana.410410611

1996, Exp Brain Res, 110, 367

10.1016/S0022-3476(05)80664-X

10.1016/0896-6273(94)90277-1

10.1001/jama.284.15.1939

10.1016/0896-6273(91)90302-G

Rorke LB (1998) Pathology of perinatal brain injury. New York: Raven.

10.1002/jnr.10472

2001, J Neurosci, 21, 8154, 10.1523/JNEUROSCI.21-20-08154.2001

1998, Can J Neurol Sci, 25, 3

2000, Epilepsia, 41, S3, 10.1111/j.1528-1157.2000.tb02163.x

2000, Epilepsia, 41, S45, 10.1111/j.1528-1157.2000.tb02171.x

1997, Neuropediatrics, 28, 149, 10.1055/s-2007-973692

2001, J Neurosci, 21, 4237, 10.1523/JNEUROSCI.21-12-04237.2001

10.1016/S0006-8993(01)03311-X

Volpe JJ (2001) Neurology of the newborn. Philadelphia: W. B. Saunders.

1992, J Biol Chem, 267, 501, 10.1016/S0021-9258(18)48523-7

1997, Epilepsia, 38, S9

10.1016/S0920-1211(97)00045-4

10.1016/S0301-7516(99)00040-X

10.1016/S0006-8993(99)02359-8

1998, Development, 125, 2901, 10.1242/dev.125.15.2901

Thông tin
Thông tin xuất bản

Journal of Neuroscience

Tập 24 Số 18

4412-4420

Thông tin tác giả