Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate
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Updated: Aug 24, 2026
Mouse Models of Periventricular Leukomalacia
Published on: May 18, 2010
Pamela L Follett1, Wenbin Deng, Weimin Dai
1Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Insights
Topiramate protects against periventricular leukomalacia, a white matter brain injury in premature infants. This drug blocks glutamate excitotoxicity, reducing cell death and neuromotor deficits without harming oligodendrocyte development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Periventricular leukomalacia (PVL) is a major cause of cerebral palsy in premature infants.
- Glutamate excitotoxicity is a key mechanism of hypoxic-ischemic brain injury in developing white matter.
- AMPA-kainate glutamate receptor blockade shows promise in rodent models of PVL.
Purpose of the Study:
- To investigate the therapeutic potential of glutamate receptor blockade for hypoxic-ischemic white matter injury.
- To determine if topiramate, an anticonvulsant, offers protection against PVL.
- To elucidate the mechanism of topiramate's protective effects on developing oligodendrocytes.
Main Methods:
- Examined AMPA receptor expression on human oligodendrocytes from 23-32 weeks gestation.
- Administered topiramate in vivo post-hypoxic-ischemic insult in a rodent model.
- Assessed topiramate's effects on oligodendrocyte cell death, calcium influx, and receptor-mediated currents, comparing it to NBQX.
Main Results:
- AMPA receptors are present on human oligodendrocytes during the critical period for PVL.
- Post-insult topiramate administration protected against white matter injury and reduced neuromotor deficits.
- Topiramate attenuated AMPA-kainate receptor-mediated cell death and calcium influx in oligodendrocytes.
- Protective doses of topiramate and NBQX did not impede normal oligodendrocyte maturation or proliferation.
Conclusions:
- AMPA-kainate receptor blockade is a potential therapeutic strategy for periventricular leukomalacia.
- Topiramate's protective effects are, in part, due to attenuating excitotoxic injury to oligodendrocytes.
- These findings support the translation of glutamate receptor blockade as a treatment for PVL.
Abstract:
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-insult in 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 either in vivo or in 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.
