White matter loss in a mouse model of periventricular leukomalacia is rescued by trophic factors
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Updated: Apr 27, 2026
Mouse Models of Periventricular Leukomalacia
Published on: May 18, 2010
Araceli Espinosa-Jeffrey1, Socorro A R Barajas2, Alfonso R Arrazola3
1Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. aespinosa@mednet.ucla.edu.
Abstract:
Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.
Insights
Transferrin and insulin growth factors (TSC1) promote oligodendrocyte regeneration and neuroprotection, offering a potential treatment for white matter loss caused by excitotoxicity, a key factor in cerebral palsy.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Developmental Neuroscience
Background:
- Periventricular leukomalacia (PVL) is a leading cause of cerebral palsy and intellectual disabilities, characterized by glutamate excitotoxicity, abnormal oligodendrocytes, and myelin deficiency.
- Current treatments for PVL are lacking, highlighting the urgent need for therapeutic strategies targeting white matter damage.
Purpose of the Study:
- To investigate the neuroprotective and regenerative effects of a combination of transferrin and insulin growth factors (TSC1) on white matter lesions induced by N-methyl-d-aspartate (NMDA).
- To evaluate TSC1's impact on oligodendrocyte progenitor cell (OPC) survival, proliferation, and neuroprotection in a rodent model of PVL.
Main Methods:
- Induction of periventricular white matter lesions using intracerebral injection of NMDA in a rodent model.
- Administration of TSC1 concurrently with NMDA to assess its effects on OPCs and neuroprotection.
- Quantification of OPC survival and proliferation via Olig2-mRNA expression.
- Assessment of neuroprotection in striatal slices by measuring NMDA-induced currents in medium-sized spiny neurons.
Main Results:
- NMDA injection reduced OPC survival and migration, while co-administration of TSC1 significantly increased OPC proliferation and survival rates (from 52% to 78%).
- TSC1 treatment led to a reduction in ventricular size, indicating a mitigation of ventriculomegaly associated with PVL.
- In vitro, TSC1 demonstrated neuroprotective effects by reducing NMDA-induced inward currents in medium-sized spiny neurons.
Conclusions:
- The combination of transferrin and insulin growth factors (TSC1) can partially rescue white matter loss by promoting OPC regeneration and providing neuroprotection against excitotoxicity.
- Early administration of TSC1 maximizes its neuroprotective benefits, suggesting its potential as a therapeutic agent for conditions like PVL.
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