White matter loss in a mouse model of periventricular leukomalacia is rescued by trophic factors.

Araceli Espinosa-Jeffrey,Paul Zhao,Jean De Vellis,Socorro Barajas,Michael Levine,Alfonso Arrazola,Pierre Gressens,Carlos Cepeda,Don Dejarme,Brian Chu,Sandra Holley,Payam Bokhoor,Alfredo Feria-Velasco,Alana Taniguchi

doi:10.3390/brainsci3041461

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.

Highlights

Myelin is the essential fatty membrane that provides insulation to nerve fibers in the brain and spinal cord
Using run-off transcription, we showed that Tf up-regulates the transcription of the myelin basic protein (MBP) gene [21] and that it synergizes with insulin growth factor-1 (IGF-1) increasing myelination
Considering the adverse events leading to lifelong disabilities in the brain of premature neonates, in the present study, we investigated the potential preclinical therapeutic use of TSC1 to reduce excitotoxic injury and preserve the integrity of motor pathways in a model of Periventricular leukomalacia (PVL) induced by intracerebral NMDA injection

Summary

Introduction

Myelin is the essential fatty membrane that provides insulation to nerve fibers in the brain and spinal cord. Myelin ensures the normal and adequate transmission of electrical signals from the brain or spinal cord to specific parts of the body and vice versa. Sensory and integrative functions depend on the rapid, seamless conduction of nerve impulses along these myelinated nerve fibers [1]. Oligodendrocytes (OLs) are cells that form and maintain myelin throughout life. The cells are generated during perinatal life, and immature OLs are vulnerable to insults, such as lack of oxygen. Treatments for myelin disorders are limited to reducing the inflammatory responses induced by hypoxia or glutamate toxicity and alleviating the symptoms, but little repair and gain-of-function are achieved. OL maturation occurs perinatally, and immature OLs are vulnerable

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