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White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors
Intellectual 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
University Center for Biological and Agricultural Sciences, University of Guadalajara, Guadalajara 44100, Mexico
French Institute of Health and Medical Research (INSERM), U676, Robert Debré Hospital, Paris 75019, France
* Authors to whom correspondence should be addressed.
Received: 8 August 2013; in revised form: 15 October 2013 / Accepted: 28 October 2013 / Published: 12 November 2013
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.
Keywords: premature birth; excitotoxicity; periventricular leukomalacia; white matter regeneration and repair; central nervous system repair; transferrin; insulin and IGF-1.
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Espinosa-Jeffrey, A.; Barajas, S.A.R.; Arrazola, A.R.; Taniguchi, A.; Zhao, P.M.; Bokhoor, P.; Holley, S.M.; Dejarme, D.P.; Chu, B.; Cepeda, C.; Levine, M.S.; Gressens, P.; Feria-Velasco, A.; de Vellis, J. White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors. Brain Sci. 2013, 3, 1461-1482.
Espinosa-Jeffrey A, Barajas SAR, Arrazola AR, Taniguchi A, Zhao PM, Bokhoor P, Holley SM, Dejarme DP, Chu B, Cepeda C, Levine MS, Gressens P, Feria-Velasco A, de Vellis J. White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors. Brain Sciences. 2013; 3(4):1461-1482.
Espinosa-Jeffrey, Araceli; Barajas, Socorro A.R.; Arrazola, Alfonso R.; Taniguchi, Alana; Zhao, Paul M.; Bokhoor, Payam; Holley, Sandra M.; Dejarme, Don P.; Chu, Brian; Cepeda, Carlos; Levine, Michael S.; Gressens, Pierre; Feria-Velasco, Alfredo; de Vellis, Jean. 2013. "White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors." Brain Sci. 3, no. 4: 1461-1482.