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

Espinosa-Jeffrey A, Barajas SA, 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 - Brain Sci (2013)

Bottom Line: In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly.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).

View Article: PubMed Central - PubMed

Affiliation: 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. 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.

No MeSH data available.


Related in: MedlinePlus

Myelination is partially rescued from excitotoxicity by TSC1. Representative para-sagittal brain sections (28 μm thick) stained with the Spielmeyer’s method for frozen sections. These views show (A) the myelination pattern with saline treatment 40 days post-injection (PI). The extent of tissue damage, ventricle enlargement, and myelin loss in mice treated with NMDA (B) and its recovery with TSC1 (C) treatment. Moreover, NMDA treated mice showed areas where tissue was spared in the CC and CPu but there was not myelin staining. In contrast, mice treated with TSC1 showed nice myelinated fibers indicating that after the excitotoxic insult functional OLs developed and actively myelinated axons. The arrow points to a bundle of myelinated axons in the CPu of a mouse treated with NMDA + TSC1 simultaneously. In contrast, the same region of mice injected with NMDA alone did not show myelinated axons. The variability within each treatment group, consisting of 6 animals, was minimal based on low magnification examination as shown in Figure 4.
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brainsci-03-01461-f004: Myelination is partially rescued from excitotoxicity by TSC1. Representative para-sagittal brain sections (28 μm thick) stained with the Spielmeyer’s method for frozen sections. These views show (A) the myelination pattern with saline treatment 40 days post-injection (PI). The extent of tissue damage, ventricle enlargement, and myelin loss in mice treated with NMDA (B) and its recovery with TSC1 (C) treatment. Moreover, NMDA treated mice showed areas where tissue was spared in the CC and CPu but there was not myelin staining. In contrast, mice treated with TSC1 showed nice myelinated fibers indicating that after the excitotoxic insult functional OLs developed and actively myelinated axons. The arrow points to a bundle of myelinated axons in the CPu of a mouse treated with NMDA + TSC1 simultaneously. In contrast, the same region of mice injected with NMDA alone did not show myelinated axons. The variability within each treatment group, consisting of 6 animals, was minimal based on low magnification examination as shown in Figure 4.

Mentions: The aim of this study was to determine at a qualitative level whether myelination could be restored after an excitotoxic insult using TSC1. Thirty-five days after treatment, we examined parasagittal brain sections obtained from mice receiving the various treatments. The Spielmeyer’s myelin staining method was used. We observed that, similar to the ILV of mice injected with NMDA alone or with NMDA + TSC1, the third ventricle was also enlarged. However, the proportion of enlargement was reduced in the presence of TSC1, whether injected simultaneously or after a 3-day delay. In mice treated with NMDA alone some regions where tissue was spared appeared devoid of myelin. In contrast, mice treated with NMDA + TSC1 showed more myelinated fibers in the CC and the striatum demonstrating the extensive neuroprotective effect of TSC1 (Figure 4).


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

Espinosa-Jeffrey A, Barajas SA, 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 - Brain Sci (2013)

Myelination is partially rescued from excitotoxicity by TSC1. Representative para-sagittal brain sections (28 μm thick) stained with the Spielmeyer’s method for frozen sections. These views show (A) the myelination pattern with saline treatment 40 days post-injection (PI). The extent of tissue damage, ventricle enlargement, and myelin loss in mice treated with NMDA (B) and its recovery with TSC1 (C) treatment. Moreover, NMDA treated mice showed areas where tissue was spared in the CC and CPu but there was not myelin staining. In contrast, mice treated with TSC1 showed nice myelinated fibers indicating that after the excitotoxic insult functional OLs developed and actively myelinated axons. The arrow points to a bundle of myelinated axons in the CPu of a mouse treated with NMDA + TSC1 simultaneously. In contrast, the same region of mice injected with NMDA alone did not show myelinated axons. The variability within each treatment group, consisting of 6 animals, was minimal based on low magnification examination as shown in Figure 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061895&req=5

brainsci-03-01461-f004: Myelination is partially rescued from excitotoxicity by TSC1. Representative para-sagittal brain sections (28 μm thick) stained with the Spielmeyer’s method for frozen sections. These views show (A) the myelination pattern with saline treatment 40 days post-injection (PI). The extent of tissue damage, ventricle enlargement, and myelin loss in mice treated with NMDA (B) and its recovery with TSC1 (C) treatment. Moreover, NMDA treated mice showed areas where tissue was spared in the CC and CPu but there was not myelin staining. In contrast, mice treated with TSC1 showed nice myelinated fibers indicating that after the excitotoxic insult functional OLs developed and actively myelinated axons. The arrow points to a bundle of myelinated axons in the CPu of a mouse treated with NMDA + TSC1 simultaneously. In contrast, the same region of mice injected with NMDA alone did not show myelinated axons. The variability within each treatment group, consisting of 6 animals, was minimal based on low magnification examination as shown in Figure 4.
Mentions: The aim of this study was to determine at a qualitative level whether myelination could be restored after an excitotoxic insult using TSC1. Thirty-five days after treatment, we examined parasagittal brain sections obtained from mice receiving the various treatments. The Spielmeyer’s myelin staining method was used. We observed that, similar to the ILV of mice injected with NMDA alone or with NMDA + TSC1, the third ventricle was also enlarged. However, the proportion of enlargement was reduced in the presence of TSC1, whether injected simultaneously or after a 3-day delay. In mice treated with NMDA alone some regions where tissue was spared appeared devoid of myelin. In contrast, mice treated with NMDA + TSC1 showed more myelinated fibers in the CC and the striatum demonstrating the extensive neuroprotective effect of TSC1 (Figure 4).

Bottom Line: In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly.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).

View Article: PubMed Central - PubMed

Affiliation: 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. 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.

No MeSH data available.


Related in: MedlinePlus