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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: 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).Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection.Furthermore, we showed that early TSC1 administration maximizes neuroprotection.

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

Acute NMDA elicits the expression of HSP-90 in the CPu and TSC1 neutralizes the NMDA effect. Views of the CPu of 300 μm coronal slices used for the acute treatment of NMDA alone or in slices pre-incubated with TSC1. After electrophysiology, slices were fixed and immunolabeled for the cell stress marker HSP-90 and the OL marker CNPase. HSP-90 was expressed in some cells located in the CPu white matter. Non-treated slices (A–D) displayed nestin-expressing cells that were negative for HSP-90 (B–empty circle). Slices directly exposed to NMDA (E–H); showed colocalization of nestin and HSP-90 (E,F) and few cells co-express the three markers (open arrows). CNP-expressing cells lost processes or expression of CNPase in their processes. Slices incubated with TSC1 prior to NMDA. TSC1 appeared to maintain the tissue in a mild stage of stress with fewer nestin-expressing cells co-expressing HSP-90 (panel I) and increased number of CNPase-positive OL (K). Arrowheads show cells co-expressing HSP-90 and CNPase (K). Insets show detail of the label distribution of the cell marked with arrowheads, the merged view allows for the visualization of HSP-90 in the cell soma while CNPase is distributed in the cell body and numerous cell processes (L). K-inset shows a healthy OL that did not express HSP-90 (I-circle).
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brainsci-03-01461-f007: Acute NMDA elicits the expression of HSP-90 in the CPu and TSC1 neutralizes the NMDA effect. Views of the CPu of 300 μm coronal slices used for the acute treatment of NMDA alone or in slices pre-incubated with TSC1. After electrophysiology, slices were fixed and immunolabeled for the cell stress marker HSP-90 and the OL marker CNPase. HSP-90 was expressed in some cells located in the CPu white matter. Non-treated slices (A–D) displayed nestin-expressing cells that were negative for HSP-90 (B–empty circle). Slices directly exposed to NMDA (E–H); showed colocalization of nestin and HSP-90 (E,F) and few cells co-express the three markers (open arrows). CNP-expressing cells lost processes or expression of CNPase in their processes. Slices incubated with TSC1 prior to NMDA. TSC1 appeared to maintain the tissue in a mild stage of stress with fewer nestin-expressing cells co-expressing HSP-90 (panel I) and increased number of CNPase-positive OL (K). Arrowheads show cells co-expressing HSP-90 and CNPase (K). Insets show detail of the label distribution of the cell marked with arrowheads, the merged view allows for the visualization of HSP-90 in the cell soma while CNPase is distributed in the cell body and numerous cell processes (L). K-inset shows a healthy OL that did not express HSP-90 (I-circle).

Mentions: After electrophysiology, coronal brain slices (300 μm thickness) were fixed and examined by double immunofluorescence for the cell stress marker HSP-90 and cyclic nucleotide 3′-phosphohydrolase (CNPase), an oligodendrocyte marker. The double staining showed that HSP-90 was not expressed in non-treated slices. In contrast, HSP-90 was expressed as “puncta” mainly along myelin tracks. Some OLs recognized by CNPase co-expressed HSP-90 in NMDA treated slices. Slices pre-incubated in TSC1 had HSP-90 expressing cells that co-expressed CNPase, but the myelin tracks were not labeled by the stress protein, suggesting neuroprotection through TSC1 (Figure 7).


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)

Acute NMDA elicits the expression of HSP-90 in the CPu and TSC1 neutralizes the NMDA effect. Views of the CPu of 300 μm coronal slices used for the acute treatment of NMDA alone or in slices pre-incubated with TSC1. After electrophysiology, slices were fixed and immunolabeled for the cell stress marker HSP-90 and the OL marker CNPase. HSP-90 was expressed in some cells located in the CPu white matter. Non-treated slices (A–D) displayed nestin-expressing cells that were negative for HSP-90 (B–empty circle). Slices directly exposed to NMDA (E–H); showed colocalization of nestin and HSP-90 (E,F) and few cells co-express the three markers (open arrows). CNP-expressing cells lost processes or expression of CNPase in their processes. Slices incubated with TSC1 prior to NMDA. TSC1 appeared to maintain the tissue in a mild stage of stress with fewer nestin-expressing cells co-expressing HSP-90 (panel I) and increased number of CNPase-positive OL (K). Arrowheads show cells co-expressing HSP-90 and CNPase (K). Insets show detail of the label distribution of the cell marked with arrowheads, the merged view allows for the visualization of HSP-90 in the cell soma while CNPase is distributed in the cell body and numerous cell processes (L). K-inset shows a healthy OL that did not express HSP-90 (I-circle).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

brainsci-03-01461-f007: Acute NMDA elicits the expression of HSP-90 in the CPu and TSC1 neutralizes the NMDA effect. Views of the CPu of 300 μm coronal slices used for the acute treatment of NMDA alone or in slices pre-incubated with TSC1. After electrophysiology, slices were fixed and immunolabeled for the cell stress marker HSP-90 and the OL marker CNPase. HSP-90 was expressed in some cells located in the CPu white matter. Non-treated slices (A–D) displayed nestin-expressing cells that were negative for HSP-90 (B–empty circle). Slices directly exposed to NMDA (E–H); showed colocalization of nestin and HSP-90 (E,F) and few cells co-express the three markers (open arrows). CNP-expressing cells lost processes or expression of CNPase in their processes. Slices incubated with TSC1 prior to NMDA. TSC1 appeared to maintain the tissue in a mild stage of stress with fewer nestin-expressing cells co-expressing HSP-90 (panel I) and increased number of CNPase-positive OL (K). Arrowheads show cells co-expressing HSP-90 and CNPase (K). Insets show detail of the label distribution of the cell marked with arrowheads, the merged view allows for the visualization of HSP-90 in the cell soma while CNPase is distributed in the cell body and numerous cell processes (L). K-inset shows a healthy OL that did not express HSP-90 (I-circle).
Mentions: After electrophysiology, coronal brain slices (300 μm thickness) were fixed and examined by double immunofluorescence for the cell stress marker HSP-90 and cyclic nucleotide 3′-phosphohydrolase (CNPase), an oligodendrocyte marker. The double staining showed that HSP-90 was not expressed in non-treated slices. In contrast, HSP-90 was expressed as “puncta” mainly along myelin tracks. Some OLs recognized by CNPase co-expressed HSP-90 in NMDA treated slices. Slices pre-incubated in TSC1 had HSP-90 expressing cells that co-expressed CNPase, but the myelin tracks were not labeled by the stress protein, suggesting neuroprotection through TSC1 (Figure 7).

Bottom Line: 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).Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection.Furthermore, we showed that early TSC1 administration maximizes neuroprotection.

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