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Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion.

Ma J, Zhang J, Hou WW, Wu XH, Liao RJ, Chen Y, Wang Z, Zhang XN, Zhang LS, Zhou YD, Chen Z, Hu WW - Sci Rep (2015)

Bottom Line: We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO).In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases.So, early therapeutic time window may be crucial for its application in SIVD.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China [2] Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P. R. China.

ABSTRACT
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

No MeSH data available.


Related in: MedlinePlus

The total oligodendrocytes (Olig2+), OPCs (NG2+) and mature oligodendrocytes (CC1+) after minocycline (mino) D0-3 treatment were calculated as the percentage of the total cells (labeled by DAPI) at 3 days after rUCCAO (B), with the representative photomicrographs in (A) (the cells with arrows or arrowhead were enlarged in insets). Western blot analysis of NG2+, PDGFRα+ and Olig2 was also performed at 3 days after rUCCAO (C). The apoptosis of mature oligodendrocytes was analyzed by TUNEL staining, with representative photomicrographs in (D) and the quantitative analyses in (E and F), which were calculated as the percentage of the total cells (labeled by DAPI). Scale bar: 50 μm in A and 25 μm in C. A, B: n = 6–8; E, F: n = 4. Values are represented as mean ± s.d. ###P < 0.001, vs. the sham group; *P < 0.05, **P < 0.01, ***P < 0.001, vs. the rUCCAO group.
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f4: The total oligodendrocytes (Olig2+), OPCs (NG2+) and mature oligodendrocytes (CC1+) after minocycline (mino) D0-3 treatment were calculated as the percentage of the total cells (labeled by DAPI) at 3 days after rUCCAO (B), with the representative photomicrographs in (A) (the cells with arrows or arrowhead were enlarged in insets). Western blot analysis of NG2+, PDGFRα+ and Olig2 was also performed at 3 days after rUCCAO (C). The apoptosis of mature oligodendrocytes was analyzed by TUNEL staining, with representative photomicrographs in (D) and the quantitative analyses in (E and F), which were calculated as the percentage of the total cells (labeled by DAPI). Scale bar: 50 μm in A and 25 μm in C. A, B: n = 6–8; E, F: n = 4. Values are represented as mean ± s.d. ###P < 0.001, vs. the sham group; *P < 0.05, **P < 0.01, ***P < 0.001, vs. the rUCCAO group.

Mentions: Myelin is made up by oligodendrocytes, which progress through a series of maturation steps to become myelinating oligodendrocytes: (1) OPCs, (2) pre-oligodendrocytes (OLs), (3) immature/premyelinating oligodendrocytes, and (4) mature oligodendrocytes2728. We evaluated the oligodendrocyte population on D3 after early treatment of minocycline (Fig. 4A,B). The number of total oligodendrocytes (oligodendrocyte transcription factor2, Olig2 + cells) and OPCs (NG2 chondroitin sulfate proteoglycan, NG2 + cells) was increased on D3 after rUCCAO. Administration of minocycline on D0-3 further increased the number of total oligodendrocytes (P < 0.001) and OPCs (P < 0.001). Minocycline also increased the expression of Olig2, NG2 and platelet-derived growth factor receptor-alpha (PDGFRα, OPC biomarker) on D3 after rUCCAO, which also suggested the increase of the total oligodendrocyte and OPC population following the early treatment of minocycline (Fig. 4C). For mature oligodendrocyte (adenomatous polyposis coli, CC-1 + cells) population, we found that they declined following rUCCAO (P < 0.001), while minocycline treatment increased the number of mature oligodendrocytes (P < 0.001). To explore the protection effect of minocycline on oligodendrocytes, the TdT-mediated dUTP nick end labeling (TUNEL) assay was performed. The number of apoptotic cells in the corpus callosum was markedly increased after rUCCAO, which was partly reversed by minocycline (Fig. 4D,E, P < 0.05). Furthermore, by counting the TUNEL + CC-1 + double positive cells, we found that most of apoptotic cells in the corpus callosum are mature oligodendrocytes (72.7 ± 4.8% of TUNEL + cells), and minocycline had a prominent protection on these cells (Fig. 4D,F, P < 0.01). On the other hand, the number of immature/premyelinating oligodendrocytes (O4 + cells) was decreased after rUCCAO (P < 0.001), and minocycline has no effect on it (Supplementary Fig. S3). Therefore, early treatment of minocycline upregulated the number of OPCs and reduced apoptosis of mature oligodendrocytes, that may account for its protection on the white matter.


Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion.

Ma J, Zhang J, Hou WW, Wu XH, Liao RJ, Chen Y, Wang Z, Zhang XN, Zhang LS, Zhou YD, Chen Z, Hu WW - Sci Rep (2015)

The total oligodendrocytes (Olig2+), OPCs (NG2+) and mature oligodendrocytes (CC1+) after minocycline (mino) D0-3 treatment were calculated as the percentage of the total cells (labeled by DAPI) at 3 days after rUCCAO (B), with the representative photomicrographs in (A) (the cells with arrows or arrowhead were enlarged in insets). Western blot analysis of NG2+, PDGFRα+ and Olig2 was also performed at 3 days after rUCCAO (C). The apoptosis of mature oligodendrocytes was analyzed by TUNEL staining, with representative photomicrographs in (D) and the quantitative analyses in (E and F), which were calculated as the percentage of the total cells (labeled by DAPI). Scale bar: 50 μm in A and 25 μm in C. A, B: n = 6–8; E, F: n = 4. Values are represented as mean ± s.d. ###P < 0.001, vs. the sham group; *P < 0.05, **P < 0.01, ***P < 0.001, vs. the rUCCAO group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4502604&req=5

f4: The total oligodendrocytes (Olig2+), OPCs (NG2+) and mature oligodendrocytes (CC1+) after minocycline (mino) D0-3 treatment were calculated as the percentage of the total cells (labeled by DAPI) at 3 days after rUCCAO (B), with the representative photomicrographs in (A) (the cells with arrows or arrowhead were enlarged in insets). Western blot analysis of NG2+, PDGFRα+ and Olig2 was also performed at 3 days after rUCCAO (C). The apoptosis of mature oligodendrocytes was analyzed by TUNEL staining, with representative photomicrographs in (D) and the quantitative analyses in (E and F), which were calculated as the percentage of the total cells (labeled by DAPI). Scale bar: 50 μm in A and 25 μm in C. A, B: n = 6–8; E, F: n = 4. Values are represented as mean ± s.d. ###P < 0.001, vs. the sham group; *P < 0.05, **P < 0.01, ***P < 0.001, vs. the rUCCAO group.
Mentions: Myelin is made up by oligodendrocytes, which progress through a series of maturation steps to become myelinating oligodendrocytes: (1) OPCs, (2) pre-oligodendrocytes (OLs), (3) immature/premyelinating oligodendrocytes, and (4) mature oligodendrocytes2728. We evaluated the oligodendrocyte population on D3 after early treatment of minocycline (Fig. 4A,B). The number of total oligodendrocytes (oligodendrocyte transcription factor2, Olig2 + cells) and OPCs (NG2 chondroitin sulfate proteoglycan, NG2 + cells) was increased on D3 after rUCCAO. Administration of minocycline on D0-3 further increased the number of total oligodendrocytes (P < 0.001) and OPCs (P < 0.001). Minocycline also increased the expression of Olig2, NG2 and platelet-derived growth factor receptor-alpha (PDGFRα, OPC biomarker) on D3 after rUCCAO, which also suggested the increase of the total oligodendrocyte and OPC population following the early treatment of minocycline (Fig. 4C). For mature oligodendrocyte (adenomatous polyposis coli, CC-1 + cells) population, we found that they declined following rUCCAO (P < 0.001), while minocycline treatment increased the number of mature oligodendrocytes (P < 0.001). To explore the protection effect of minocycline on oligodendrocytes, the TdT-mediated dUTP nick end labeling (TUNEL) assay was performed. The number of apoptotic cells in the corpus callosum was markedly increased after rUCCAO, which was partly reversed by minocycline (Fig. 4D,E, P < 0.05). Furthermore, by counting the TUNEL + CC-1 + double positive cells, we found that most of apoptotic cells in the corpus callosum are mature oligodendrocytes (72.7 ± 4.8% of TUNEL + cells), and minocycline had a prominent protection on these cells (Fig. 4D,F, P < 0.01). On the other hand, the number of immature/premyelinating oligodendrocytes (O4 + cells) was decreased after rUCCAO (P < 0.001), and minocycline has no effect on it (Supplementary Fig. S3). Therefore, early treatment of minocycline upregulated the number of OPCs and reduced apoptosis of mature oligodendrocytes, that may account for its protection on the white matter.

Bottom Line: We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO).In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases.So, early therapeutic time window may be crucial for its application in SIVD.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China [2] Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P. R. China.

ABSTRACT
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

No MeSH data available.


Related in: MedlinePlus