Abstract

Microglia are brain resident macrophages rapidly responding to various stimuli to exert appropriate inflammatory responses. Although they have recently been exploited as an attractive candidate for imaging neuroinflammation, it is still difficult to visualize them at the cellular and molecular levels. Here we imaged activated microglia by establishing intracranial window chamber (ICW) in a mouse model of focal cerebral ischemia by using two-photon microscopy (TPM), in vivo. Intravenous injection of fluorescent antibodies allowed us to detect significantly elevated levels of Iba-1 and CD68 positive activated microglia in the ipsilateral compared to the contralateral side of the infarct. We further observed that indomethacin, a non-steroidal anti-inflammatory drug significantly attenuated CD68-positive microglial activation in ICW, which was further confirmed by qRT-PCR biochemical analyses. In conclusion, we believe that in vivo TPM imaging of ICW would be a useful tool to screen for therapeutic interventions lowering microglial activation hence neuroinflammation.

© 2015 Optical Society of America

Full Article  |  PDF Article
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    [Crossref] [PubMed]

2015 (4)

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
[Crossref] [PubMed]

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

J. Qian, Z. Zhu, C. W. Leung, W. Xi, L. Su, G. Chen, A. Qin, B. Z. Tang, and S. He, “Long-term two-photon neuroimaging with a photostable AIE luminogen,” Biomed. Opt. Express 6(4), 1477–1486 (2015).
[Crossref] [PubMed]

2014 (3)

M. G. Velasco and M. J. Levene, “In vivo two-photon microscopy of the hippocampus using glass plugs,” Biomed. Opt. Express 5(6), 1700–1708 (2014).
[Crossref] [PubMed]

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

2013 (5)

S. Venneti, B. J. Lopresti, and C. A. Wiley, “Molecular imaging of microglia/macrophages in the brain,” Glia 61(1), 10–23 (2013).
[Crossref] [PubMed]

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
[PubMed]

T. Zheng, Z. Yang, A. Li, X. Lv, Z. Zhou, X. Wang, X. Qi, S. Li, Q. Luo, H. Gong, and S. Zeng, “Visualization of brain circuits using two-photon fluorescence micro-optical sectioning tomography,” Opt. Express 21(8), 9839–9850 (2013).
[Crossref] [PubMed]

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
[Crossref] [PubMed]

S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
[Crossref] [PubMed]

2011 (3)

C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nat. Med. 17(7), 796–808 (2011).
[Crossref] [PubMed]

H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
[Crossref] [PubMed]

A. Thiel and W. D. Heiss, “Imaging of microglia activation in stroke,” Stroke 42(2), 507–512 (2011).
[Crossref] [PubMed]

2010 (3)

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics 7(4), 354–365 (2010).
[Crossref] [PubMed]

2009 (1)

2008 (2)

S. Sakadzić, U. Demirbas, T. R. Mempel, A. Moore, S. Ruvinskaya, D. A. Boas, A. Sennaroglu, F. X. Kaertner, and J. G. Fujimoto, “Multi-photon microscopy with a low-cost and highly efficient Cr:LiCAF laser,” Opt. Express 16(25), 20848–20863 (2008).
[Crossref] [PubMed]

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
[Crossref] [PubMed]

2007 (1)

S. T. Dheen, C. Kaur, and E.-A. Ling, “Microglial activation and its implications in the brain diseases,” Curr. Med. Chem. 14(11), 1189–1197 (2007).
[Crossref] [PubMed]

2005 (2)

A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science 308(5726), 1314–1318 (2005).
[Crossref] [PubMed]

B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke 36(12), 2718–2724 (2005).
[Crossref] [PubMed]

2003 (4)

M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science 302(5651), 1760–1765 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref] [PubMed]

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

1999 (1)

Z. Y. Du and X. Y. Li, “Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro,” Int. J. Immunopharmacol. 21(3), 219–225 (1999).
[Crossref] [PubMed]

1998 (1)

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Ahn, G. O.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Anrather, J.

C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nat. Med. 17(7), 796–808 (2011).
[Crossref] [PubMed]

Arnberg, F.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Backes, H.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Ballesteros, I.

M. I. Cuartero, I. Ballesteros, I. Lizasoain, and M. A. Moro, “Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia,” Brain Res.In Press.

Betts, K.

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
[Crossref] [PubMed]

Block, M. L.

M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics 7(4), 354–365 (2010).
[Crossref] [PubMed]

Boas, D. A.

Chen, G.

Chen, J. W.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Chen, N. H.

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
[Crossref] [PubMed]

Chernikova, S.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Chin, F. T.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Chua, J. Y.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Clausen, B. E.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Cord, K.-T.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Corr, M.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Cramer, T.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Cuartero, M. I.

M. I. Cuartero, I. Ballesteros, I. Lizasoain, and M. A. Moro, “Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia,” Brain Res.In Press.

De Simoni, M.-G.

S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
[Crossref] [PubMed]

Demirbas, U.

Denk, W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Dheen, S. T.

S. T. Dheen, C. Kaur, and E.-A. Ling, “Microglial activation and its implications in the brain diseases,” Curr. Med. Chem. 14(11), 1189–1197 (2007).
[Crossref] [PubMed]

Du, Z. Y.

Z. Y. Du and X. Y. Li, “Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro,” Int. J. Immunopharmacol. 21(3), 219–225 (1999).
[Crossref] [PubMed]

Durst, M. E.

Fenn, A. M.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Ferrara, N.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Fink, G. R.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Firestein, G. S.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Förster, I.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Fujimoto, J. G.

Fukuuchi, Y.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Fumagalli, S.

S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
[Crossref] [PubMed]

Gao, Y.

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
[Crossref] [PubMed]

Gensel, J. C.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Gerber, H. P.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Godbout, J. P.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Gong, H.

Graf, R.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Graves, E. E.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Gulyás, B.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Guo, J.

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
[Crossref] [PubMed]

Guzman, R.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Haase, V. H.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Häggkvist, J.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Halldin, C.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Hanisch, U. K.

H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
[Crossref] [PubMed]

He, S.

Heiss, W. D.

A. Thiel and W. D. Heiss, “Imaging of microglia activation in stroke,” Stroke 42(2), 507–512 (2011).
[Crossref] [PubMed]

Helmchen, F.

A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science 308(5726), 1314–1318 (2005).
[Crossref] [PubMed]

Hoehn, B. D.

B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke 36(12), 2718–2724 (2005).
[Crossref] [PubMed]

Hoehn, M.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Holmin, S.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Huang, Y.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Hyman, B. T.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Iadecola, C.

C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nat. Med. 17(7), 796–808 (2011).
[Crossref] [PubMed]

Imai, Y.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Ito, D.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Jaenisch, R.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

James, M. L.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Jin, R.

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

Johnson, R. S.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Kaertner, F. X.

Kaur, C.

S. T. Dheen, C. Kaur, and E.-A. Ling, “Microglial activation and its implications in the brain diseases,” Curr. Med. Chem. 14(11), 1189–1197 (2007).
[Crossref] [PubMed]

Kettenmann, H.

H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
[Crossref] [PubMed]

Kirchhoff, F.

A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science 308(5726), 1314–1318 (2005).
[Crossref] [PubMed]

Kobat, D.

Kohsaka, S.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Lartey, F. M.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Lee, S. W.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Leung, C. W.

Levene, M. J.

Li, A.

Li, G.

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

Li, P.

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
[Crossref] [PubMed]

Li, S.

Li, T.

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
[Crossref] [PubMed]

Li, X. Y.

Z. Y. Du and X. Y. Li, “Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro,” Int. J. Immunopharmacol. 21(3), 219–225 (1999).
[Crossref] [PubMed]

Lifshitz, J.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Ling, E.-A.

S. T. Dheen, C. Kaur, and E.-A. Ling, “Microglial activation and its implications in the brain diseases,” Curr. Med. Chem. 14(11), 1189–1197 (2007).
[Crossref] [PubMed]

Little, P.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Liu, F.

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
[PubMed]

Liu, H.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Liu, R.

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
[Crossref] [PubMed]

Lizasoain, I.

M. I. Cuartero, I. Ballesteros, I. Lizasoain, and M. A. Moro, “Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia,” Brain Res.In Press.

Loo, B. W.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Lopresti, B. J.

S. Venneti, B. J. Lopresti, and C. A. Wiley, “Molecular imaging of microglia/macrophages in the brain,” Glia 61(1), 10–23 (2013).
[Crossref] [PubMed]

Lull, M. E.

M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics 7(4), 354–365 (2010).
[Crossref] [PubMed]

Luo, Q.

Lv, X.

Mackman, N.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

McCullough, L. D.

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
[PubMed]

Mempel, T. R.

Monje, M. L.

M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science 302(5651), 1760–1765 (2003).
[Crossref] [PubMed]

Moore, A.

Moro, M. A.

M. I. Cuartero, I. Ballesteros, I. Lizasoain, and M. A. Moro, “Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia,” Brain Res.In Press.

Mulder, J.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Murphy, T. H.

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
[Crossref] [PubMed]

Nakajima, K.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Neumaier, B.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Nikitin, A. Y.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Nimmerjahn, A.

A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science 308(5726), 1314–1318 (2005).
[Crossref] [PubMed]

Nishimura, N.

Nizet, V.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Noda, M.

H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
[Crossref] [PubMed]

Ohsawa, K.

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
[Crossref] [PubMed]

Ortolano, F.

S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
[Crossref] [PubMed]

Palmer, T. D.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke 36(12), 2718–2724 (2005).
[Crossref] [PubMed]

M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science 302(5651), 1760–1765 (2003).
[Crossref] [PubMed]

Pang, S.

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
[Crossref] [PubMed]

Patel, A. R.

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
[PubMed]

Pawlinski, R.

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
[Crossref] [PubMed]

Perego, C.

S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
[Crossref] [PubMed]

Pisani, L. J.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Popovich, P. G.

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
[Crossref] [PubMed]

Qi, X.

Qian, J.

Qin, A.

Ritzel, R.

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
[PubMed]

Rosenblum, S.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Rueger, M. A.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Ruvinskaya, S.

Sakadzic, S.

Schaffer, C. B.

Schroeter, M.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Sennaroglu, A.

Shen, B.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Smith, T.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Steinberg, G. K.

B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke 36(12), 2718–2724 (2005).
[Crossref] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Su, L.

Tang, B. Z.

Thiel, A.

A. Thiel and W. D. Heiss, “Imaging of microglia activation in stroke,” Stroke 42(2), 507–512 (2011).
[Crossref] [PubMed]

Tirouvanziam, R.

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
[Crossref] [PubMed]

Toda, H.

M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science 302(5651), 1760–1765 (2003).
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Tóth, M.

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
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S. Venneti, B. J. Lopresti, and C. A. Wiley, “Molecular imaging of microglia/macrophages in the brain,” Glia 61(1), 10–23 (2013).
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H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
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Walberer, M.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Walter, H. L.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Wang, X.

Wang, Z. Z.

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
[Crossref] [PubMed]

Webb, W. W.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
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W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[Crossref] [PubMed]

Wiedermann, D.

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
[Crossref] [PubMed]

Wiley, C. A.

S. Venneti, B. J. Lopresti, and C. A. Wiley, “Molecular imaging of microglia/macrophages in the brain,” Glia 61(1), 10–23 (2013).
[Crossref] [PubMed]

Williams, R. M.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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Wong, A. W.

Wu, X.

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
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Xi, W.

Xia, C. Y.

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
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Xu, C.

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T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
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R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
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R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

Yang, Z.

Yu, Y.

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
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Zeng, S.

Zhang, S.

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
[Crossref] [PubMed]

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
[Crossref] [PubMed]

Zheng, T.

Zhou, Z.

Zhu, Z.

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref] [PubMed]

Biol. Psychiatry (1)

A. M. Fenn, J. C. Gensel, Y. Huang, P. G. Popovich, J. Lifshitz, and J. P. Godbout, “Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia,” Biol. Psychiatry 76(7), 575–584 (2014).
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Biomed. Opt. Express (2)

Brain (1)

T. Li, S. Pang, Y. Yu, X. Wu, J. Guo, and S. Zhang, “Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke,” Brain 136(12), 3578–3588 (2013).
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Brain Res. Mol. Brain Res. (1)

D. Ito, Y. Imai, K. Ohsawa, K. Nakajima, Y. Fukuuchi, and S. Kohsaka, “Microglia-specific localisation of a novel calcium binding protein, Iba-1,” Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).
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Brain Struct. Funct. (1)

M. Tóth, P. Little, F. Arnberg, J. Häggkvist, J. Mulder, C. Halldin, B. Gulyás, and S. Holmin, “Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking,” Brain Struct. Funct. 429, 970 (2015).
[Crossref] [PubMed]

Cell (1)

T. Cramer, Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman, V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, G. S. Firestein, H. P. Gerber, N. Ferrara, and R. S. Johnson, “HIF-1alpha is essential for myeloid cell-mediated inflammation,” Cell 112(5), 645–657 (2003).
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Curr. Med. Chem. (1)

S. T. Dheen, C. Kaur, and E.-A. Ling, “Microglial activation and its implications in the brain diseases,” Curr. Med. Chem. 14(11), 1189–1197 (2007).
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Glia (2)

S. Venneti, B. J. Lopresti, and C. A. Wiley, “Molecular imaging of microglia/macrophages in the brain,” Glia 61(1), 10–23 (2013).
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S. Fumagalli, C. Perego, F. Ortolano, and M.-G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia 61(6), 827–842 (2013).
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Int. Immunopharmacol. (1)

C. Y. Xia, S. Zhang, Y. Gao, Z. Z. Wang, and N. H. Chen, “Selective modulation of microglia polarization to M2 phenotype for stroke treatment,” Int. Immunopharmacol. 25(2), 377–382 (2015).
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Int. J. Immunopharmacol. (1)

Z. Y. Du and X. Y. Li, “Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro,” Int. J. Immunopharmacol. 21(3), 219–225 (1999).
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Int. J. Physiol. Pathophysiol. Pharmacol. (1)

A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” Int. J. Physiol. Pathophysiol. Pharmacol. 5(2), 73–90 (2013).
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J. Leukoc. Biol. (2)

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
[Crossref] [PubMed]

R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” J. Leukoc. Biol. 87(5), 779–789 (2010).
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J. Neurosci. (1)

T. H. Murphy, P. Li, K. Betts, and R. Liu, “Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines,” J. Neurosci. 28(7), 1756–1772 (2008).
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Mol. Imaging Biol. (1)

F. M. Lartey, G. O. Ahn, B. Shen, K.-T. Cord, T. Smith, J. Y. Chua, S. Rosenblum, H. Liu, M. L. James, S. Chernikova, S. W. Lee, L. J. Pisani, R. Tirouvanziam, J. W. Chen, T. D. Palmer, F. T. Chin, R. Guzman, E. E. Graves, and B. W. Loo., “PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06,” Mol. Imaging Biol. 16(1), 109–117 (2014).
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Nat. Biotechnol. (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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Nat. Med. (1)

C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nat. Med. 17(7), 796–808 (2011).
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Neuroscience (1)

H. L. Walter, M. Walberer, M. A. Rueger, H. Backes, D. Wiedermann, M. Hoehn, B. Neumaier, R. Graf, G. R. Fink, and M. Schroeter, “In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke,” Neuroscience 292, 71–80 (2015).
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Neurotherapeutics (1)

M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics 7(4), 354–365 (2010).
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Opt. Express (3)

Physiol. Rev. (1)

H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiol. Rev. 91(2), 461–553 (2011).
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Proc. Natl. Acad. Sci. U.S.A. (1)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100(12), 7075–7080 (2003).
[Crossref] [PubMed]

Science (3)

M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science 302(5651), 1760–1765 (2003).
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W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
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A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science 308(5726), 1314–1318 (2005).
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Stroke (2)

A. Thiel and W. D. Heiss, “Imaging of microglia activation in stroke,” Stroke 42(2), 507–512 (2011).
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B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke 36(12), 2718–2724 (2005).
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Other (1)

M. I. Cuartero, I. Ballesteros, I. Lizasoain, and M. A. Moro, “Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia,” Brain Res.In Press.

Supplementary Material (6)

NameDescription
» Visualization 1: MP4 (2085 KB)      Two-photon imaging of Iba-1 positive microglia in ICW of GFP mouse subjected to sham procedure that had been injected with PerCP-Iba-1 antibodies
» Visualization 2: MP4 (10261 KB)      Two-photon imaging of Iba-1 positive microglia in ICW of GFP mouse subjected to MCAO procedure that had been injected with PerCP-Iba-1 antibodies
» Visualization 3: MP4 (11005 KB)      In vivo two-photon imaging of activated microglia in ICW in the ipsilateral side of MCAO
» Visualization 4: MP4 (2438 KB)      In vivo two-photon imaging of activated microglia in ICW in the contralateral side of MCAO
» Visualization 5: MP4 (6379 KB)      In vivo two-photon microscopy for activated microglia in ICW-bearing MCAO mice after vehicle treatment
» Visualization 6: MP4 (6602 KB)      In vivo two-photon microscopy for activated microglia in ICW-bearing MCAO mice after indomethacin treatment

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Figures (4)

Fig. 1
Fig. 1

ICW set up and microglia in a mouse model of focal cerebral ischemia. (a) Surgical procedures demonstrating ICW implantation. ICW was approximately 2 - 3 mm in diameter (black line). (b) Immunostaining of the brain at 24 hr post MCAO for Iba-1 (red) and CD68 (green). Nuclei are shown with DAPI (blue). IC and P represent ‘ischemic core’ and ‘penumbra’ regions, respectively. (c) FACS analysis of Iba-1 and CD68 expression levels in the ipsilateral side of the brain harvested from MCAO (pink line) or sham (black line) mice. Brain samples were pooled from a group of 4 mice. (d) In vivo TPM imaging of ICW for microglia using Iba-1 antibodies at 6 hr after sham (Visualization 1) or MCAO (Visualization 2) surgeries. Note that GFP-positive cells (green) in the brain are observed in both groups of mice, whereas Iba-1-positive microglia (red) were only detected in mice undergone MCAO. Scale bars in (b) and (d) indicate 100 μm.

Fig. 2
Fig. 2

In vivo imaging of activated microglia in ICW of MCAO mice by TPM. (a) A representative picture showing ICW implanted in the ipsilateral or contralateral side of mice subjected to the left MCAO. (b) TPM images for activated microglia in ICW implanted either in the ipsilateral (Visualization 3) or contralateral side (Visualization 4) of the ischemic infarct (n = 3 for ipsilateral; n = 2 for contralateral). Mice were administered with an antibody cocktail containing PerCP-Iba-1 (red) and AMCA-CD68 (blue) immediately prior to the TPM imaging. Scale bars indicate 100 μm. (c) Quantification of Iba-1 and CD68 expression levels in (b) at the ipsilateral (open bars) or contralateral side (closed bars). Data are the mean ± SEM (n = 3 for ipsilateral; n = 2 for contralateral) with * and ** indicate P < 0.05 and 0.01, respectively.

Fig. 3
Fig. 3

Increased cerebrovascular permeability in the ipsilateral side of focal cerebral ischemia. (a) Representative images of the brain perfused with FITC-lectin (n = 2). Note that a significant amount of FITC-lectin was extravasated in the ipsilateral side compared to the contralateral side of the infarct. (b) Evans blue extravasation in the ipsilateral (Ipsi) or contralateral (Contra) side at 24 hr post-MCAO. Data are the mean ± SEM for triplicate determinations with ** indicating P < 0.01 (n = 2 per group). (c) Immunostaining images of CD68-positive activated microglia in the ipsilateral or contralateral side of MCAO mice (n = 6 per group). Nuclei are shown with DAPI (blue). Scale bars in (a) and (c) denote 100 μm.

Fig. 4
Fig. 4

Indomethacin significantly attenuates microglial activation in ICW. (a) TPM images of activated microglia in ICW-bearing MCAO mice treated with either vehicle (Visualization 5) or indomethacin (Indo; Visualization 6) (n = 3 for vehicle; n = 4 for indomethacin). Imaging was performed at 24 hr post MCAO. Results are a representative image obtained from at least two independent areas per mouse, two animals per group. Scale bars denote 100 μm. (b) Quantification of Iba-1 and CD68 expression levels in MCAO mice treated with vehicle or indomethacin in (a). Data are the mean ± SEM with *** indicating P < 0.001 (n = 3 for vehicle; n = 4 for indomethacin). (c) mRNA expression levels in microglia isolated from MCAO or sham mice by FACS. (d) mRNA expression levels in microglia obtained from MCAO mice treated with vehicle or indomethacin (Indo) by FACS.

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