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Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model

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Abstract

MRI was employed to follow the neurodegenerative foci and the localization of inflammatory cells by magnetically labeled CD4+ or CD8+ lymphocytes in the ischemia/reperfusion long-lived rats (9 and 13 months after 10 min of cardiac arrest). MRI of ischemic rats showed: (1) blood–brain barrier (BBB) leakage in the area of the dorsal hippocampus and brainstem-hindbrain level in basal cerebellum, (2) unlike anti-CD8 magnetic antibodies anti-CD4 ultra small paramagnetic iron oxide particles (USPIO) antibodies revealed hypointense areas in the brainstem-interbrain region and caudoputamen not found in animals that were not injected with USPIO antibodies, and (3) dilation in the retrosplenial area. Immunocytochemistry revealed microglial activation in the hippocampus and striatum, with indications of activation in thalamic lateral dorsal nuclei and the subventricular zone. In the CA1 and CA3 regions, it was noted that OX42- and ED1-positive granules appear in neuronal somata. Immunostaining of lymphocytes with TCR confirmed the T-cell presence in ischemic brain parenchyma of the hippocampus and striatum. The above observations thus point to a persistent dysfunction of BBB that in long-term may still lead to infiltration of T cells that are predominantly of helper (CD4+) type. Such inflammatory processes are backed by microglial activity even up to 1 year after ischemia/reperfusion. Moreover, in these animals an augmented expression of neurogenesis markers and neuroblast migration was also revealed in the subventricular zone. Thus, a balance of degenerative processes and inflammatory surveillance with neurogenesis could determine the long-term outcome of global ischemia survival or the previously proposed formation of amyloid plaques and Alzheimer’s-type dementia.

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Abbreviations

BBB:

Blood–brain barrier

CLIO:

Cross-linked iron oxide

CNS:

Central nervous system

DCX:

Doublecortin

FITC-streptavidin:

Streptavidin labeled with fluorescein isothiocyanate

FoW:

Field of view

Gd-DTPA:

Gadolinium-diethylenetriaminepentaacetic acid

MRI:

Magnetic resonance imaging

PECAM:

Platelet endothelial cell adhesion molecule

RF:

Radio frequency

SPIO:

Small paramagnetic iron oxide particles

SVZ:

Subventricular zone

T1:

Longitudinal relaxation time

T1W:

T1-weighted relaxation

T2*:

Transversal relaxation time-“star” protocol

T2*W:

T2*-weighted relaxation

TCR:

T cell receptor

TE:

Time to echo

TR:

Repetition time

TSE:

Turbo spin echo protocol

USPIO:

Ultra small paramagnetic iron oxide particles

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Acknowledgments

The authors are grateful to Dr. Goran Bačić for his continuous expert support in designing and analyzing MRI experiments. This study was supported by grant of Ministry of Science and Technological Development Republic of Serbia (Grant No. 41005), funds from Mossakowski Medical Research Centre (T5), Polish Ministry of Science and Higher Education (2007–2010-Cost/253/2006), and ESF-COST Action B30.

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Authors and Affiliations

  1. Faculty of Biology, Department of Physiology and Biochemistry, Center for Laser Microscopy, University of Belgrade, P.O. Box 52, Studentski trg 16, 11000, Belgrade, Serbia

    Vera Sekeljic, Danijela Bataveljic, Stefan Stamenkovic, Lidija Radenovic & Pavle R. Andjus

  2. Laboratory of Ischemic and Neurodegenerative Brain Research, Department for Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 St, 02-106, Warsaw, Poland

    Marzena Ułamek & Ryszard Pluta

  3. Department of Orthopaedics and Rehabilitation, Lublin Medical University, Jaczewskiego 8 St, 20-954, Lublin, Poland

    Mirosław Jabłoński

Authors
  1. Vera Sekeljic
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  2. Danijela Bataveljic
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  3. Stefan Stamenkovic
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  4. Marzena Ułamek
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  5. Mirosław Jabłoński
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  6. Lidija Radenovic
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  7. Ryszard Pluta
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  8. Pavle R. Andjus
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Corresponding author

Correspondence to Pavle R. Andjus.

Additional information

R. Pluta and P. R. Andjus contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

429_2011_336_MOESM1_ESM.mpg

Supplementary material 1 Online Resource 1. Animated reconstruction of the Z-stack of the image in Fig. 1e for the postischemic CA1 hippocampal region (optical slice thickness – 0.79 μm, number of slices – 52, stack size – 40.2 μm) (MPEG 621 kb)

429_2011_336_MOESM2_ESM.mpg

Supplementary material 2 Online Resource 2. Animated reconstruction of the Z-stack of the image in Fig. 1e for the postischemic striatal region (optical slice thickness – 1.99 μm, number of slices – 14, stack size – 25.9 μm) (MPEG 469 kb)

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Sekeljic, V., Bataveljic, D., Stamenkovic, S. et al. Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. Brain Struct Funct 217, 411–420 (2012). https://doi.org/10.1007/s00429-011-0336-7

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  • DOI: https://doi.org/10.1007/s00429-011-0336-7

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