Elsevier

Neuroscience

Volume 122, Issue 2, 2003, Pages 373-380
Neuroscience

Tumor necrosis factor-α expression in areas of remote degeneration following middle cerebral artery occlusion of the rat

https://doi.org/10.1016/S0306-4522(03)00498-6Get rights and content

Abstract

Remote areas undergoing delayed neuronal degeneration after focal brain ischemia display a preceding glial activation. The expression of proinflammatory cytokines there has not been examined so far. We examined the expression of TNFα in the thalamus and the substantia nigra pars reticulata (SNr) 1, 3 and 7 days after transient middle cerebral artery occlusion (MCAO) of the rat. We used antibodies against glial fibrillary acidic protein (GFAP), OX-42, NeuN and tumor necrosis factor-α (TNFα) for immunohistochemistry/double-immunofluorescent labeling to investigate the time course of glial activation and the cellular localization of TNFα. Neuronal degeneration was measured by means of cell counting in Nissl-stained sections. In the ipsilateral thalamus, TNFα was upregulated already 1 day after MCAO. Microglia and astroglia were activated after 3 days. A cellular colocalisation of GFAP and TNFα was observed. Neuronal degeneration was evident at day 14. In the SNr, TNFα expression was enhanced 3 days after MCAO. Microglia was activated after 3 days and astroglia after 7 days. A cellular colocalisation of NeuN and TNFα was observed. Neuronal degeneration was evident at day 14. Thus, in both areas, expression of TNFα precedes astrogliosis and neuronal degeneration.

The different patterns of TNFα upregulation of the substantia nigra pars reticulata and the thalamus following middle cerebral artery occlusion may reflect different pathophysiological mechanisms leading to remote neuronal degeneration.

Section snippets

MCAO

The procedures of the experiments performed in the present study were in accordance with institutional guidelines. All efforts were made to minimize the number of animals and their suffering. For each investigated survival time n=4 animals were killed. Furthermore, three non-operated rats served as controls. In male Sprague–Dawley rats (220–250 g) MCAO was induced by means of the intraluminal suture technique (Longa et al., 1989). Under 2% halothane in 30% oxygen/70% nitrous oxide anesthesia

Glial reaction, TNFα expression and neuronal degeneration within the thalamus

GFAP-immunolabeling of the thalamus of non-operated rats and contralateral to the lesion site revealed a dense network of fiber processes. The GFAP positive cells showed the typical morphology of astrocytes with small cell bodies, the margin of the cytoplasm bearing small rounded edges, and with thin long processes (Fig. 1A). 1 day after MCAO, GFAP positive cells within the thalamus ipsilateral to the lesion site displayed a similar morphology, whereas from 3 days onwards astrocytic cell

Discussion

This is the first paper describing TNFα expression in the substantia nigra and the thalamus following MCAO. These areas displayed no signs of infarction following MCAO; however, selective neuronal damage developed after several days. Similar results have been shown by others Kataoka et al., 1989, Nagasawa and Kogure, 1990, Tamura et al., 1990. The substantia nigra and the thalamus are supplied by the posterior cerebral artery which is not affected by the MCAO technique performed with a 4-0

Acknowledgements

This work has been supported by the START-program, medical faculty of the RWTH Aachen.

References (41)

  • D.T. Ross et al.

    Thalamic retrograde degeneration following cortical injuryan excitotoxic process?

    Neuroscience

    (1990)
  • G. Stoll et al.

    Inflammation and glial responses in ischemic brain lesions

    Prog Neurobiol

    (1998)
  • A. Tamura et al.

    Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat

    Brain Res

    (1990)
  • O. Touzani et al.

    Potential mechanisms of interleukin-1 involvement in cerebral ischaemia

    J Neuroimmunol

    (1999)
  • K. Yamada et al.

    Continuous intraventricular drug infusion for the in vivo study of transneuronal degeneration in the striatonigral system of the rat

    Brain Res Brain Res Protoc

    (1997)
  • Z. Yu et al.

    Tumor necrosis factor alpha increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase- and NF-kappaB-dependent mechanism

    Neurobiol Dis

    (2002)
  • F. Block et al.

    Expression of IL-6 in the ischemic penumbra

    Neuroreport

    (2000)
  • F. Block et al.

    Rolipram reduces excitotoxic neuronal damage

    Neuroreport

    (2001)
  • F. De Bilbao et al.

    Cell death is prevented in thalamic fields but not in injured neocortical areas after permanent focal ischemia in mice overexpressing the anti-apoptotic protein Bcl-2

    Eur J Neurosci

    (2000)
  • W.M. Clark et al.

    Potential of anticytokine therapies in central nervous system ischaemia

    Expert Opin Biol Ther

    (2001)
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