Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia
Introduction
Cytokines and inflammation in the central nervous system (CNS) have been primarily studied in the context of autoimmune and infectious diseases. However, ‘nonimmune’ lesions such as focal brain ischemia likewise trigger a strong inflammatory response that involves the recruitment of macrophages and T cells as well as activation of local glia (Arvin et al., 1996, Stoll et al., 1998). The role of cytokines for lesion development is incompletely understood. At least in some in vitro paradigms proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) exerted neurotoxic effects that depended on the concomitant induction of the inducible nitric oxide synthase (iNOS) in activated glial cells (Hewett et al., 1994, Chao et al., 1995). In ischemic brain lesions in vivo, resident glia (Bidmon et al., 1998a, Loihl et al., 1999) as well as infiltrating leukocytes and blood vessels (Iadecola et al., 1995, Galea et al., 1998) have been suggested as potential sources of iNOS activity. In line with a role of iNOS in the exacerbation of ischemic brain damage targeting of the iNOS gene in mice significantly reduced the delayed expansion of ischemic brain lesions induced by permanent occlusion of the middle cerebral artery (Iadecola et al., 1997). TNF-α moreover increases the adhesiveness of the microvascular endothelium for circulating polymorphonuclear cells that exacerbate brain damage by plugging of capillaries during subsequent reperfusion of the ischemic tissue (Zhang et al., 1995, Connolly et al., 1996). In some studies, early neutralization of TNF-α and IL-1β decreased the lesion size after permanent middle cerebral artery occlusion in rats (Relton and Rothwell, 1992, Barone et al., 1997). Contrastingly, findings in TNF receptor-deficient mice suggested a protective role of endogenously produced TNF-α in focal ischemia (Bruce et al., 1996) that is supported by in vitro studies showing a decrease of excitotoxic neuronal death after pretreatment with inflammatory cytokines (Cheng et al., 1994, Strijbos and Rothwell, 1995). Similarly, pretreatment of animals with either TNF-α or IL-1β decreased neuronal damage upon subsequent brain ischemia (Ohtsuki et al., 1996, Nawashiro et al., 1997).
Cellular responses to focal ischemia are not restricted to the ischemic lesion but likewise involve nonischemic cortical areas with activation of glial cells and neuronal expression of the inflammatory enzyme cyclooxygenase-2 (Schroeter et al., 1995, Schroeter et al., 1999, Miettinen et al., 1997). Most of these changes are observed in the ipsilateral but not contralateral hemisphere and can be blocked by the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 suggesting that they are mainly induced by infarct-triggered cortical spreading depression. Functionally, spreading depression exacerbates ischemic brain damage in the penumbra zone of the lesion (Hossmann, 1996) but induces protective effects in nonischemic ipsilateral cortical areas (Kobayashi et al., 1995). To clarify the possible contribution of inflammation to remote effects of focal brain ischemia we have analyzed the spatiotemporal pattern of TNF-α, IL-1β, and iNOS expression in rat models of focal brain ischemia and addressed the role of NMDA receptor signaling in the induction of postischemic inflammatory gene expression.
Section snippets
Animal experiments
Focal cortical infarctions were induced in adult male Wistar rats by either permanent occlusion of the middle cerebral artery (MCAO) or photothrombosis of cortical microvessels under inhalation anesthesia with halothane [1.3% in an O2/N2 (1:2) mixture] as described in detail elsewhere (Schroeter et al., 1994, Jander et al., 1995). All animal experiments were performed in accordance with institutional guidelines. In the MCAO model, infarcted and noninfarcted contralateral cortex was analyzed at
Results
In the MCAO model of focal ischemia large infarcts are produced making a clear differentiation between ischemic and nonischemic tissue difficult. For the reliable analysis of cytokine induction in noninfarcted ipsilateral cortex we therefore chose the photothrombosis model in which small, sharply demarcated lesions are induced noninvasively. In initial experiments using semiquantitative RT-PCR we compared the inflammatory responses within photochemically induced ischemic lesions to those
Discussion
As main finding our study shows that the expression of TNF-α and IL-1β mRNA after focal brain ischemia was not restricted to the ischemic lesions but likewise occurred in all representative tissue samples removed from non-infarcted frontal, lateral, and occipital cortex of the ipsilateral, but not contralateral hemisphere. In contrast to both cytokines iNOS mRNA remained restricted to the ischemic lesion at all time points. Cytokine induction in the nonischemic ipsilateral cortex was almost
Acknowledgements
We thank B. Blomenkamp for excellent technical assistance, B. Ehle for statistical analysis, and U. Pippirs for help with automated DNA sequencing. This study was supported by the Deutsche Forschungsgemeinschaft (SFB 194, B6). GS holds a Hermann- and Lilly-Schilling professorship.
References (51)
- et al.
The role of inflammation and cytokines in brain injury
Neurosci. Biobehav. Rev.
(1996) - et al.
The dominant role of exogenous or endogenous interleukin-1 β on expression and activity of inducible nitric oxide synthase in rat microvascular brain endothelial cells
Neurosci. Lett.
(1997) - et al.
Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat
Neuroscience
(1996) - et al.
Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-d-aspartate receptors
Brain Behav. Immunol.
(1995) - et al.
Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis
Neuron
(1994) - et al.
Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice
Brain Res.
(1998) - et al.
Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non-neuronal cells
J. Biol. Chem.
(1993) - et al.
Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS
Neuron
(1994) - et al.
Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat
J. Neuroimmunol.
(1998) - et al.
Cortical spreading depression induces long-term alterations of BDNF levels in cortex and hippocampus distinct from lesion effects: implications for ischemic tolerance
Neurosci. Res.
(1997)
Expression of nitric oxide synthase (NOS)-2 following permanent focal ischemia and the role of nitric oxide in infarct generation in male, female and NOS-2 gene-deficient mice
Brain Res.
Activity-dependent release of brain-derived neurotrophic factor underlies the neuroprotective effect of N-methyl-d-aspartate
J. Biol. Chem.
Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat
Brain Res. Bull.
Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion
J. Neuroimmunol.
Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex
Neuroscience
Inflammation and glial responses in ischemic brain lesions
Prog. Neurobiol.
Tumor necrosis factor-α: a mediator of focal ischemic brain injury
Stroke
Transient changes in the presence of nitric oxide synthases and nitrotyrosine immunoreactivity after focal cortical lesions
Neuroscience
Structural alterations and changes in cytoskeletal proteins and proteoglycans after focal cortical ischemia
Neuroscience
Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia
Mol. Med.
Spatiotemporal relationship of apoptotic cell death to lymphomonocytic infiltration in photochemically induced focal ischemia of the rat cerebral cortex
Acta Neuropathol. (Berl.)
Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors
Nat. Med.
Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion: role of neutrophil adhesion in the pathogenesis of stroke
J. Clin. Invest.
Photothrombotic infarction triggers multiple episodes of cortical spreading depression in distant brain regions
J. Cereb. Blood Flow Metab.
Inducible nitric oxide synthase expression in human cerebral infarcts
Acta Neuropathol. (Berl.)
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