Inflammation in areas of remote changes following focal brain lesion.

Focal brain lesions can lead to metabolic and structural changes in areas distant from but connected to the lesion site. After focal ischemic or excitotoxic lesions of the cortex and/or striatum, secondary changes have been observed in the thalamus, substantia nigra pars reticulata, hippocampus and spinal cord. In all these regions, inflammatory changes characterized by activation of microglia and astrocytes appear. In the thalamus, substantia nigra pars reticulata and hippocampus, an expression of proinflammatory cytokine like tumor necrosis factor-alpha and interleukin-1beta is induced. However, time course of expression and cellular localisation differ between these regions. Neuronal damage has consistently been observed in the thalamus, substantia nigra and spinal cord. It can be present in the hippocampus depending on the procedure of induction of focal cerebral ischemia. This secondary neuronal damage has been linked to antero- and retrograde degeneration. Anterograde degeneration is associated with somewhat later expression of cytokines, which is localised in neurons. In case of retrograde degeneration, the expression of cytokines is earlier and is localised in astrocytes. Pharmacological intervention aiming at reducing expression of tumor necrosis factor-alpha leads to reduction of secondary neuronal damage. These first results suggest that the inflammatory changes in remote areas might be involved in the pathogenesis of secondary neuronal damage.

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

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 TNFalpha 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-alpha (TNFalpha) for immunohistochemistry/double-immunofluorescent labeling to investigate the time course of glial activation and the cellular localization of TNFalpha. Neuronal degeneration was measured by means of cell counting in Nissl-stained sections. In the ipsilateral thalamus, TNFalpha was upregulated already 1 day after MCAO. Microglia and astroglia were activated after 3 days. A cellular colocalisation of GFAP and TNFalpha was observed. Neuronal degeneration was evident at day 14. In the SNr, TNFalpha expression was enhanced 3 days after MCAO. Microglia was activated after 3 days and astroglia after 7 days. A cellular colocalisation of NeuN and TNFalpha was observed. Neuronal degeneration was evident at day 14. Thus, in both areas, expression of TNFalpha precedes astrogliosis and neuronal degeneration. The different patterns of TNFalpha 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.

Interleukin-6 expression in exo-focal neurons after striatal cerebral ischemia.

Although anatomical and biochemical properties of the rat entopeduncular nucleus (EPN) closely resemble those of the substantia nigra pars reticulata (SNr), the present study shows that, unlike in the SNr, focal cerebral ischemia does not cause trans-synaptic degeneration of EPN neurons, despite striatal infarction and a similar delayed glial activation in both nuclei. In this study, interleukin-6 (IL-6) expression was found within EPN neurons 3 and 7 days after striatal ischemia. Since it has been reported that neuroprotective properties seem to predominate IL-6 function and that distinct SNr regions which demonstrate low trans-synaptic neuronal degeneration show high IL-6 expression and vice versa, IL-6 expression within partially deafferentiated but surviving EPN neurons could represent an intrinsic neuroprotective mechanism.

Time course of glial proliferation and glial apoptosis following excitotoxic CNS injury.

Activation of microglial cells and astrocytes after CNS injury results in changes in their morphology, immunophenotype and proliferative activity and has neurotrophic as well as neurotoxic consequences. However, little is known about the exact time course of glial activation as regards their proliferative activity and their fate. In this study, quantification of the densities of proliferating and non-proliferating microglial cells and astrocytes was carried out over 30 days by counting differentially labeled cells in the striatum and substantia nigra pars reticulata (SNr) after injection of quinolinic acid into the rat striatum. The TdT-mediated dUTP nick end labeling (TUNEL)-reaction was used to detect possible apoptotic mechanisms which limit the glial reaction. At 1 day post injection (p.i.) non-proliferating ameboid microglia/macrophages were seen in the striatum, but at 3 and 5 days p.i. many proliferating, ameboid microglia/macrophages and hypertrophic microglia were detected. At 10 days p.i., the time point with the highest density of hypertrophic microglia, TUNEL-positive microglial cells were observed indicating that apoptotic processes play a role in restricting this reaction. In contrast to this, at early time points, a reduction in the density and glial fibrillary acidic protein (GFAP)-immunoreactivity of astrocytes in the striatum was detected. At later time points, a dense astrogliosis with proliferating astrocytes developed in the dorsal and medial striatum. At 30 days p.i., in the entire striatum a dense astrogliosis was detected. The SNr showed a short period of microglial activation and proliferation and a long lasting astrogliosis without proliferation

Focal ischemia induces transient expression of IL-6 in the substantia nigra pars reticulata.

We examined the expression of IL-6 in the substantia nigra pars reticulata (SNr) at various time points after transient (3 h) middle cerebral artery occlusion (MCAO) in rats. The animals were killed at 1, 3, 7 or 14 days following operation. Coronal brain sections were processed for immunohistochemistry with antibodies against GFAP, OX-42 and IL-6 and for Nissl staining. Microglial activation was detected 3 and 7 days after ischemia. Reactive astrocytes have been found 7 and 14 days after ischemia. IL-6 expression was detected 3 and 7 days after ischemia. IL-6-positive cells beared the typical morphology of neurons. Distribution of IL-6-positive cells within the SNr was not homogenous. The lateral area of the SNr bears the highest number of IL-6-positive neurons while the central core bears the lowest. Quantification of intact neurons in the SNr 14 days after reperfusion shows that the highest amount of cell loss was found in the central core of the SNr and less neuronal cell loss was observed in the lateral area of the SNr. Thus, the SNr area with the highest IL-6 expression 3 and 7 days after ischemia bears the highest number of intact neurons 14 days after ischemia. This finding could be a clue for the neuroprotective role of IL-6 in the remote region SNr after focal cerebral ischemia.

[Raeder- and Collet-Siccard-Syndrome. Acute pareses of cranial nerves symptomatic of a dissection of internal carotid artery]. / Raeder- und Collet-Siccard-Syndrom. Akute Hirnnervenparesen als Symptom einer A. carotis interna-Dissektion.

Acute cerebral nerve paresis can be caused in many different ways. One of the more rare causes of paresis of one or more neural pathways is dissection of the internal carotid artery. Early diagnosis is important, even with atypical symptoms, since prompt anticoagulative therapy can hinder stroke from embolism due to the dissection. We report on two patients with Raeder's syndrome and Collet-Sicard syndrome resulting from dissection of the internal carotid artery. Besides the cranial and caudal nerves involved in our study, loss of function has also been reported with the sixth to eighth cranial nerves, so that any painful, sudden cranial nerve deficiency can indicate possible carotid dissection.