Microglia and Cerebral Ischemia

Local microglial activation and hematogenous macrophage infiltration are hallmarks of focal cerebral ischemia, which also leads to prompt breakdown of the BBB. Microglia are activated early in the border zone of infarcts, retract processes, round up, and partly transform into phagocytes (Fig. 4). In conjunction with a dramatic influx of hematogenous macrophages during the first 2 weeks after focal ischemia, microglia rapidly remove necrotic debris. Activation of microglia is accompanied by upregulation of MHC class I and II molecules. Morphological transition of microglia from normal brain tissue toward the infarct border can regularly be seen in human infarcts of recent age (Fig. 4). Macrophages are presumably attracted by chemokines released by astrocytes in the penumbra zone of infarction. The relative contribution of microglia/macrophages to the pool of phagocytes was formally assessed by depletion experiments in the model of photochemically induced focal ischemia in the rat. Macrophages can be depleted temporarily from the blood and lymphoid organs by intravenous application of dichloromethylene dipho-sphonate-containing liposomes, a treatment that does not affect microglia. In these macrophage-depleted rats there was no difference in the number of phagocytes on Day 3 after ischemia, but there were significantly fewer phagocytes on Day 6 compared to controls. This means that in the initial phase after focal ischemia, microglia to some extent transform into phagocytes and macrophages are recruited secondarily to aid in the removal of debris. The timing of macrophage recruitment as shown here for photo-thrombotic ischemic lesions may differ in other stroke models and other species.

Further phenotypical characterization revealed that besides CD4+ microglia/macrophages, which are regularly seen in degenerating fiber tracts in the CNS, a novel population of microglia/macrophages appeared surrounding the infarcts predominantly between Days 3 and 6. This observation was independent of the mode of infarct induction and was a consistent finding also after permanent occlusion of the middle cerebral artery. By confocal laser microscopy and reverse transferase-polymerase chain reaction, we could show that this subpopulation of microglia/macrophages expressed the CD8a/b hetero-dimer, so far only described on cytotoxic/suppressor T cells. Secondarily degenerating fiber tracts and nuclei after cerebral ischemia showed the slow microglial activation and low phagocytic activity known from transected CNS fiber tracts as decribed previously and did not contain CD8 + microglia/macrophages. The functional role and particular cytokine profile of this novel CD8 + microglia/macrophage population in the rat CNS are unknown. Moreover, it is unclear whether this distinct microglia/macrophage population also exits in species other than the rat.

Reactive phagocytes can release neurotoxins after ischemic and traumatic injury to the CNS and thereby could aggravate tissue damage. However, neurotoxi-city of microglia/macrophages in ischemic brain lesions has not been formally proven in vivo. The cytokine TNF-a apparently plays a key role in ischemia-induced microglial responses, although functional data are conflicting. In mice genetically deficient in TNF receptors, microglial responses were attenuated although neuronal damage increased after focal ischemia. In addition to their presumed neurotoxic actions, microglia/macrophages can also exert beneficial effects through production of neurotrophic factors.

Microglial activation is not restricted to infarcts and their immediate border zones but encompasses the entire ipsilateral, but not contralateral, hemisphere. A similar remote activation occurs in astrocytes that upregulate glial fibrillary acidic protein. This micro-glial and astroglial activation is transient and can partly be blocked by the NMDA receptor antagonist MK-801. This suggests that the remote glial responses are induced by periinfarct spreading depression like depolarization during the first hours after focal ischemia. The functional consequences are currently under investigation.

In contrast to the almost immediate onset of neuronal loss in permanent focal ischemia, transient global cerebral ischemia leads to delayed neuronal death in vulnerable areas. After brief periods of global ischemia (up to 15 min) damage is mainly restricted to CA1 pyramidal cells in the hippocampus. In areas of impending neuronal loss that can be delineated at 2-4

Figure 4 Microglia and macrophage responses in the human brain 5 days after cerebral ischemia (autopsy case). (A) The infarct is on the left side. Immunocytochemistry for the activation marker MHC class II reveals characteristic morphological changes in microglia from normal brain tissue (right) toward the edge of infarction (left). (B-D) Details of this morphological transformation from the typical ramified microglia (B) to "stout" microglia with loss of ramification (C) and finally to round phagocytes (D). At the stage of phagocytic transformation within the inner infarct border zone microglia and hematogenous macrophage are indistinguishable. Scale bars = 50 mm in A and 25 mm in B-D.

Figure 4 Microglia and macrophage responses in the human brain 5 days after cerebral ischemia (autopsy case). (A) The infarct is on the left side. Immunocytochemistry for the activation marker MHC class II reveals characteristic morphological changes in microglia from normal brain tissue (right) toward the edge of infarction (left). (B-D) Details of this morphological transformation from the typical ramified microglia (B) to "stout" microglia with loss of ramification (C) and finally to round phagocytes (D). At the stage of phagocytic transformation within the inner infarct border zone microglia and hematogenous macrophage are indistinguishable. Scale bars = 50 mm in A and 25 mm in B-D.

days after global ischemia, microglia show signs of higher hypoxic resistance microglial activation is also activation within 24 hr after reperfusion and later observed, but in the absence of neuronal degeneration cluster around degenerating neurons. In areas with a it occurs only transiently.

Was this article helpful?

0 0
Stop Anxiety Attacks

Stop Anxiety Attacks

Here's How You Could End Anxiety and Panic Attacks For Good Prevent Anxiety in Your Golden Years Without Harmful Prescription Drugs. If You Give Me 15 minutes, I Will Show You a Breakthrough That Will Change The Way You Think About Anxiety and Panic Attacks Forever! If you are still suffering because your doctor can't help you, here's some great news...!

Get My Free Ebook


Post a comment