Regional Differences in Late-Onset Iron Deposition, Ferritin, Transferrin, Astrocyte Proliferation, and Microglial Activation after Transient Forebrain Ischemia in Rat Brain

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Abstract
With use of iron histochemistry and immuno-histochemistry, regional changes in the appearance of iron, ferritin, transferrin, glial fibrillary acidic protein–positive astrocytes, and activated microglia were examined from 1 to 24 weeks after transient forebrain ischemia (four-vessel occlusion model) in rat brain. Expression of the C3bi receptor and the major histocompatibility complex class II antigen was used to identify microglia. Neuronal death was confirmed by hematoxylin–eosin staining only in pyramidal cells of the hippocampal CA, region, which is known as the area most vulnerable to ischemia. Perls' reaction with 3,3′-diaminobenzidine intensification revealed iron deposits in the CA, region after week 4, which gradually increased and formed clusters by week 24. Iron also deposited in layers III-V of the parietal cortex after week 8 and gradually built up as granular deposits in the cytoplasm of pyramidal cells in frontocortical layer V. An increasing astroglial reaction and the appearance of ferritin-immunopositive microglia paralleled the iron accumulation in the hippocampal CA, region, indicating that iron deposition was probably produced in the process of gliosis. Neither neuronal death nor atrophy was found in the cerebral cortex. Nevertheless, an astroglial and ferritin-immunopositive microglial reaction became evident at week 8 in the parietal cortex. On the other hand, the granular iron deposition in the pyramidal neurons of frontocortical layer V was not accompanied by any glial reaction in the chronic stage of ischemia. Three different types of iron deposition in the chronic phase after transient forebrain ischemia were shown in this study. In view of the neuronal damage caused by iron-catalyzed free radical formation, the late-onset iron deposition may be relevant to the pathogenesis of the chronic brain dysfunction seen at a late stage after cerebral ischemia.