Astroglial and Microglial Activation in Hippocampus of Rat After Global Forebrain Ischemia

Summary

The astroglial and microglial reaction to ischemic neuronal death was studied in hippocampus of rats submitted to 30-min, near-complete forebrain ischemia. The global metabolic response to ischemia was assessed by measuring energy metabolism and protein synthesis, and the cell-specific reactions by using a battery of histological, in situ hybridization and immunocytochemical techniques.

Ischemia caused instantaneous suppression of electrophysiological function and global breakdown of energy metabolism, followed by rapid restoration of energy state and gradual recovery of electroencephalogram (EEG) upon recirculation. Protein synthesis was severely inhibited for several hours in all brain regions and remained permanently suppressed in the pyramidal neurons of the vulnerable CA1 sector. In this region neuronal death became histologically visible after 2–3 days.

Thirty min after the beginning of recirculation, the mRNAs of immediate-early genes (c-jun, c-fos) were expressed in neurons from all parts of the hippocampus, followed after about 1 h by the expression of various stress proteins such as heat shock protein 70 and glucose-regulated protein 78 (hsp70, grp78, respectively). After 3–7 days these changes normalized first in the resistant and later also in the vulnerable parts of the hippocampus. Expression of mRNAs of glia-associated proteins followed distinctly later. The message of astroglia-specific proteins such as glial fibrillary acidic protein and sulphated glycoprotein-2 (gfap, sgp-2, respectively) became visible between 6h and 12h, and that of microglia such as CR3 complement receptor β subunit and transforming growth factor β1 (CR3β, TGF-β1) from day 1 on. Glial protein products GFAP, vimentin, MUC 101, MUC 102, and OX-42, reached their maximum between 1 and 3 days and were still present after 7 days. Expression was most pronounced in CA1 sector but to a lesser degree also affected the resistant parts of hippocampus. These data suggest that gene products of reactive glia are not causally involved in neuronal death but are important components of the glial phenotype in regions with neuronal damage.