Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid.

Cerebral ischemia and also excitotoxicity induce the expression of 72,000 mol. wt heat shock protein (Hsp70), c-Fos, and cyclooxygenase-2. In the present work we have examined whether Hsp70, c-Fos and cyclooxygenase-2 are expressed by the same cells in the rat brain at 6, 12 and 24 h following transient focal ischemia or kainic acid administration, by means of single and double immunohistochemistry. At 6 h after kainic acid, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen in pyramidal hippocampal neurons and superficial cortical layers, however by 24 h such colocalization became rare within the cortex but was partially maintained in the hippocampus. Cyclooxygenase-2 was seen in many neurons that were also immunoreactive for c-Fos in superficial cortical layers, dentate gyrus and pyramidal cell layer of the hippocampus from 6 h after kainic acid. Co-localization of cyclooxygenase-2 and c-Fos was also observed in superficial cortical layers within the ipsilateral hemisphere at 6 h following focal ischemia. Also, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen at this time. However, by 24 h cyclooxygenase-2 and c-Fos-immunoreactive cells were restricted to perifocal regions, and only a very limited co-localization with Hsp70 was seen in perifocal neurons located in the border of the penumbra-like area that surrounds the ischemic core and is strongly immunoreactive for Hsp70. This study shows a selective and dynamic cellular expression of inducible proteins following either ischemia or kainic acid, with a remarkable neuronal co-localization of c-Fos and cyclooxygenase-2. The results suggest that, first, stimuli underlying neuronal c-Fos expression can also lead to the induction of cyclooxygenase-2; second, transient co-localization of Hsp70 and c-Fos can take place in non-vulnerable neurons; and finally, expression of c-Fos, cyclooxygenase-2, and/or Hsp70 at a given time-point is part of the response to altered environmental conditions and can be related to the particular cellular sensitivity rather than the pathological outcome.