Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat.

Cell cycle proteins play key roles in cell survival or death under pathological conditions. Expression of growth arrest and DNA damage-inducible protein, GADD34 and proliferating cell nuclear antigen (PCNA) have been investigated in the core and peri-infarct zone at 2 and 24 h after middle cerebral artery occlusion (MCAO). At these times after MCAO, numerous GADD34-positive cells were present, particularly in the peri-infarct zone (e.g. 24 +/- 4 and 52 +/- 6 immunopositive cells/0.25 mm2 at 2 and 24 h, respectively, in cortex). PCNA-immunopositive cells were barely detectable in the peri-infarct zone at 2 h; however, numerous PCNA-immunopositive cells were present in this zone by 24 h (0.7 +/- 0.3 and 10.6 +/- 1.5 immunopositive cells/0.25 mm2, respectively) as well as in the adjacent cortex and in the contralateral cingulate cortex. Most GADD34-immunopositive cells coexpressed the neuronal marker Neu-N with a smaller number coexpressing the microglial marker, Mrf-1. Evidence of morphologically 'abnormal' and 'normal' GADD34 immunopositive neurons was found within the peri-infarct zone. The majority of PCNA immunopositive cells were Mrf-1 positive with a smaller number Neu-N positive. Double-labelling revealed colocalization of GADD34 and PCNA in some cells within the peri-infarct zone and in the ependymal cells lining the ventricles. The presence of GADD34 and PCNA in a key anatomical location pertinent to the evolving ischaemic lesion indicates that GADD34, either alone or in combination with PCNA, has the potential to influence cell survival in ischaemically compromised tissue.