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.