Tissue-type transglutaminase (TG-2) has been implicated in neurodegenerative diseases. In this study, induction of TG-2 was studied in rats following transient middle cerebral artery occlusion. Alterations in 2,3,5-triphenylterazolium chloride staining revealed maximum infarction 3 days after injury. Measurement of mRNA transcript levels by real-time PCR analysis showed both forms of TG-2 mRNA peaking on day 5 after injury in ipsilateral cortex, with greater induction of the full-length TG-2 (TG-L) transcript than the truncated form of the TG-2 (TG-S) transcript. However, in the ipsilateral hippocampus, peak induction of both forms of TG-2 mRNA peaked 1 day after injury and to a lesser extent than observed in the ipsilateral cortex. Western blot analysis demonstrated that TG-L protein expression progressively increased from 1 to 7 days after ischemia, with greater expression in cortex than hippocampus (525 +/- 10% vs. 196 +/- 8% of control, respectively). However, expression of TG-S was not detected. These results demonstrate that increased TG-2 mRNA and protein expression occurs in a delayed fashion following ischemic injury. The temporal profile of TG-2 induction after ischemia was similar to that observed after traumatic brain injury (previously described), suggesting a similar role of TG-2 in both pathological conditions.