Introduction
New cells from the subventricular zone (SVZ) may help repair the brain after injury, but their long-term survival may be inhibited by inflammation. We investigated if treatment with the non-steroidal anti-inflammatory drug indomethacin (INDO) improves cell survival following focal cerebral ischemia.
Methods
Ischemia was induced in adult rats by middle cerebral artery occlusion for 2 h. INDO-treated and control animals received daily BrdU injections for 6 days and were sacrificed on day 7, 14, or 28. Brains were immunostained for BrdU and lineage-specific markers and examined under a confocal microscope. Western blots were run for COX-2 and ppar-gamma. Behavioral testing was conducted on separate groups of animals at one week intervals starting 7 d before ischemia.
Results
We observed an unexpected, marked decrease in labeling by the proliferation marker bromo-deoxyuridine (BrdU) at the time of reperfusion in the SVZ. BrdU-labeled migrating neuroblasts appeared within the neighboring parenchyma along with increases in BrdU-labeled cells within the neighboring striatum and overlying cortex. Co-labeling with BrdU and a lineage-specific marker (DCX, NG2, GFAP, NeuN, or nestin) in high-GFAP regions of the cortex and striatum (ischemic penumbra; n=12) showed that the proportion of BrdU+ cells expressing all lineages was increased compared to controls in INDO-treated animals at 14 and 28 days post-ischemia. The increase in co-labeling in the cortex was greatest with nestin (5.2 fold) and NG2 (6.4 fold). Few BrdU+/NeuN+ cells were seen even 28 days after stroke. Western blots showed decreased COX-2 at 0 and 7 d and increased ppar-gammaat 7 d with a concurrent decrease in immune cell activation in ischemic animals treated with INDO. There was no effect of INDO on behavioral recovery at any time point.
Conclusions
Indomethacin improved cell survival and neurogenesis following stroke by increasing ppar-gammaanddecreasing COX-2 and immune cell activation. These effects were not accompanied by reduced infarct sizes or improvement in behavioral recovery, however, which may reflect the severity of the injury. These data contribute to a growing literature indicating that reducing inflammation after brain injury may be beneficial