We have examined how transient cerebral ischemia affects the mRNA expression of a family of methyl CpG-binding domain (MBD)-containing factors in the rat hippocampus. Our results show that each member of this family is affected by cerebral ischemia challenge, but with differing patterns of responsiveness. At 3, 6 and 12 h following reperfusion, MeCP2 and MBD1 expression is maintained at control levels throughout the hippocampus. At 24 h, MeCP2 and MBD1 are induced in both the CA1 and CA3 subfields. This delayed pattern of induction is in contrast to the responses of MBD2 and MBD3. Both MBD2 and MBD3 display significant changes in expression at early times following reperfusion, although their changes are opposite in direction. MBD2 expression is induced throughout the hippocampal formation at 6 h, and remains elevated at 12 and 24 h. MBD3 expression decreases as early as 3 h following insult in the CA3 and dentate gyrus, and the decreased expression remains in the vulnerable CA1 subfield at 6, 12, and 24 h. Taken together, these results are the first to illustrate that the expression of methyl DNA-binding factors are affected by challenges to the brain, and they also illustrate that each methyl DNA-binding factor responds differently to cerebral ischemic challenge. As each of these family members is associated either directly or indirectly with the inhibition of gene transcription, our results suggest that following cerebral ischemia the normal pattern of transcriptional inhibition provided by these factors may be altered in the hippocampus.