Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia

Cyclooxygenases (COX; prostaglandin endoperoxide H synthases) are key enzym es in the conversion of arachidonic acid into prostanoids which mediate inf lammation, immunomodulation, mitogenesis, ovulation, fewer, apoptosis and b lood flow. Here, we report COX-1 expression following focal cerebral infarc tions (FCI). In healthy control brains, COX-1 was localized by immunohistoc hemistry to a few endothelial cells, single neurons and rare, evenly distri buted brain microglia/macrophages. In infarctioned brains, COX-1(+) cells a ccumulated highly significantly (P < 0.0001) in peri-infarctional areas and in the developing necrotic core early after infarction. Here, cell numbers remained persistently elevated up to several months post infarction. Furth er, clusters of COX-1(+) cells were located in perivascular regions related to the Virchow-Robin space. Double-labeling experiments confirmed coexpres sion of COX-1 by CD68(+) microglia/macrophages. Co-expression of the activa tion antigens HLA-DR, -DP, -DQ (MHC class II) or the macrophage inhibitor f actor-related protein MRP-8 (S100A8) by most COX-1(+) microglia/macrophages was only seen early after infarction. Thus, COX-1 appeared to be expressed in microglial cells regardless of their activation state. However, the pro longed accumulation of COX-1+ microglia/macrophages restricted to peri-infa rctional areas enduring the acute post-ischemic inflammatory response point s to a role of COX-1 in tissue remodeling or in the pathophysiology of seco ndary injury. We have identified localized, accumulated COX-1 expression as a potential pharmacological target following FCI. Therefore we suggest tha t therapeutic approaches based on selective COX-2 blocking might not be suf ficient for suppressing the local synthesis of prostanoids.