Unilateral upregulation of cyclooxygenase-2 following cerebral, cortical photothrombosis in the rat: suppression by MK-801 and co-distribution with enzymes involved in the oxidative stress cascade

Cyclooxygenase-2 (COX-2) is an essential enzyme for prostaglandin synthesis from arachidonic acid, during which considerable amounts of superoxide are produced. During pathological conditions, superoxide and nitric oxide (NO) rapidly form peroxynitrite, a potent cytotoxin, causing symptoms referred to as oxidative stress response. Superoxide is controlled by enzymes such a s manganese- or copper-zinc-dependent superoxide dismutase (Mn-SOD, CuZn-SO D), glutathione peroxidase (GPx) and antioxidants derived from heme oxygena se (HO) activity such as biliverdin and bilirubin. NO derives from 3 NO-syn thases (NOS I-III) from which the calcium-dependent NOS-I and III are activ ated rapidly due to hyperexcitation. We studied the induction of COX-2 by i mmunohistochemistry at days 1, 2 and 5 following cortical photothrombosis i n normal and MK-801 treated rats. The results showed a weak constitutive, n euronal expression of COX-2 in cortex and amygdala. Layers II+III contained considerably more COX-2 than infragranular layers. One and 2 days followin g injury COX-2 was highly upregulated in the supragranular layers of the wh ole injured hemisphere compared with sham-operated animals and compared to the contralateral unlesioned hemisphere, whereas at day 5 COX-2 levels had returned to baseline. MK-801 treatment caused a reduction in COX-2 upregula tion at day one and by day 2 no significant differences between injured and contralateral hemisphere were measurable. COX-2 positive neurons were foun d in close association with NOS-I containing neurons and their fibers but w ere not colocalized. In addition, codistribution of COX-2 was found with HO -1, CuZn-SOD and GPx containing cells, whereas COX-2 was colocalized with H O-2 and/or MnSOD in cortical neurons. (C) 2000 Elsevier Science B.V. All ri ghts reserved.