SPREADING DEPRESSION AND FOCAL BRAIN ISCHEMIA INDUCE CYCLOOXYGENASE-2IN CORTICAL-NEURONS THROUGH N-METHYL-D-ASPARTIC ACID-RECEPTORS AND PHOSPHOLIPASE A(2)

Repetitive spreading depression (SD) waves, involving depolarization o f neurons and astrocytes and upregulation of glucose consumption, is t hought to lower the threshold of neuronal death during and immediately after ischemia., Using rat models for SD and focal ischemia me invest igated the expression of cyclooxygenase-1 (COX-1), the constitutive fo rm, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme i n prostaglandin biosynthesis and the target enzymes for nonsteroidal a nti-inflammatory drugs, Whereas COX-I mRNA levels were undetectable an d uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia, The cortical induction was reduced by MK-801, an N-methyl-D -aspartic acid-receptor antagonist, and by dexamethasone and quinacrin e, phospholipase A(2) (PLA(2)) inhibiting compounds, MK-801 acted by b locking SD whereas treatment with PLA(2) inhibitors preserved the wave propagation. NBQX, an lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropio nic acid/kainate-receptor antagonist, did not affect the Sn-induced CO X-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, N-G-nitro-L-arginine methyl ester, t ended to enhance the COX-2 mRNA expression, In addition, ischemia indu ced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells, Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptor s and PLA(2), most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.