Involvement of COX-2 in the Neurovascular Unit Damage Through Up-Regulating Calpain/PARP/NF-κB Inflammatory Signaling...

Cyclooxygenase-2 (COX-2), a key enzyme to catalyzes the formation of prostanoids from arachidonic acid, is involved in inflammatory events. Furthermore, the calpain/PARP/NF-κB inflammatory pathway has been implicated in the damage to the neurovascular unit (NVU) following ischemic stroke. This study investigated the effects of parecoxib, a specific COX-2 inhibitor, on calpain, PARP, NF-κB inflammatory signaling, and NVU damage in the rat model of ischemic stroke. Male Sprague-Dawley rats (n = 107) were subjected to 90 min of ischemia, followed by reperfusion. Parecoxib was administered intraperitoneally 5 min post-ischemia, and the activation of calpain, PARP, and NF-κB-inflammatory signaling, and the NVU damage were evaluated 24 h post-ischemia. It was found that parecoxib alleviated neurological deficits, brain swelling and apoptotic cell death, and decreased infarct volumes 24 h post-ischemia. It decreased the levels of calpain 1 and 2, enhanced the levels of calpastatin, and repressed the activities of calpain in penumbra and core. Meanwhile, it reduced the levels of cytosolic PARP and HMGB1, elevated the level of cytosolic IκBα, lowered the levels of nuclear PARP, poly(ADP-ribose) and NF-κB p65, lessened the levels of cytosolic ICAM-1, IL-1β, MMP-2, and MMP-9, and suppressed the MPO activities in penumbra and core. Additionally, it attenuated the NVU and blood-brain barrier damage in penumbra and core. These data demonstrated that parecoxib exerts its protective effects on the NVU by blocking the over-activation of calpain and PARP, as well as by suppressing NF-κB-mediated inflammatory response during ischemic stroke. Moreover, the findings suggest that COX-2 contributes to NVU damage by up-regulating the calpain/PARP/NF-κB inflammatory pathway during brain ischemia.