Celecoxib delays cognitive decline in an animal model of neurodegeneration

Abstract Cyclooxygenase-2 (COX-2) is thought to play a role in the pathogenesis of various neurodegenerative disorders. However, clinical trials with COX-2 inhibitors have yielded contradictory results. In the present study we investigated whether COX-2 plays a role in the behavioral and cognitive impairments seen in olfactory bulbectomized rats. These impairments arise from neurodegenerative processes. First, we determined the time course of the OBX-induced behavioral (hyperactivity) and cognitive changes (fear memory) and how these correlate with changes in COX-2 mRNA expression in hippocampus. This experiment showed that the major impairments in behavior and cognition developed between Days 3 and 14 after OBX surgery, which correlated with changes in mRNA levels of COX-2, which increased at Days 7 and 14 after surgery but not anymore at day 28. In a subsequent experiment, rats were treated, starting two days before surgery, with the COX-2 inhibitor celecoxib (10 mg/kg, dissolved in drinking water) for 4 weeks. OBX-induced hyperactivity in the open field was normalized after 2 weeks of celecoxib treatment, but not longer after 4 weeks. Celecoxib partly rescued fear learning and memory deficits without affecting spatial memory. The effects of celecoxib on fear memory lasted up to 1 week posttreatment, but disappeared thereafter. Our results show that COX-2 plays a limited role (both in magnitude and time) in the development of the OBX syndrome.