Celecoxib delays cognitive decline in an animal model of neurodegeneration.
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.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, Netherlands. y.e.borre@uu.nl
Yuliya
Y
Borre
Susan
S
Lemstra
Koen G C
KG
Westphal
Mary E
ME
Morgan
Berend
B
Olivier
Ronald S
RS
Oosting
D000704:Analysis of Variance; D000818:Animals; D000068579:Celecoxib; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005434:Flow Cytometry; D008297:Male; D019636:Neurodegenerative Diseases / Q000150:complications*; D009830:Olfactory Bulb / Q000293:injuries; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D000068579:Celecoxib