Assessment of the effects of the cyclooxygenase-2 inhibitor rofecoxib on visuospatial learning and hippocampal cell death following kainate-induced seizures in the rat.
Kainate-induced seizures result in hippocampal neurodegeneration and spatial learning deficits in rodents. Previous studies show that rofecoxib, a selective cyclooxygenase-2 inhibitor, protects against kainate-induced hippocampal cell death 3 days after seizures. Our aim was to determine whether rofecoxib attenuates visuospatial learning deficits and late neuronal death after kainate-induced seizures. Seizures were induced in Sprague-Dawley rats with kainic acid (10 mg/kg, i.p.). Eight hours later, animals received rofecoxib (10 mg/kg; n = 15) or vehicle (dimethylsulfoxide, n = 11). Animals were then treated daily for additional 2 or 9 days. Visuospatial learning was assessed in the Morris water maze (MWM) on days 5-9 after seizures. Seizure animals learned the MWM task significantly slower than non-seizure controls, but seizure animals showed higher swim speed (P < 0.05). Seizure animals receiving rofecoxib for 2 days showed no significant improvement in acquisition of the task compared to the vehicle group, even though mean latencies in the rofecoxib group were shorter from the third trial day onwards. This tendency was lost when rofecoxib was given for 9 days. TdT-mediated dUTP nick end labelling showed cell death in limbic structures 9 days after seizures. The time course of kainate-induced hippocampal cell death might be delayed by rofecoxib treatment, as the attenuation of cell death observed 3 days after seizures was no longer present after 9 days. We conclude that even though increasing evidence points to an injurious role of cyclooxygenase-2 products in acute brain injury processes, rofecoxib treatment failed to attenuate seizure-induced visuospatial learning deficits and the late phase of hippocampal neurodegeneration.
Kunz
Tina
T
Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, SE-751 24 Uppsala, Sweden. t.kunz@dundee.ac.uk
Marklund
Niklas
N
Hillered
Lars
L
Oliw
Ernst H
EH
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists; D006624:Hippocampus / Q000166:cytology / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000523:psychology*; D013450:Sulfones / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D018690:Excitatory Amino Acid Agonists; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D007608:Kainic Acid