Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor.
Cyclooxygenase (COX), which is present in two isoforms (COX1 and 2), synthesizes prostaglandins from arachidonic acid; it plays a crucial role in inflammation in both central and peripheral tissues. Here, we describe its role in synaptic plasticity and spatial learning in vivo via an effect on brain-derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2; both measured by Elisa). We found that broad-spectrum COX inhibition (BSCI) inhibits the induction of long-term potentiation (LTP; the major contemporary model of synaptic plasticity), and causes substantial and sustained deficits in spatial learning in the watermaze. Increases in BDNF and PGE2 following spatial learning and LTP were also blocked. Importantly, 4 days of prior exercise in a running wheel increased endogenous BDNF levels sufficiently to reverse the BSCI of LTP and spatial learning, and restored a parallel increase in LTP and learning-related BDNF and PGE2. In control experiments, we found that BSCI had no effect on baseline synaptic transmission or on the nonhippocampal visible-platform task; there was no evidence of gastric ulceration from BSCI. COX2 is inhibited by glucorticoids; there was no difference in blood corticosterone levels as measured by radioimmunoassay in any condition. Thus, COX plays a previously undescribed, permissive role in synaptic plasticity and spatial learning via a BDNF-associated mechanism.
Shaw
Kendra N
KN
Department of Psychology and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
Commins
Sean
S
O'Mara
Shane M
SM
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000032:analysis; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D007052:Ibuprofen / Q000494:pharmacology*; D007124:Immunoenzyme Techniques / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013037:Spatial Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D003345:Corticosterone; D007052:Ibuprofen