The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain.
OBJECTIVE
In adults, neurogenesis persists in the hippocampus and the subventricular zone (SVZ), and this is important for learning and memory. Inhibitors of COX-2 suppress ischaemia-induced neurogenesis in the hippocampus. Here, we have determined the effects of COX-2 inhibitors on neurogenesis throughout the normal adult mouse brain.


METHODS
Young adult mice were treated with COX-2 inhibitors, and the proliferation of neural progenitor cells was measured in the SVZ and hippocampus. In addition, the local uptake of lentiviral vectors in the rostral migratory stream enabled the formation of new neurons in the olfactory bulb (OB) to be assessed.


RESULTS
The COX-2 inhibitor meloxicam suppressed progenitor cell proliferation in the SVZ and hippocampus. A significant decrease in the appearance of new neurons in the OB was also observed. Similar effects on progenitor proliferation in the SVZ were seen with nimesulide. The absence of COX-2 expression in the proliferating progenitors in vivo, and the lack of effect of the COX-2 inhibitors on the growth rate of a cultured progenitor cell line, suggest that the effect is indirect. The specific expression of COX-2 in resting microglia that closely associate with the proliferating progenitor cells provides for a possible site of action.


CONCLUSIONS
Treatment with a COX-2 inhibitor results in a substantial inhibition of adult neurogenesis. Studies on human tissues are warranted in order to determine if this effect extends to humans, and whether inhibition of neurogenesis should be considered as an adverse effect of these drugs.
Goncalves
Maria Beatriz
MB
Wolfson Centre for Age-related Diseases, King's College, London, UK.
Williams
Emma-Jane
EJ
Yip
Ping
P
Yáñez-Muñoz
Rafael J
RJ
Williams
Gareth
G
Doherty
Patrick
P
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D000077239:Meloxicam; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; D051546:Cyclooxygenase 2; C012655:nimesulide; D000077239:Meloxicam