Comparison of pharmacological and genetic inhibition of cyclooxygenase-2: effects on adult neurogenesis in the hippocampal dentate gyrus

Abstract

Inducible cyclooxygenase-2 (COX-2) has received much attention because of its role in neuro-inflammation and synaptic plasticity. Even though COX-2 levels are high in healthy animals, the function of this factor in adult neurogenesis has not been clearly demonstrated. Therefore, we performed the present study to compare the effects of pharmacological and genetic inhibition of COX-2 on adult hippocampal neurogenesis. Physiological saline or the same volume containing celecoxib was administered perorally every day for 5 weeks using a feeding needle. Compared to the control, pharmacological and genetic inhibition of COX-2 reduced the appearance of nestin-immunoreactive neural stem cells, Ki67-positive nuclei, and doublecortin-immunoreactive neuroblasts in the dentate gyrus. In addition, a decrease in phosphorylated cAMP response element binding protein (pCREB) at Ser133 was observed. Compared to pharmacological inhibition, genetic inhibition of COX-2 resulted in significant reduction of neural stem cells, cell proliferation, and neuroblast differentiation as well as pCREB levels. These results suggest that COX-2 is part of the molecular machinery that regulates neural stem cells, cell proliferation, and neuroblast differentiation during adult hippocampal neurogenesis via pCREB. Additionally, genetic inhibition of COX-2 strongly reduced neural stem cell populations, cell proliferation, and neuroblast differentiation in the dentate gyrus compared to pharmacological inhibition.

Age-associated alterations in constitutively expressed cyclooxygenase-2 immunoreactivity and protein levels in the hippocampus

“…COX-2 immunoreactivity was identified in the granule cells of the dentate gyrus, and the pyramidal cells of the hippocampal CA2/3 region. This result is consistent with previous studies involving mice and rats (7,9). In humans, significant neuronal COX-2 immunoreactivity has been identified in the CA3 region, subiculum, entorhinal cortex and transentorhinal cortex (17).…”

“…Previous studies have demonstrated that constitutive COX-2 expression is closely associated with neuroblast differentiation in the dentate gyrus (7,9). The present study observed age-associated alterations in constitutive COX-2 expression in the hippocampus.…”

“…Previous studies have demonstrated that treadmill exercise significantly increases neurogenesis and COX-2 immunoreactivity in the rat hippocampus (7,8). In addition, the pharmacological or genetic inhibition of COX-2 significantly reduces constitutive COX-2 immunoreactivity, as well as the number of differentiated neuroblasts in the hippocampus (7,9).…”

Hypothyroidism increases cyclooxygenase-2 levels and pro-inflammatory response and decreases cell proliferation and neuroblast differentiation in the hippocampus

“…In certain types of brain injury, COX-2 serves multiple roles in the regulation of adult hippocampal neurogenesis in the dentate gyrus ( 20 – 22 ). Knockdown of COX-2 significantly reduces the number of proliferating cells and differentiated neuroblasts in the dentate gyrus compared with wild-type littermates ( 21 , 22 ). In a previous study ( 23 ), we demonstrated that the blocking constitutive COX-2 in the hippocampus by celecoxib, a COX-2 inhibitor, significantly decreased cell proliferation and neuroblast differentiation in the dentate gyrus.…”

Neuro-inflammatory effects of photodegradative products of bilirubin

“…Numerous studies have also reported that pro-inflammatory cytokines exert harmful effects on neurogenesis 34 . Upregulation of pro-inflammatory IL-1β, IL-6, and TNF-α triggers additional pathways, such as COX-2 37 , which is also implicated neuro-inflammation and neurogenesis 38 , although COX-2 seems to have an opposite effect compared to pro-inflammatory cytokines. The upregulation of COX-2 observed in our study might represent a feedback mechanism that is invoked to compensate for impaired (e.g.…”