Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide

Abstract

BackgroundCyclooxygenase-2 (COX-2) is induced in inflammatory cells in response to cytokines and pro-inflammatory molecules, suggesting that COX-2 has a role in the inflammatory process. The objective of the current study was to examine whether celecoxib, a selective COX-2 inhibitor, could ameliorate lipopolysaccharide (LPS)-induced brain inflammation, dopaminergic neuronal dysfunction and sensorimotor behavioral impairments.MethodsIntraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in rat pups on postnatal Day 5 (P5), and celecoxib (20 mg/kg) or vehicle was administered (i.p.) five minutes after LPS injection. Sensorimotor behavioral tests were carried out 24 h after LPS exposure, and brain injury was examined on P6.ResultsOur results showed that LPS exposure resulted in impairment in sensorimotor behavioral performance and injury to brain dopaminergic neurons, as indicated by loss of tyrosine hydroxylase (TH) immunoreactivity, as well as decreases in mitochondria activity in the rat brain. LPS exposure also led to increases in the expression of α-synuclein and dopamine transporter proteins and enhanced [3H]dopamine uptake. Treatment with celecoxib significantly reduced LPS-induced sensorimotor behavioral disturbances and dopaminergic neuronal dysfunction. Celecoxib administration significantly attenuated LPS-induced increases in the numbers of activated microglia and astrocytes and in the concentration of IL-1β in the neonatal rat brain. The protective effect of celecoxib was also associated with an attenuation of LPS-induced COX-2+ cells, which were double labeled with TH + (dopaminergic neuron) or glial fibrillary acidic protein (GFAP) + (astrocyte) cells.ConclusionSystemic LPS administration induced brain inflammatory responses in neonatal rats; these inflammatory responses included induction of COX-2 expression in TH neurons and astrocytes. Application of the COX-2 inhibitor celecoxib after LPS treatment attenuated the inflammatory response and improved LPS-induced impairment, both biochemically and behaviorally.

Characterization of mitochondrial bioenergetics in neonatal anoxic model of rats

“…This demonstrates the sensorimotor deficiencies in early postnatal days in rats. It was reported that such deficits in sensorimotor activity are likely caused by subcortical damage in the neonatal brain (Fan et al 2005;Kaizaki et al 2013). The loss in sensorimotor function was observed when there was also loss of mitochondrial function post second episode of anoxia, but not after first episode.…”

“…The loss in sensorimotor function was observed when there was also loss of mitochondrial function post second episode of anoxia, but not after first episode. Therefore, our results indicate that in anoxic condition mitochondrial bioenergetics plays an important role in development of sensorimotor functions (Kaizaki et al 2013).…”

Cyclooxygenase 2 Inhibitor Celecoxib Inhibits Glutamate Release by Attenuating the PGE2/EP2 Pathway in Rat Cerebral Cortex Endings

“…These effects are likely to be associated with the neuroprotective activity of celecoxib (Hunter et al, 2007;López-Villodres et al, 2012;Kaizaki et al, 2013). We observed that celecoxib reduced glutamate release from nerve terminals, and this effect was dose-dependent and peaked at 30 mM with an IC 50 of 7 mM.…”

“…anti-inflammatory activity, and its neuroprotective action is generally assumed to be associated with this property (Hunter et al, 2007;López-Villodres et al, 2012;Kaizaki et al, 2013). However, the pharmacological mechanisms underlying the neuroprotective effects of celecoxib have not been fully clarified.…”

“…Celecoxib is a selective COX-2 inhibitor, and its neuroprotective action has been observed in several in vitro and in vivo experimental studies. For example, celecoxib attenuates oxygen and glucose deprivation-induced neuronal cell death (López-Villodres et al, 2012), protects against ischemiaor lipopolysaccharide-induced brain damage (Abd El-Aal et al, 2013;Fan et al, 2013;Kaizaki et al, 2013), improves kainic acid-induced cognitive impairment (Gobbo and O'Mara, 2004), and delays the progress of brain degeneration (Drachman et al, 2002;Small et al, 2008). Celecoxib is known to possess This work was supported by the National Science Council of Taiwan (NSC 101-2314-B-418-001).…”