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.
Highlights
Cyclooxygenase-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
Celecoxib improved sensorimotor behavioral deficits induced by LPS exposure Compared with the control group, LPS-injection in postnatal Day 5 (P5) rats resulted in sensorimotor behavioral deficits at P6 (Figure 1A, B)
The current study showed that treatment with a selective COX-2 inhibitor, celecoxib, elicited anti-inflammatory effects, as evidenced by the attenuation of LPS-induced increases in the number of activated microglia and in the concentration of IL-1β in neonatal rat brains
Summary
Cyclooxygenase-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. The timing of maternal infection during pregnancy appears to play a crucial role in the neurodevelopmental responses/outcomes of offspring, and late gestational infection has been reported to induce perseverative behavior, which is implicated in schizophrenia and autistic spectrum disorders [1]. Our recent studies have shown that neonatal exposure to lipopolysaccharide (LPS) through an intracerebral (i.c.) injection in the rat brain (at P5, relevant to human intrauterine infection in late gestation) can produce brain inflammation, nigrostriatal dopaminergic injury and neurobehavioral dysfunction [3,4,5,6,7,8]. It is possible that LPS may reach the fetal brain during maternal infection
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