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

Journal of Neuroinflammation

Lir-Wan Fan¹  Abhay J Bhatt¹  Satoshi Numazawa³  Sachiko Tanaka³  Zhengwei Cai¹  Yi Pang¹  Lu-Tai Tien²  Asuka Kaizaki³ 

[1] Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA;School of Medicine, Fu Jen Catholic University, Xinzhuang Dist, New Taipei City, 24205, Taiwan;Department of Pharmacology, Toxicology and Therapeutics, Division of Toxicology, School of Pharmacy, Showa University, Shingawa-ku, Tokyo, 142-8555, Japan

关键词: Astrocyte;    Microglia;    Substantia nigra;    Dopamine uptake;    Cyclooxygenase-2;   

Others  :  1160001
DOI  :  10.1186/1742-2094-10-45

 received in 2012-11-26, accepted in 2013-03-21,  发布年份 2013

【 摘 要 】

Background

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.

Methods

Intraperitoneal (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.

Results

Our 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.

Conclusion

Systemic 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.

【 授权许可】

   
2013 Kaizaki et al.; licensee BioMed Central Ltd.

【 图 表 】

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