Acetate supplementation modulates brain adenosine metabolizing enzymes and adenosine A2A receptor levels in rats subjected to neuroinflammation

Journal of Neuroinflammation

Thad A Rosenberger¹  Jonathan D Geiger¹  Dhaval P Bhatt¹  Mark D Smith¹ 

[1] Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota 58203, USA

关键词: neuroinflammation;    lipopolysaccharide;    glyceryl triacetate;    ecto-5’-nucleotidase;    brain;    adenosine A_2A receptor;    adenosine kinase;    adenosine;    acetate;   

Others  :  803870
DOI  :  10.1186/1742-2094-11-99

 received in 2013-11-12, accepted in 2014-05-19,  发布年份 2014

【 摘 要 】

Background

Acetate supplementation reduces neuroglia activation and pro-inflammatory cytokine expression in rat models of neuroinflammation and Lyme neuroborreliosis. Because single-dose glyceryl triacetate (GTA) treatment increases brain phosphocreatine and reduces brain AMP levels, we postulate that GTA modulates adenosine metabolizing enzymes and receptors, which may be a possible mechanism to reduce neuroinflammation.

Methods

To test this hypothesis, we quantified the ability of GTA to alter brain levels of ecto-5’-nucleotidase (CD73), adenosine kinase (AK), and adenosine A_2A receptor using western blot analysis and CD73 activity by measuring the rate of AMP hydrolysis. Neuroinflammation was induced by continuous bacterial lipopolysaccharide (LPS) infusion in the fourth ventricle of the brain for 14 and 28 days. Three treatment strategies were employed, one and two where rats received prophylactic GTA through oral gavage with LPS infusion for 14 or 28 days. In the third treatment regimen, an interventional strategy was used where rats were subjected to 28 days of neuroinflammation, and GTA treatment was started on day 14 following the start of the LPS infusion.

Results

We found that rats subjected to neuroinflammation for 28 days had a 28% reduction in CD73 levels and a 43% increase in AK levels that was reversed with prophylactic acetate supplementation. CD73 activity in these rats was increased by 46% with the 28-day GTA treatment compared to the water-treated rats. Rats subjected to neuroinflammation for 14 days showed a 50% increase in levels of the adenosine A_2A receptor, which was prevented with prophylactic acetate supplementation. Interventional GTA therapy, beginning on day 14 following the induction of neuroinflammation, resulted in a 67% increase in CD73 levels and a 155% increase in adenosine A_2A receptor levels.

Conclusion

These results support the hypothesis that acetate supplementation can modulate brain CD73, AK and adenosine A_2A receptor levels, and possibly influence purinergic signaling.

【 授权许可】

   
2014 Smith et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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Figure 3.

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