title: Acetate supplementation modulates brain adenosine metabolizing enzymes and adenosine A₂A receptor levels in rats subjected to neuroinflammation.
abstract: 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 A2A 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 A2A 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 A2A receptor levels.
  
  
  CONCLUSIONS
  These results support the hypothesis that acetate supplementation can modulate brain CD73, AK and adenosine A2A receptor levels, and possibly influence purinergic signaling.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Smith
authors.forename: Dhaval P
authors.initials: DP
authors.lastname: Bhatt
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Geiger
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota 58203, USA. thad.rosenberger@med.und.edu.
authors.forename: Thad A
authors.initials: TA
authors.lastname: Rosenberger
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000248:Adenosine Kinase / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000085:Acetates; D008070:Lipopolysaccharides; D043683:Receptors, Adenosine A2; D000248:Adenosine Kinase; D015720:5'-Nucleotidase