title: Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation.
abstract: Glyceryl triacetate (GTA), a compound effective at increasing circulating and tissue levels of acetate was used to treat rats subjected to a continual 28 day intra-ventricular infusion of bacterial lipopolysaccharide (LPS). This model produces a neuroinflammatory injury characterized by global neuroglial activation and a decrease in choline acetyltransferase immunoreactivity in the basal forebrain. During the LPS infusion, rats were given a daily treatment of either water or GTA at a dose of 6 g/kg by oral gavage. In parallel experiments, free-CoA and acetyl-CoA levels were measured in microwave fixed brains and flash frozen heart, liver, kidney and muscle following a single oral dose of GTA. We found that a single oral dose of GTA significantly increased plasma acetate levels by 15 min and remained elevated for up to 4 h. At 30 min the acetyl-CoA levels in microwave-fixed brain and flash frozen heart and liver were increased at least 2.2-fold. The concentrations of brain acetyl-CoA was significantly increased between 30 and 45 min following treatment and remained elevated for up to 4 h. The concentration of free-CoA in brain was significantly decreased compared to controls at 240 min. Immunohistochemical and morphological analysis demonstrated that a daily treatment with GTA significantly reduced the percentage of reactive glial fibrillary acidic protein-positive astrocytes and activated CD11b-positive microglia by 40-50% in rats subjected to LPS-induced neuroinflammation. Further, in rats subjected to neuroinflammation, GTA significantly increased the number of choline acetyltransferase (ChAT)-positive cells by 40% in the basal forebrain compared to untreated controls. These data suggest that acetate supplementation increases intermediary short chain acetyl-CoA metabolism and that treatment is potentially anti-inflammatory and neuroprotective with regards to attenuating neuroglial activation and increasing ChAT immunoreactivity in this model.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Reisenauer
authors.forename: Dhaval P
authors.initials: DP
authors.lastname: Bhatt
authors.forename: Dane J
authors.initials: DJ
authors.lastname: Mitteness
authors.forename: Evan R
authors.initials: ER
authors.lastname: Slanczka
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Gienger
authors.forename: John A
authors.initials: JA
authors.lastname: Watt
authors.forename: Thad A
authors.initials: TA
authors.lastname: Rosenberger
mesh_terms: D000085:Acetates / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004660:Encephalitis / Q000139:chemically induced* / Q000178:diet therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000085:Acetates; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D002795:Choline O-Acetyltransferase