| Autor: |
Yang J; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA., Betterton RD; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Williams EI; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Stanton JA; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Reddell ES; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Ogbonnaya CE; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Dorn E; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Davis TP; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Lochhead JJ; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Ronaldson PT; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA. |
| Abstrakt: |
The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood-brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague-Dawley rats (12-16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [ 14 C]sucrose and [ 3 H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [ 14 C]sucrose "leak" and brain [ 3 H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products. |
