ABSTRACT
AIMS: To determine whether the blood-brain barrier (BBB) opens to enhance drug delivery during the acute stage of unsaturated fat embolism. METHODS: We infused oleic, linoleic, and linolenic acid emulsions through the right common carotid artery of rats, followed by trypan blue for gross and lanthanum for electron microscopic (EM) examination. Doxorubicin and temozolomide were also administered, and then the rats were euthanized at 30 min, 1 h, and 2 h. Trypan blue hue was analyzed to semiquantitatively measure BBB opening. Desorption electrospray ionization-mass spectrometry (DESI-MS) imaging was used to evaluate drug delivery. RESULTS: Trypan blue staining observed in each group 30 min after emulsion infusion increased at 1 h and decreased after 2 h in the oleic acid group. The linoleic and linolenic acid groups showed weak staining over time. The hue and trypan blue analysis results were corroborative. EM showed tight junction opening, whereas DESI-MS imaging showed increased doxorubicin and temozolomide signal intensities in ipsilateral hemispheres of all three groups. CONCLUSION: We demonstrated that oleic, linoleic, and linolenic acid emulsions opened the BBB, promoting drug delivery to the brain. Hue analysis and DESI-MS imaging are appropriate for analysis of doxorubicin and temozolomide concentrations in brain tissue.
Subject(s)
Fatty Acids, Nonesterified , alpha-Linolenic Acid , Rats , Animals , Emulsions , Temozolomide , Trypan Blue , Brain , Carotid Arteries , Carotid Artery, Common , Doxorubicin/pharmacologyABSTRACT
Aim: The purpose of this study was to assess changes in doxorubicin concentration in rabbit brain with respect to time after BBB opening induced by triolein emulsion infusion via a carotid artery and the mechanism of BBB opening.Materials and Methods: Doxorubicin (2.4 mg/kg) was infused immediately after triolein emulsion (1%) into rabbit carotid arteries. Bilateral hemispheres were harvested 2, 4, 6 12 and 24 h later and doxorubicin concentrations were measured fluorometrically. Doxorubicin concentration ratios of ipsilateral versus contralateral hemispheres were calculated, and a TEM study was performed to investigate the mechanism responsible for the increased vascular permeability induced by triolein.Results: Doxorubicin concentrations were higher in ipsilateral hemispheres at all time points, and peaked at 2 h after treatment. Doxorubicin was still detected in ipsilateral hemispheres at 24 h after treatment. TEM showed tight junction opening by triolein emulsion with lanthanum tracer spillage into neural interstitium and transcytotic vesicles.Conclusion: Doxorubicin was delivered into neural interstitium because of the increased vascular permeability of the BBB induced by triolein emulsion. Doxorubicin concentrations in brain peaked within 2 h of triolein and doxorubicin administration and remained high for 24 h. The study shows increased vascular permeability induced by triolein emulsion may involve paracellular and transcellular pathways.
