ABSTRACT
An in vivo method is presented that allows quantification and imaging of fatty acid incorporation into different brain phospholipids in relation to membrane synthesis, neuroplasticity, and signal transduction. The method can be used with positron emission tomography, and may help to evaluate brain phospholipid metabolism in humans with brain tumors, neurodegenerative disease, cerebral ischemia or trauma, or neurotoxic effects of drugs or other agents.
Subject(s)
Animals, Domestic , Brain/metabolism , Fatty Acids/metabolism , Neuronal Plasticity , Phospholipids/metabolism , Signal Transduction , Animals , Brain/diagnostic imaging , Brain/pathology , Fatty Acids/administration & dosage , Humans , Injections, Intravenous , Radionuclide ImagingABSTRACT
Awake adult rats were given a solution of [9,10-3H]palmitate ([3H]PAM) by gavage. The appearance of radiolabel in plasma lipid fractions was monitored by thin-layer chromatography at fixed intervals thereafter. At 2 h, the rats were killed by microwave irradiation and radioactivity in whole brain and individual brain phospholipids was determined. In plasma, esterified [3H]PAM was mainly associated with triglyceride, phospholipid, and cholesterol ester. Radioactivity appeared to a larger extent in triglyceride than in unesterified fatty acid, suggesting that unesterified [3H]PAM in plasma was largely due to release from esterified [3H]PAM by lipoprotein lipase hydrolysis. Brain radioactivity could be accounted for entirely by incorporation of unesterified plasma [3H]PAM. Esterified [3H]PAM in chylomicrons or lipoproteins was calculated to make no measurable contribution using a published value for the incorporation coefficient of [3H]PAM into brain in the evaluation. These results suggest that ingested palmitic acid (PAM) in adult rats enters blood as esterified triglyceride within chylomicrons and lipoproteins and, in part, eventually is converted to circulating unesterified PAM. It is the circulating unesterified PAM that is incorporated into brain from blood, whereas esterified PAM within plasma chlomicrons and lipoproteins makes no measurable direct contribution.
Subject(s)
Brain/metabolism , Esters/metabolism , Palmitic Acid/metabolism , Phospholipids/metabolism , Administration, Oral , Animals , Cholesterol Esters/blood , Chylomicrons/blood , Chylomicrons/metabolism , Esters/blood , Kinetics , Lipoproteins/blood , Lipoproteins/metabolism , Male , Palmitic Acid/blood , Rats , Rats, Sprague-Dawley , Triglycerides/bloodABSTRACT
The therapeutic efficacy of many anticancer drugs against intracerebral tumors is limited by poor uptake into the central nervous system. One way to enhance brain delivery is to design agents that are transported into the brain by the saturable nutrient carriers of the blood-brain barrier. In this paper, we describe a nitrogen mustard amino acid, DL-2-amino-7-bis[(2-chloroethyl)amino/bd-1,2,3,4-tetrahydro-2-napthoi c acid, that is taken up into brain with high affinity by the large neutral amino acid carrier of the blood-brain barrier. Brain transport of DL-2-amino-7-bis[(2-chloroethyl)aminol-1,2,3,4-tetrahydro-2-naphth oic acid in the rat was found to be rapid (cerebrovascular permeability-surface area product approximately 2 x 10(-2) ml/s/g), saturable and inhibitable by large neutral amino acids. Maximal influx rate (Vmax) and half-saturation (Km) constants equaled 0.26 nmol/min/g and 0.19 microM, respectively, in the parietal cortex. Regional brain uptake of acid exceeded that of the clinical analogue, melphalan, by greater than 20-fold. The results demonstrate that drug modification to produce high-affinity ligands for the cerebrovascular nutrient carriers is a viable means to enhance drug delivery to brain for the treatment of brain tumors and other central nervous system disorders.
