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Suppressive action of propentofylline on coupled and uncoupled glucose oxidations in brain synaptosomes
Author(s) -
Andjus R. K.,
Ćirković T.,
Marjanović M.,
Stefanovich V.
Publication year - 1988
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430130107
Subject(s) - xanthine , chemistry , pharmacology , in vivo , depressant , metabolism , oxidative phosphorylation , ischemia , theophylline , xanthine oxidase , biochemistry , hypothermia , medicine , biology , microbiology and biotechnology , enzyme
Abstract In view of a possible beneficial action of some of the xanthine derivatives in brain ischemia or anoxia, metabolic effects of synthetic propentofylline (3‐methyl‐[5′ oxohexyl]‐7‐propyl‐xanthine) have been studied in multiple‐dose experiments with suspensions of rat brain synaptosomes incubated at various temperatures. The rate of D‐[ 14 C] glucose conversion to 14 CO 2 was measured in the absence or in the presence of 2,4‐dinitrophenol (DNP) used to uncouple oxidative phosphorylations and thus simulate mitochondrial uncoupling accompanying neuronal damage in brain ischemia. Propentofylline suppressed synaptosomal glucose oxidations in a dose‐dependent logit‐linear manner. At 15°C, ED 50 concentrations (responsible for the suppression of initial oxidation rates by one half) were highest (8 × 10 −3 M) in the case of low‐rate oxidations in Na‐free media and were lowest (7.4 × 10 −4 M) in respect to the high‐rate DNP‐stimulated metabolism, which thus appeared as particularly susceptible to propentofylline. Cold‐induced modifications of the metabolic responsiveness of snaptosomes to DNP (flattening of the biphasic DNP log dose‐response profile at reduced incubation temperatures) were intensified by propentofylline, suggesting a synergism between hypothermia and the depressant action of the drug. At equal concentrations, propentofylline strongly inhibited uncoupled oxidations while theophylline remained ineffective or induced even additional stimulatory effects. This is similar to the differential in vivo effects of the two xanthines on brain metabolism and blood flow coupling and further supports the possibility of a protective energy‐sparing role of propentofylline in brain ischemia, particularly effective in association with hypothermia.