Effect of desipramine and fluoxetine on energy metabolism of cerebral mitochondria.
Brain bioenergetic abnormalities in mood disorders were detected by neuroimaging in vivo studies in humans. Because of the increasing importance of mitochondrial pathogenetic hypothesis of Depression, in this study the effects of sub-chronic treatment (21days) with desipramine (15mg/kg) and fluoxetine (10mg/kg) were evaluated on brain energy metabolism. On mitochondria in vivo located in neuronal soma (somatic) and on mitochondria of synapses (synaptic), the catalytic activities of regulatory enzymes of mitochondrial energy-yielding metabolic pathways were assayed. Antidepressants in vivo treatment modified the activities of selected enzymes of different mitochondria, leading to metabolic modifications in the energy metabolism of brain cortex: (a) the enhancement of cytochrome oxidase activity on somatic mitochondria; (b) the decrease of malate, succinate dehydrogenase and glutamate-pyruvate transaminase activities of synaptic mitochondria; (c) the selective effect of fluoxetine on enzymes related to glutamate metabolism. These results overcome the conflicting data so far obtained with antidepressants on brain energy metabolism, because the enzymatic analyses were made on mitochondria with diversified neuronal in vivo localization, i.e. on somatic and synaptic. This research is the first investigation on the pharmacodynamics of antidepressants studied at subcellular level, in the perspective of (i) assessing the role of energy metabolism of cerebral mitochondria in animal models of mood disorders, and (ii) highlighting new therapeutical strategies for antidepressants targeting brain bioenergetics.
Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy. Electronic address: robertofederico.villa@unipv.it.
Roberto Federico
RF
Villa
Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
Federica
F
Ferrari
Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
Antonella
A
Gorini
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Nicoletta
N
Brunello
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Fabio
F
Tascedda
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D020543:Proteome / Q000187:drug effects; D040901:Proteomics; D017207:Rats, Sprague-Dawley
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D020543:Proteome; D005473:Fluoxetine; D003891:Desipramine
Functional Proteomics; brain energy metabolism; desipramine; fluoxetine; mitochondria