Nucleotidases e depressão: efeito de fármacos antidepressivos no catabolismo do ATP extracelular

• Ano de defesa: 2007
• Autor(a) principal: Pedrazza, Eduardo Luiz
• Orientador(a): Bonan, Carla Denise
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre
• Palavras-chave em Português: BIOLOGIA CELULAR; ANTIDEPRESSIVOS; DEPRESSÃO; NEUROTRANSMISSORES
• Link de acesso: http://hdl.handle.net/10923/1312

Depression is the most common manifestation of affective disorders. It is one of the most disable diseases, and causes a significant burden to both the individual and the society and, if not treated, it can increase morbidity and mortality. The use of antidepressants drugs is the base of depression treatment. The selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, and the tricyclic antidepressants, nortriptyline and clomipramine, are constantly used in the treatment for depression. Evidence has shown the important role performed by ATP and adenosine in the central nervous system. ATP can be stored and co-released with other neurotransmitters, such as noradrenaline and serotonin. Extracellular ATP can be hydrolyzed to adenosine by the action of ecto-nucleotidases. These ecto-enzymes promoted the enzymatic conversion of ATP, controlling the levels of this nucleotide and its nucleoside adenosine. Among the ecto-nucleotidases, we can highlight the NTPDases family and the ecto-5´-nucleotidase. Considering that: (i) adenosine exerts an important neuromodulatory role, (ii) ATP can be co-released with serotonin and noradrenaline, and (iii) the ecto-nucleotidases represent the main pathway for extracellular adenosine formation through ATP catabolism, become important to evaluate the effects of antidepressant drugs on the ecto-nucleotidases. Fluoxetine, sertraline, nortriptyline and clomipramine were tested for in vitro treatment, in the concentrations of 100, 250 and 5007M, in the blood serum and in hippocampal and cerebral cortex synaptosomes from rats. ATP and ADP hydrolysis were inhibited in a dose-dependent manner in the in vitro treatment with the four drugs in the hippocampal and cerebral cortex synaptosomes from rats, but AMP hydrolysis was not altered. The in vitro treatment did not affect any enzyme activities tested in rat blood serum. Fluoxetine and nortriptyline were used for the in vivo treatment in a dose of the 10mg/Kg. The acute treatment (1 hour after the administration) with nortriptyline promoted an inhibition on ATP hydrolysis in rat blood serum. However, the chronic treatment (14 dias) with both drugs caused an inhibition on NTPDases and ecto-5´-nucleotidasis activities in blood serum. Fluoxetine acute treatment did not alter the enzymes activities in synaptosomes of hippocampus and cerebral cortex. The acute treatment with nortriptyline induced an increase of ADP hydrolysis in cerebral cortex and a decrease of ATP and ADP hydrolysis in the hippocampus. The chronic treatment with fluoxetine promoted an inhibition of the ATP hydrolysis in the hippocampus and cerebral cortex and increased the ADP and AMP hydrolysis in the cerebral cortex. After chronic treatment with nortriptyline, there was a decrease of ATP hydrolysis in the hippocampus, but it was observed an increase of enzymes activities in cerebral cortex. The gene expressions of NTPDases and ecto-5´- nucleotidase were altered after acute and chronic treatments with fluoxetine and nortriptyline in hippocampus and cerebral cortex of rats. The findings demonstrated that these antidepressants drugs can affect the enzymes involved in the adenosine production, suggesting that the purinergic system can be a target to neurochemical effects promoted by these drugs.