Efeito neuroprotetor da inibição do transportador de glicina do tipo 1

• Ano de defesa: 2014
• Autor(a) principal: Mauro Cunha Xavier Pinto
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Neuroproteção; Transportador de glicina do tipo 1; Neurotransmissão glutamatérgica; Isquemia; Pré-condicionamento cerebral; Precondicionamento isquêmico; Fármacos neuroprotetores/uso terapêutico; Glicina; Isquemia encefálica; Drogas neurotrópicas; Neurofarmacologia; Proteínas de transporte de neurotransmissores
• Link de acesso: http://hdl.handle.net/1843/BUBD-9HLFPK

Brain ischemic tolerance is a protective mechanism achieve by a preconditioning stimulus that prepare the tissue against a harmful insult. This phenomenon can be induced by activation of NMDA receptors (NMDAR) in neurons. Recently, the glycine transporters type 1 (GlyT-1) have been shown to potentiate glutamate neurotransmission through NMDA receptors, suggesting an alternative pathway to induce brain preconditioning. In this study, we evaluated the brain preconditioning induced by two GIyT-1 inhibitors (sarcosine and NFPS) in different models of brain damage. In the first part, we tested sarcosine, a competitive blocker of GlyT-1, which was administered for seven consecutive days before the induction of ischemia models in rats. Sarcosine preconditioning reduced cell death in hippocampal slices submitted to oxygen glucose deprivation (OGD) and four vessels occlusion (4VO) model. During the period of ischemia, the preconditioned animals with sarcosine showed a reduction of glutamate release, the production of nitric oxide and reactive oxygen species. These effects were associated with reduction in glycine transporters expression (GIyT-1 and GlyT-2), reduction of [3H]-glycine uptake and reduction in the glycine level in hippocampus. Interestingly, sarcosine preconditioning reduced expression of NR2Bcontaning NMDAR, which is associated with high susceptibility to excitotoxicity. In the second step, we evaluated the effect of preconditioning with NFPS, a noncompetitive blocker of GIyT-1, in mice submitted to excitotoxic damage induced by intrahippocampal injection of NMDA. NFPS preconditioning generated a neuroprotective effect in hippocampus, being this effect also related to reduction of NR2B-contaning NMDAR. This study demonstrates that brain preconditioning with GlyT-1 inhibitors induces ischemic tolerance and resistance against excitotoxicity, being that neuroprotection related to neuromodulation of glycinergic neurotransmission and reduction of NR2B-contaning NMDAR.