RESUMO
Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.
Assuntos
Multimerização Proteica , Receptor A2A de Adenosina/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptor A2A de Adenosina/química , Receptor Tipo 1 de Angiotensina/química , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/metabolismoRESUMO
Este trabalho relata a influência da escultura do palato das próteses totais na reabilitação fonética de um paciente vítima de acidente vascular cerebral. A técnica mostrou-se eficaz para facilitar a adaptação fonética no período pós-instalação das próteses, conferindo segurança e melhor convívio social ao paciente
