Avaliação dos efeitos de um inibidor da calcineurina em modelos experimentais da doença de Alzheimer

Abstract

Alzheimer’s disease (AD) is the main cause of dementia worldwide. Thus, a better comprehension of its physiopathology and the search for new therapeutic targets are necessary. In this sense, the calcineurin (CN), a protein involved in various functions, such as synaptic plasticity, neuronal survival and immune response, seems to play an important role in the physiopathology of DA. The aim of the present study was to investigate the effects of FK506 (FK), a calcineurin inhibitor, on behavioral, histological and biochemical changes observed in models of neurotoxicity induced by NMDA or Aβ, in the transgenic mouse model for DA and in organotypic hippocampal slice cultures stimulated with NMDA. For this, male C57BL/6 mice, aged 8 to 12 weeks, were treated with 2.5, 5 or 10 mg/kg of FK or vehicle, 80 minutes before receiving intrahippocampal microinjection of Aβ (400 pmol) or NMDA (40 nmol), or even sterile saline. For cognitive evaluation, we performed the novel object recognition test (NORT). In addition, we evaluated neuronal viability, microgliosis and activation of pro-survival pathways in the hippocampus (HIP) of these mice. We observed impairment in TRO in animals injected with NMDA or Aβ. The behavioral impairment was associated with Fluoro-Jade C staining (FJC) and microgliosis in HIP. The treatment with FK had a protective effect on cognitive impairment in both NMDA and Aβ model and reduced the FJC staining and the microgliosis found in Aβ model. The FK also protected against the reduction of NeuN expression induced by NMDA in organotypic cultures. Additionally, we evaluated the effects of the chronic treatment with FK in the APP/PS1 transgenic model. For this purpose, male APP/PS1 or littermates, aged 12 months, were treated for 30 days with FK (5 mg/kg) or vehicle. Behavioral analysis was performed using open field task (OF), elevated-plus maze (EPM), social interaction (SI) and social memory (SM). We also evaluated neuronal viability, Aβ plaques load, and microgliosis in the HIP and the levels of neurotrophic factors and cytokines in the HIP and in the prefrontal cortex. The chronic treatment with FK reversed the behavioral changes in EPM and SI observed in APP/PS1 mice. In addition, FK treatment reduced the microgliosis found in the CA1 of hippocampus of transgenic animals. Together, these results suggest the potential protective effect of FK in the pathology observed in AD.