Avaliação do efeito da rapamicina sobre a neuroinflamação e neurodegeneração em modelo de excitotoxicidade induzido por injeção intraestriatal de ácido quinolínico

Abstract

Huntington's disease (HD) is a autosomal dominant neurodegenerative disorder, characterized by symptoms attributed to the death of striatal and cortical neurons in the brain. The mechanism of neurodegeneration in HD seems to be related to excitotoxicity, oxidative stress and mitochondrial dysfunction. The intrastriatal injection of quinolinic acid is known to produce neurochemical alterations and motor impairment similar to that seen in Huntington's disease. The excitotoxic process may induce the production of inflammatory mediators that are regulated by several signaling pathways, such as activation of the PI3K/mTOR pathway. PI3K/mTOR pathway participates in neuronal excitability and glutamate uptake by astrocytes, events that may contribute to hyperexcitability and neuronal excitotoxicity. However, the exact role of mTOR in excitotoxicity is not currently understood. The objective of this study was to investigate the effects of mTOR inhibition against damage caused by striatal administration of single and unilateral QA (200 nmol) in mice .Rapamycin (0,2, 2, 20 µM/250 nL volume) was injected 15 minutes before the administration of QA and it was evaluated motility disorders, neurodegeneration and glial activation (astrocytes and microglia) 2 days after the administration of QA. Inflammatory mediators and neurotrophic factors were evaluated after 8 hours of QA administration. A single intrastriatal injection of QA (200 nmol) led to a significant decrease in motor coordination, increased mediators pro - inflammatory (IL-1β, IL-6 and TNF-α) and increased neurodegeneration in the ipsilateral striatum compared with the negative control group. The results of pharmacological treatment with rapamycin showed a distinct profile among the tested doses. In inflammatory parameter, all doses reversed the expression of pro - inflammatory cytokines and even the dose of 0.2 µM increased the expression of the anti-inflammatory cytokine IL-10. Furthermore, the lowest dose of rapamycin avoided the reduction of the astrocytic immunoreactivity induced by QA and reversed the motor impairment compared to the QA group. The results of this study provided evidence of the involvement of mTOR in the pathogenesis of Huntington's disease.