RESUMEN
Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 µg · kg-1 · d-1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg-1 · d-1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 µΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.
Asunto(s)
Artemisininas/uso terapéutico , Microglía/efectos de los fármacos , Trastornos Neurocognitivos/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/patología , Muerte Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Microglía/metabolismo , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/metabolismo , Neuronas/efectos de los fármacos , Sepsis/inducido químicamente , Sepsis/complicaciones , Sepsis/metabolismoRESUMEN
Recent studies demonstrated that FoxO3 circular RNA (circFoxO3) plays an important regulatory role in tumourigenesis and cardiomyopathy. However, the role of circFoxO3 in neurodegenerative diseases remains unknown. The aim of this study was to examine the possible role of circFoxO3 in neurodegenerative diseases and the underlying mechanisms. To model human neurodegenerative conditions, hippocampus-derived neurons were treated with glutamate. Using molecular and cellular biology approaches, we found that circFoxO3 expression was significantly higher in the glutamate treatment group than that in the control group. Furthermore, silencing of circFoxO3 protected HT22 cells from glutamate-induced oxidative injury through the inhibition of the mitochondrial apoptotic pathway. Collectively, our study demonstrates that endogenous circFoxO3 plays a key role in inducing apoptosis and neuronal cell death and may act as a novel therapeutic target for neurodegenerative diseases.
