RESUMEN
The prevention and treatment of sepsis associated encephalopathy (SAE) remains challenging in clinic. Besides the anti-infection treatments and goal-directed supportive treatments, no specific method is reported for the prevention and treatment of SAE. This study tried to investigate the effects and underlying mechanisms of small dose of L-dopa/Benserazide hydrochloride (L-DA) on SAE. We found that L-DA administration (i.p.) at early stage of sepsis, but not at late stage, improved learning and memory of sepsis surviving mice in Cecal ligation and perforation (CLP) model. Corresponding to the improvement of learning and memory in CLP model, L-DA administration limited neuroinflammation, improved neuroplasticity, reversed sepsis-induced decrease of hippocampal dopamine level, but had no obvious effects on the survival and body weight recovery. Further studies showed that specific inhibitors of dopamine D1 or D2 receptors both partly reduced the protective effect of L-DA on the learning and memory of lipopolysaccharides (LPS) treated mice. D1 receptor specific inhibitor significantly blocked the anti-neuroinflammation effects of L-DA in LPS treated mice, but D2 receptor inhibitor did not. All these suggest that L-DA administration could prevent and treat SAE via dopamine D1 and D2 receptors. Dopamine D1 receptor is a potential target of anti-neuroinflammation.
Asunto(s)
Benserazida/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Levodopa/uso terapéutico , Neuroinmunomodulación/efectos de los fármacos , Animales , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Hipocampo/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroinmunomodulación/fisiología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Sepsis/complicaciones , Encefalopatía Asociada a la Sepsis/fisiopatologíaRESUMEN
Neuroinflammation plays a critical role in the pathogenesis of postoperative cognitive dysfunction (POCD) of the elderly patients. Receptor-interacting protein kinase1 (RIPK1) is a key molecular switch modulating inflammation, apoptosis and necroptosis. Here, we investigated whether inhibiting RIPK1 by necrostatin-1 (Nec-1) could limit neuroinflammation and attenuate POCD in D-Galactose (D-Gal)-induced aged mice. The mice were subjected to anesthesia and partial hepatectomy, and necrostatin-1 was administered intraperitoneally 1 h prior to anesthesia and surgery. Cognitive function and movement were tested 24 h after surgery by open field, Barnes maze and puzzle box. The hippocampal tissues were collected to detect the following: neuroinflammation (Iba-1, IL-1α, IL-1ß, TNF-α), Necroptosis (Propidium Iodide (PI) labeling, RIPK1, nuclear transcription factor kappa B (NF-κB) and neuroplasticity (doublecortin (DCX), NR2B, GluA1, GluA2). We found that anesthesia and surgery induced a significant deficit in spatial memory acquisition and impairment of executive function and memory to simple task in D-Galactose-induced aged mice. Inhibiting RIPK1 by necrostatin-1 strikingly mitigated cognitive impairment and alleviated postoperative amplified neuroinflammation, necroptosis and GluA1 loss in hippocampus. These suggest that targeting RIPK1 by necrostatin-1 may serve as a promising therapeutics for prevention of POCD in elderly patients.
RESUMEN
Occurrence of postoperative cognitive dysfunction (POCD) is age-dependent and heterogenous. Factors deciding the occurrence of POCD in patients of the same age undergone same surgeries remain unclear. Here we investigated the effects of pre-existing weakness on the occurrence of POCD in mice of the same age. Pre-existing weakness of mice was induced by intraperitoneal injection of lipopolysaccharide (8mg/kg) and was evaluated by physical frailty index (by open field test), neuroinflammation level (by Iba1 immunostaining and inflammatory factors TNF-α and IL-1ß), and neuronal activity (by p-CREB immunostaining). POCD was induced by partial hepatolobectomy and was evaluated by puzzle box test and Morris water maze test. The brains were collected to detect the levels of neuroinflammation, synaptophysin and NMDA receptor subunits NR2A, NR2B and NR1 (by western blot), and oxidative stress (by Dihydroethidium). Compared to the normal adult mice of the same age, LPS pretreated mice had increased physical frailty index, higher levels of neuroinflammation, and lower neuronal activity. Partial hepatolobectomy induced obvious impairments in executive function, learning and memory in LPS pretreated mice after surgery, but not in normal mice of the same age. Partial hepatolobectomy also induced heightened neuroinflammation, obvious loss of NMDA receptor subunits, strong oxidative stress in LPS pretreated mice on the 1st and 3rd postoperative day. However, the POCD-associated pathological changes didn't occur in normal mice of the same age after surgery. These results suggest that pre-existing weakness is critical for the occurrence of POCD in mice of the same age.