■接受手术的老年患者容易出现认知功能下降,称为围手术期神经认知障碍(PND)。多项研究表明,手术引起的肠道小胶质细胞活化和短链脂肪酸(SCFAs)减少可能与PND的发病机制有关。这项研究的目的是确定小胶质细胞和短链脂肪酸是否参与老年大鼠的认知功能障碍。
■将11-12月龄雄性野生型Wistar大鼠随机分为对照组(Ctrl:Veh组),丙酸组(Ctrl:PA组),根据是否进行剖腹探查(LP)或PA预处理21天,剖腹探查组(LP:Veh组)和丙酸剖腹探查组(LP:PA组)。术后第3天(POD3)通过开放视野测试评估大鼠的运动能力,然后通过Y迷宫测试和恐惧条件测试评估认知功能。IL-1β的表达,RT-qPCR检测海马IL-6、RORγt和IL-17AmRNA,Westernblot检测海马IL-17A和IL-17RA的表达,免疫荧光法检测小胶质细胞的活化。
■通过剖腹手术成功建立了PND大鼠模型。与Ctrl:Veh组相比,LP:Veh组体重下降,Y迷宫中自发交替的百分比降低(P<0.001),情境恐惧测验中冻结时间百分比下降(P<0.001)。手术引发神经炎症,表现为炎性细胞因子IL-1β(P<0.001)和IL-6(P<0.001)水平升高,转录因子RORγt(P=0.0181,POD1;P=0.0073,POD5)和主要炎症因子IL-17A(P=0.0215,POD1;P=0.0071,POD5)的表达增加,Iba1的平均荧光强度增加(P<0.001,POD1;P<0.001,POD5)。PA预处理后,LP:PA组大鼠的恢复速度快于LP:Veh组,POD1组大鼠的体重下降(P=0.0148)接近POD5组的基线水平(P=0.1846),他们在行为测试中表现更好。POD1上海马IL-1β(P<0.001)和IL-6(P=0.0035)炎症因子水平降低,Iba1平均荧光强度降低(P=0.0024,POD1;P<0.001,POD5),代表神经炎症明显改善。此外,海马中RORγtmRNA(P=0.0231,POD1;P=0.0251,POD5)和IL-17AmRNA(P=0.0208,POD1;P=0.0071,POD5)的表达以及IL-17A(P=0.0057,POD1;P<0.001,POD5)和IL-17RA(P=0.0388)的表达降低。
■PA预处理可减少术后神经炎症并改善认知功能,可能归因于PA对Th17介导的免疫反应的调节作用。
UNASSIGNED: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats.
UNASSIGNED: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence.
UNASSIGNED: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1β (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased.
UNASSIGNED: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.