Abstract
Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication. Neuroinflammation is a major cause that leads to PND. Autophagy, an intracellular process of lysosomal degradation, plays an important role in the development and maintenance of nervous system. PK11195 is a classic translocator protein (TSPO) ligand, which can improve the cognitive function of rats. In this study, we evaluate the protective effect of PK11195 on the learning and memory of rats. A rat model of lipopolysaccharide (LPS)-induced cognitive dysfunction was established by intraperitoneal injection of LPS. Morris Water Maze (MWM), Western blot, qRT-PCR, confocal microscopy and transmission electron microscopy (TEM) were used to study the role of TSPO-specific ligand PK11195 in LPS-activated mitochondrial autophagy in rat hippocampus. We found that PK11195 ameliorated LPS-induced learning and memory impairment, as indicated by decreased escape latencies, swimming distances and increased target quadrant platform crossing times and swimming times during MWM tests. TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA expression increased in the hippocampus of PND model rats. The hippocampal microglia of PND model rats also have severe mitochondrial damage, and a large number of autophagosomes and phagocytic vesicles can be seen. PK11195 pretreatment significantly decreased the expression of TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA, as well as mitochondrial damage. These findings suggested that PK11195 may alleviate the damage of LPS-induced cognitive dysfunction of rats by inhibiting microglia activation and autophagy.
Highlights
Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication that affects all aspects of cognitive function (He et al, 2019) such as learning, memory, attention and executive function
Our results showed that PK11195 may play a neuroprotective role to improve the cognitive function of rats by inhibiting microglial activation and mitochondrial autophagy
It was found that continuous intraperitoneal injection of 1 mg/kg LPS caused cognitive dysfunction in rats which is in consistent with previous studies (Anaeigoudari et al, 2016), In addition, we used PK11195 at 3 mg/kg 30 min before LPS injection to establish a PK11195 + LPS rat model according to Ma’s protocol (Ma et al, 2016)
Summary
Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication that affects all aspects of cognitive function (He et al, 2019) such as learning, memory, attention and executive function. Lipopolysaccharide (LPS), the main component of the cell wall of gram-negative bacteria (Takeuchi and Akira, 2010), can produce neuroinflammation and promote cell apoptosis to cause cognitive impairment (Bossu et al, 2012; Zhang et al, 2015). Researches on cognitive impairment are mainly focused on neuroinflammatory response (Yuan et al, 2019), structural and functional integrity disorders of blood-brain barrier (Mansour et al, 2019), Aβ metabolic disorders (Wang et al, 2020) and cholinergic dysfunction (Shin et al, 2019), but its mechanism is still unclear. Li et al found that 1.5% Isoflurane exposure may impair the spatial cognitive function and the formation of hippocampal phagophore in rats (Li et al, 2015). Zhang et al found that autophagy is involved in cognitive dysfunction in rats induced by sevoflurane anesthesia (Zhang et al, 2016)
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