Physostigmine Restores Impaired Autophagy in the Rat Hippocampus after Surgery Stress and LPS Treatment

Abstract

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.

Proinflammatory Extracellular Vesicle-Mediated Signaling Contributes to the Induction of Neuroinflammation in Animal Models of Endotoxemia and Peripheral Surgical Stress

“…It has been shown that pharmacologic cholinesterase inhibition improves survival in experimental sepsis (Hofer et al 2008). Accordingly the acetylcholinesterase inhibitor physostigmine attenuates neuroinflammation induced by surgical stress or endotoxemia (Kalb et al 2013;Plaschke et al 2018bPlaschke et al , 2016von Haefen et al 2018). In our present study, physostigmine attenuated the pro-neuroinflammatory action of LPS-and HpX-derived EVs.…”

The Potential Role of the NLRP3 Inflammasome Activation as a Link Between Mitochondria ROS Generation and Neuroinflammation in Postoperative Cognitive Dysfunction

“…Deficient autophagy impairs mitochondrial integrity and promotes generation of mtROS, consequently contributing to activation of inflammasome (Razani et al, 2012). Defects in autophagy, along with neuroinflammation, have been implicated in the pathogenesis of postoperative cognitive decline (von Haefen et al, 2018). Additionally, evidence has shown that activating α7nAChR enhances microglial autophagy, which suppresses neuroinflammation and thus plays an alleviative role in neurodegenerative disorders (Jeong and Park, 2015; Shao et al, 2017).…”

Dexmedetomidine Restores Autophagic Flux, Modulates Associated microRNAs and the Cholinergic Anti-inflammatory Pathway upon LPS-Treatment in Rats

“…Therefore, to understand the working mechanism of DEX during inflammation, we used lipopolysaccharide (LPS) to generate an inflammation model in adult male Wistar rats. We previously showed that both, peripheral surgery combined with LPS as well as an LPS injection alone, trigger a pro-inflammatory immune response and impair autophagy within the rat brain (Kalb et al 2013 ; Paeschke et al 2017 ; von Haefen et al 2018 ). In this study, we have now investigated the effect of DEX on the immune system, autophagy and associated miRNAs, and the cholinergic anti-inflammatory pathway in the spleen and brain.…”