Autophagy Is Involved in the Sevoflurane Anesthesia-Induced Cognitive Dysfunction of Aged Rats

Abstract

Autophagy is associated with regulation of both the survival and death of neurons, and has been linked to many neurodegenerative diseases. Postoperative cognitive dysfunction is commonly observed in elderly patients following anesthesia, but the pathophysiological mechanisms are largely unexplored. Similar effects have been found in aged rats under sevoflurane anesthesia; however, the role of autophagy in sevoflurane anesthesia-induced hippocampal neuron apoptosis of older rats remains elusive. The present study was designed to investigate the effects of autophagy on the sevoflurane-induced cognitive dysfunction in aged rats, and to identify the role of autophagy in sevoflurane-induced neuron apoptosis. We used 20-month-old rats under sevoflurane anesthesia to study memory performance, neuron apoptosis, and autophagy. The results demonstrated that sevoflurane anesthesia significantly impaired memory performance and induced hippocampal neuron apoptosis. Interestingly, treatment of rapamycin, an autophagy inducer, improved the cognitive deficit observed in the aged rats under sevoflurane anesthesia by improving autophagic flux. Rapamycin treatment led to the rapid accumulation of autophagic bodies and autophagy lysosomes, decreased p62 protein levels, and increased the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I in hippocampal neurons through the mTOR signaling pathway. However, administration of an autophagy inhibitor (chloroquine) attenuated the autophagic flux and increased the severity of sevoflurane anesthesia-induced neuronal apoptosis and memory impairment. These findings suggest that impaired autophagy in the hippocampal neurons of aged rats after sevoflurane anesthesia may contribute to cognitive impairment. Therefore, our findings represent a potential novel target for pro-autophagy treatments in patients with sevoflurane anesthesia-induced neurodegeneration.

Cistanches alleviates sevoflurane‐induced cognitive dysfunction by regulating PPAR‐γ‐dependent antioxidant and anti‐inflammatory in rats

“…Remarkably, a singledose cistanche (50 mg/kg) could exert anti-inflammatory, antioxidant, anti-apoptosis, anti-activation of microglia and neuroprotection effects on the sevoflurane-induced aged rats by activating PPAR-γ signalling.Sevoflurane, a volatile anaesthetic, is most commonly used in patients of all ages in modern anaesthesiology. In the present study, we demonstrated that 24-but not 3-month-old rats have cognitive impairments on day 3 after the induction of anaesthesia with 2.6% sevoflurane in 100% oxygen during 4 hours, indicating that the negative effects of the sevoflurane on the cognitive function are age-related under this condition.Numerous studies have reported that surgery and anaesthesia have been associated with a transient or permanent damage in cognitive function, whereas the aetiology of the disorders is largely unknown 25. For instance, Xu et al10 have described that short-term exposure to sevoflurane-impaired working memory in aged rats.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…83 Autophagy in the heart is enhanced in type 1 diabetes but is suppressed in type 2 (insulin-resistant) diabetes. 87,88 Even in bone marrow, where autophagy provides essential maintenance function, excessive autophagy of mesenchymal stem cells is very likely the cause of cellular senescence during hyperglycemia-induced marrow hematopoietic niche dysfunction. 85 Also, in type 2 diabetes, inhibition of autophagy by CQ can be detrimental for circulation, especially in endothelial progenitor cells that are needed to preserve ischemic angiogenesis and blood perfusion.…”

“…86 Autophagy is not always beneficial though; in excess, it can contribute to tissue damage, both in young and aged mammals. 87,88 Even in bone marrow, where autophagy provides essential maintenance function, excessive autophagy of mesenchymal stem cells is very likely the cause of cellular senescence during hyperglycemia-induced marrow hematopoietic niche dysfunction. 89 Treatment with the rapamycin can induce non-coding RNA LCPAT1 and activate autophagy, to permit growth of lung tumors.…”

Anesthetic effects on autophagy

“…Some animal studies have suggested that inhalational anesthetics may increase the risk of postoperative cognitive dysfunction, a temporary or mid-term decline in cognitive function after surgery and anesthesia that primarily affects older individuals. 32 34 51 52 The dual effects of volatiles may however depend upon the concentration of volatile anesthetics used53 or the duration of exposure, 54 in which deleterious effects occur with high concentration and long duration of use, whereas protective effects are present at low concentration and short term use. Autophagy may play a role in these effects as discussed in the following paragraphs.…”

“…There are four recent studies 27 32 34 35 that more closely examine the relationship between volatile anesthetics, autophagy, and their ties to neurocognitive disorders. Li et al 32 in 2015 conducted a study which investigated hippocampal autophagy of aged rats exposed to 1.5% isoflurane of various durations compared to oxygen.…”