Isoflurane anesthesia promotes cognitive impairment by inducing expression of β-amyloid protein-related factors in the hippocampus of aged rats

Abstract

Isoflurane anesthesia has been shown to be responsible for cognitive impairment in Alzheimer’s disease (AD) and development of AD in the older age groups. However, the pathogenesis of AD-related cognitive impairments induced by isoflurane anesthesia remains elusive. Thus, this study was designed to investigate the mechanism by which isoflurane anesthesia caused AD-related cognitive impairments. Aged Wistar rats were randomly divided into 6 groups (n = 12), 1 control group (CONT) and 5 isoflurane treated (ISO) groups (ISO 0, ISO 0.5D, ISO 1D, ISO 3D and ISO 7D). The CONT group inhaled 30% O2 for 2 h without any anesthesia. ISO groups were placed under anesthesia with 3% isoflurane and then exposed to 1.5% isoflurane delivered in 30% O2 for 2 h. Rats in each ISO group were then analyzed immediately (ISO 0) or at various time points (0.5, 1, 3 or 7 day) after this exposure. Cognitive function was assessed using the Morris water maze test. Protein levels of amyloid precursor protein (APP), β-site APP cleavage enzyme-1 (BACE-1) and Aβ42 peptide were analyzed in hippocampal samples by Western blot. β-Amyloid (Abeta) plaques were detected in hippocampal sections by Congo red staining. Compared with controls, all ISO groups showed increased escape latency and impaired spatial memory. Isoflurane increased APP mRNA expression and APP protein depletion, promoting Aβ42 overproduction, oligomerization and accumulation. However, isoflurane did not affect BACE-1 expression. Abeta plaques were observed only in those ISO groups sacrificed at 3 or 7 d. Our data indicate that aged rats exposed to isoflurane had increased APP mRNA expression and APP protein depletion, with Aβ42 peptide overproduction and oligomerization, resulting in formation of Abeta plaques in the hippocampus. Such effects might have contributed to cognitive impairments, including in spatial memory, observed in these rats after isoflurane anesthesia.

MicroRNA-188-3p is involved in sevoflurane anesthesia-induced neuroapoptosis by targeting MDM2

“…As the present study reported sevoflurane-induced cognitive dysfunction in rats, the potential underlying mechanisms of this effect were subsequently investigated. It has been well-documented that miRNAs have important roles in the regulation of gene expression in response to sevoflurane treatment ( 6 , 31 – 35 ), and bioinformatics analyses identified miR-188-3p as one of the most significantly upregulated miRNAs following sevoflurane administration ( 6 ). To confirm this observation, the expression level of miR-188-3p in the hippocampal tissue of rats with or without sevoflurane treatment was determined by RT-qPCR.…”

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…The traditional anesthesia (e.g., isoflurane-mediated anesthesia) increases the risk of AD (15)(16)(17). Some traditional anesthetic agents are associated with AD pathogenesis (18).…”

“…Some traditional anesthetic agents are associated with AD pathogenesis (18). Behavioral tests in rodent models showed that a transient exposure to anesthetic drug isoflurane caused a lasting impairment to the cognition (15,16,19). A cell co-cultured study showed that isoflurane interfered astrocytes to support neuronal growth, which may explain the association between the anesthesia application and AD pathogenesis (20).…”

Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?

“…This result may be related to the metabolism of the betaamyloid (Aβ) peptide, a key protein involved in the development of Alzheimer's disease. Isoflurane has been reported to increase the production of Aβ and promote Aβ oligomerization and accumulation in the hippocampus, which resembles the neuropathology of Alzheimer's disease [77]. Others have reported that exposure to desflurane resulted in transient spatial reference memory impairment in aged rats [78].…”