About 200 million people each year undergo surgery in the world. Most of them will have general anesthesia with volatile anesthetics as the primary anesthetics during surgery. Although volatile anesthetics generally are considered to be safe, their possible contribution to the development of post-operative cognitive dysfunction (POCD), a fairly-well documented clinical entity that occurs more frequently in elderly patients, has drawn significant attention. Because the issue is obviously significant, there is an urgent need to defin the anesthetic effects on learning and memory and to identify interventions to attenuate these effects. Our preliminary study showed that isoflurane at a clinically relevant concentration impaired the learning and memory of old rats. This detrimental effect on old rats was attenuated by intravenous lidocaine, a local anesthetic that has anti-inflammatory property. Isoflurane increased a proinflammatory cytokine expression and appeared to attenuate the learning-induced phosphorylation of the ?-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit, a critical process for learning and memory, in the hippocampus. Lidocaine also blocked these isoflurane effects. We hypothesize that volatile anesthetic-induced learning and memory impairments in elderly rats are anesthetic dose-dependent and agent-specific and are due to neuroinflammation and interruptions of biochemical processes underlying learning and memory. In this project, we will determine whether: 1) isoflurane-induced learning and memory impairments are concentration- dependent;2) the newer volatile anesthetics sevoflurane and desflurane cause learning and memory impairments and lidocaine attenuates these impairments;3) isoflurane induces mild inflammatory responses in the hippocampus and lidocaine reduces this isoflurane-caused neuroinflammation;and 4) isoflurane interrupts learning and memory-induced biochemical responses. We will use old adult male rats and exposed them to volatile anesthetics in the presence or absence of lidocaine. Learning and memory will be evaluated by Barnes maze and fear conditioning. Brains will be harvested for biochemical examination. These studies will determine not only the characteristics of volatile anesthetics-induced impairments of learning and memory but also mechanisms for these impairments. This information also will help us better understand pharmacology of volatile anesthetics in the brain and develop approaches to improve the safety profile of these commonly used drugs.

Public Health Relevance

Patients, especially the elderly, can develop significant dysfunction of learning and memory after anesthesia and surgery. We would like to determine whether drugs that are used to put patients to sleep during surgery contribute to this problem and how this problem occurs in old animals. The intention of this project is to provide information that ultimately may help improve quality of life for patients after anesthesia and surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098308-02
Application #
8549264
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2012-09-21
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$289,693
Indirect Cost
$106,343
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Zhongxing; Shan, Weiran; Cao, Jiangbei et al. (2018) Early administration of pyrrolidine dithiocarbamate extends the therapeutic time window of tissue plasminogen activator in a male rat model of embolic stroke. J Neurosci Res 96:449-458
Ryu, Jung-Hee; Do, Sang-Hwan; Han, Sung-Hee et al. (2018) Morphine reduces mouse microglial engulfment induced by lipopolysaccharide and interferon-? via ? opioid receptor and p38 mitogen-activated protein kinase. Neurol Res 40:600-606
Liang, Peng; Shan, Weiran; Zuo, Zhiyi (2018) Perioperative use of cefazolin ameliorates postoperative cognitive dysfunction but induces gut inflammation in mice. J Neuroinflammation 15:235
Xing, Wei; Huang, Pinjie; Lu, Yang et al. (2018) Amantadine attenuates sepsis-induced cognitive dysfunction possibly not through inhibiting toll-like receptor 2. J Mol Med (Berl) 96:391-402
Li, Jun; Shan, Weiran; Zuo, Zhiyi (2018) Age-Related Upregulation of Carboxyl Terminal Modulator Protein Contributes to the Decreased Brain Ischemic Tolerance in Older Rats. Mol Neurobiol 55:6145-6154
Cao, Rui; Li, Jun; Ning, Bo et al. (2017) Functional and oxygen-metabolic photoacoustic microscopy of the awake mouse brain. Neuroimage 150:77-87
Bi, Jiangjiang; Shan, Weiran; Luo, Ailin et al. (2017) Critical role of matrix metallopeptidase 9 in postoperative cognitive dysfunction and age-dependent cognitive decline. Oncotarget 8:51817-51829
Zheng, Bin; Lai, Renchun; Li, Jun et al. (2017) Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery. Brain Behav Immun 61:365-374
Wan, Li; Bi, Jiangjiang; Li, Jun et al. (2017) Glutamate transporter type 3 participates in maintaining morphine-induced conditioned place preference. Neuroscience 344:67-73
Wang, Y; Han, R; Zuo, Z (2016) Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage. Br J Anaesth 116:384-92

Showing the most recent 10 out of 40 publications