Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice

Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah J.; Marcantonio, Edward R.; Crosby, Gregory; Tanzi, Rudolph E.; Zhang, Yiying; Xie, Zhongcong

doi:10.1371/journal.pone.0096752

Cited by 49 publications

(60 citation statements)

References 24 publications

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“…A mouse-tail blood pressure cuff (Kent Scientific Cooperation, Torrington, CT) was used to measure blood pressure, and blood gases were assayed with a blood gas machine (Trupoint, ITC, Edison, NJ) as described in our previous studies. 27,28 …”

Section: Methodsmentioning

confidence: 99%

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Wang¹,

Xu²,

et al. 2015

Anesthesia &Amp; Analgesia

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Background The mechanisms of general anesthesia by volatile drugs remain largely unknown. Mitochondrial dysfunction and reduction in energy levels have been suggested to be associated with general anesthesia status. 2-Deoxy-d-glucose (2-DG), an analog of glucose, inhibits hexokinase and reduces cellular levels of adenosine triphosphate (ATP). 3-Nitropropionic acid is another compound which can deplete ATP levels. In contrast, idebenone and L-carnitine could rescue deficits of energy. We therefore sought to determine whether 2-DG and/or 3-nitropropionic acid can enhance the anesthetic effects of isoflurane, and whether idebenone and L-carnitine can reverse the actions of 2-DG. Methods C57BL/6J mice (8 months old) received different concentrations of isoflurane with and without the treatments of 2-DG, 3-nitropropionic acid, idebenone, and L-carnitine. Isoflurane-induced loss of righting reflex (LORR) was determined in the mice. ATP levels in H4 human neuroglioma cells were assessed after these treatments. Finally, 31P-magnetic resonance spectroscopy was used to determine the effects of isoflurane on brain ATP levels in the mice. Results 2-DG enhanced isoflurane-induced LORR (P = 0.002, N = 15). 3-nitropropionic acid also enhanced the anesthetic effects of isoflurane (P = 0.005, N = 15). Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.165, N = 15), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P < 0.0001, N = 15), inhibited the effects of 2-DG on enhancing isoflurane-induced LORR in mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in mice pretreated with idebenone. Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.177, N = 6), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P = 0.029, N = 6), also mitigated the effects of 2-DG on reducing ATP levels in cells, as evidenced by 2-DG not decreasing ATP levels in the cell pretreated with idebenone. Finally, isoflurane decreased ATP levels in both cultured cells and mouse brains (-ATP: P = 0.003, N = 10; -ATP/phosphocreatine: P = 0.006, N = 10; -ATP/inorganic phosphate: P = 0.001, N = 10). Conclusions These results from our pilot studies have established a system and generated a hypothesis that 2-DG enhances anesthetic effects via reducing energy levels. These findings should promote further studies to investigate anesthesia mechanisms.

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Section: Methodsmentioning

confidence: 99%

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Wang¹,

Xu²,

et al. 2015

Anesthesia &Amp; Analgesia

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“…The FCS was performed just as described in previous studies [42,27,43,44], with modification. Briefly, the pairing of the FCS was performed two hours after the isoflurane anesthesia.…”

Section: Methodsmentioning

confidence: 99%

Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment

et al. 2014

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Background Anesthetic isoflurane has been reported to induce caspase-3 activation. The underlying mechanism(s) and targeted intervention(s), however, remain largely to be determined. Vitamin C (VitC) inhibits oxidative stress and apoptosis. We therefore employed VitC to further determine the up-stream mechanisms and the down-stream consequences of the isoflurane-induced caspase-3 activation. Methods H4 human neuroglioma cells over expressed human amyloid precursor protein (H4-APP cells) and rat neuroblastoma cells were treated either with: 1) 2% isoflurane or 2) the control condition, plus saline or 400 mM VitC for three or six hours. Western blot analysis and fluorescence assay was utilized at the end of the experiments to determine caspase-3 activation, levels of reactive oxygen species and ATP, and mitochondrial function. The interaction of isoflurane (1.4% for two hours) and VitC (80 mg/kg) on cognitive function in mice was also assessed in the Fear Conditioning System. Results Here we show for the first time that the VitC treatment attenuated the isoflurane-induced caspase-3 activation. Moreover, VitC mitigated the isoflurane-induced increase in the levels of reactive oxygen species, opening of mitochondrial permeability transition pore, reduction in mitochondrial membrane potential, and the reduction in ATP levels in the cells. Finally, VitC ameliorated the isoflurane-induced cognitive impairment in the mice. Conclusion Pending confirmation from future studies, these results suggested that VitC attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings would promote further research into the underlying mechanisms and targeted interventions of anesthesia neurotoxicity.

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“…1,2 In addition, surgical stimulation itself may increase levels of neuroinflamatory mediators that can result in cognitive impairment in aged mice. 3,4 Nevertheless, findings regarding the potential association between exposure to anesthesia and long-term cognitive impairment have not been consistent in observational clinical studies. 5–10 Much of this research utilizes dementia as the primary outcome.…”

Section: Introductionmentioning

confidence: 99%

Mild Cognitive Impairment and Exposure to General Anesthesia for Surgeries and Procedures: A Population-Based Case–Control Study

Šprung

Roberts

Knopman

et al. 2017

Anesthesia &Amp; Analgesia

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Objective To examine whether exposure to general anesthesia for procedures at age ≥40 is associated with prevalent mild cognitive impairment (MCI) in the elderly. Patients and Methods A case-control study nested within a population-based cohort. Olmsted County, MN, residents ages 70–89 years, underwent baseline evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. Individuals identified with MCI (cases) at enrollment were matched 1:2 on age, sex, education and apolipoprotein genotype with participants who were cognitively normal at the time of the index visit. Medical records from age 40 until the index visit were reviewed to determine exposures to general anesthesia. Conditional logistic regression, taking into account the matched set study design and adjusting for MCI risk factors, was used to assess whether exposure to anesthesia after the age of 40 was associated with prevalent MCI. Results A total of 387 MCSA participants (219 males, 168 females) were diagnosed with MCI at enrollment with mean age 81±5 years. Exposure to general anesthesia after the age of 40 was not significantly associated with prevalent MCI when analyzed as a dichotomous variable (any vs. none, adjusted OR 0.97 [95% CI 0.68–1.40]) or the number of exposures OR 1.13 [0.74–1.72], 0.81 [0.53–1.22], and 1.03 [0.67–1.58] for 1, 2–3, and ≥4 exposures, respectively, with no exposure as the reference. Similar results were obtained for anesthesia exposure after the age 60, and during 5, 10 and 20 years prior to the first visit. Conclusion Exposure to general anesthesia for procedures at ages ≥ 40 years was not associated with prevalent MCI in the elderly.

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Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice

Cited by 49 publications

References 24 publications

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment

Mild Cognitive Impairment and Exposure to General Anesthesia for Surgeries and Procedures: A Population-Based Case–Control Study

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