Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

Ni, Cheng; Li, Zhengqian; Qian, Min; Zhou, Yang; Wang, Jun; Guo, Xiangyang

doi:10.1016/j.bbrc.2015.03.083

Cited by 30 publications

(22 citation statements)

References 38 publications

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“…Furthermore, isoflurane may induce overactivation of inositol 1,4,5-trisphosphate or ryanodine receptors located on the endoplasmic reticulum (ER) membrane (27), leading to Ca 2+ escaping from the ER. Based on the results presented in the current study and a previous study (28), CaN, a Ca 2+ -dependent serine/threonine protein kinase, is activated following cytosolic Ca 2+ elevation, which may initiate mitochondrial retrograde signaling.…”

Section: Discussionsupporting

confidence: 75%

“…A previous study indicated that consistent with intermediate to severe AD, the nuclear translocation of NFATc4 in the hippocampus may also involve in CaN-mediated memory impairment following isoflurane exposure (28). Moreover, the cAMP response element-binding protein, CCAAT enhancer binding protein δ, and the heterogeneous ribonucleoprotein A2 are reportedly involved in CaN-mediated mitochondrial retrograde signaling and contribute to the regulation of downstream target gene expression (42).…”

Section: Discussionmentioning

confidence: 94%

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Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Xia

et al. 2016

Molecular Medicine Reports

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It is known that inhaled anesthetics induce neuroinflammation and facilitate postoperative cognitive dysfunction (POCD) in aged individuals; however, the mechanisms by which they mediate these effects remain elusive. Inhalation of the isoflurane anesthetic leads to opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. Therefore, mitochondrial retrograde signaling, which is an adaptive mechanism that facilitates the transmission of signals from dysfunctional mitochondria to the nucleus to activate target gene expression, may be activated during isoflurane inhalation. Therefore, the present study was designed to investigate the role of mitochondrial retrograde signaling in isoflurane-induced hippocampal neuroinflammation and cognitive impairment in aged rats. As calcineurin (CaN) serves an important role in the initiation of mitochondrial retrograde signaling, and nuclear factor-κB (NF-κB) is involved in CaN signaling, their effects on isoflurane-induced hippocampal neuroinflammation and cognitive impairment were investigated. Reactive oxygen species and mitochondrial membrane potential fluorescence staining, western blotting, colorimetric analysis, ELISA, immunofluorescence and the Morris water maze test were used in the present study. The results indicate that isoflurane induced hippocampal mitochondrial dysfunction and activated CaN, which subsequently lead to the putative activation of NF-κB. These resulted in the elevation of interleukin-1β (IL-1β) expression (a typical marker of neuroinflammation), and was associated with cognitive impairment in aged rats. In addition, CaN and NF-κB inhibition attenuated isoflurane-induced neuroinflammation and subsequent cognitive impairment. In conclusion, the results of the present study demonstrate the role of mitochondrial retrograde signaling and associated protein factors in inhaled anesthetic-induced neuroinflammation and cognitive impairment. These protein factors may therefore present promising therapeutic targets for the prevention of POCD.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 94%

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Xia

et al. 2016

Molecular Medicine Reports

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“…MCLR effect was prevented by FK506 treatment. In addition, NFATc4 mediated light-induced retinal ganglion cell apoptosis by upregulating Fas ligand (FasL) expression on retinal neurons [236], and the overactivation of calcineurin/NFATc3 signaling induced the typical neuronal toxicity and functional alterations observed in murine developing hippocampal neurons following the inhalation of anesthetic isoflurane, including cognitive impairment [237]. A recent study in this model of postoperative cognitive dysfunction revealed that abnormal calcineurin/NFAT signaling associated with isoflurane exposure may mediate its detrimental effects by promoting the degradation of the survival molecule signal transducer and activator of transcription 3 (STAT3) [238].…”

Section: Controversial Roles In Nervous System Diseasesmentioning

confidence: 99%

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Kipanyula

Kimaro

Etet

2016

Journal of Aging Research

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The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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“…Though the neurotoxicity of sevoflurane has been observed for a long time, its mechanisms remain unknown (Feng et al, ; Jevtovic‐Todorovic et al, ; Liu, Rossaint, Sanders, & Coburn, ). The most popular proposed mechanism for the neurotoxicity of sevoflurane was the receptor theory (Amrock et al, ; Jevtovic‐Todorovic et al, ; Liu et al, ; Ni et al, ; Yu et al, ). GABA is an inhibitory transmitter that acts through a receptor channel that is complex but permeable mainly for chloride anions and leads to neuronal excitability reduction.…”

Section: Discussionmentioning

confidence: 99%

“…Though the neurotoxicity of sevoflurane has been observed for a long time, its mechanisms remain unknown (Feng et al, 2012;Jevtovic-Todorovic et al, 2003;Liu, Rossaint, Sanders, & Coburn, 2014). The most popular proposed mechanism for the neurotoxicity of sevoflurane was the receptor theory (Amrock et al, 2015;Jevtovic-Todorovic et al, 2003;Liu et al, 2015;Ni et al, 2015;Yu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABA_AR α1/GABA_AR α2 ratio

Xie

et al. 2017

J of Neuroscience Research

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Exposure of neonatal rat to sevoflurane leads to neurodegeneration and deficits of spatial learning and memory in adulthood. However, the underlying mechanisms remain unclear. The type A γ-aminobutyric acid receptor (GABA R) is a target receptor for sevoflurane. The present study intends to investigate the changes in GABA R α1/α2 expression and its relationship with the neurotoxicity effect due to sevoflurane in neonatal rats. After a dose-response curve was constructed to determine minimum alveolar concentration (MAC) and safety was guaranteed in our 7-day-old neonatal rat pup mode, we conducted two studies among the following groups: (A) the control group; (B) the sham anesthesia group; and (C) the sevoflurane anesthesia group and all three groups were treated in the same way as the model. First, poly(ADP-ribose) polymerase-1 protein (PARP-1) expression was determined in the different brain areas at 6 hr after anesthesia. Second, the expression of PARP-1 and GABA R α1/GABA R α2 in the hippocampus area was tested by Western blotting at 6 hr, 24 hr, and 72 hr after anesthesia in all three groups. After 4 hr, with 0.8 MAC (2.1%) sevoflurane anesthesia, the PARP-1 expression was significantly higher in the hippocampus than the other brain areas (p < .05). Compared with Groups A and B, the expression of PARP-1 in the hippocampus of Group C significantly increased at 6 hr after sevoflurane exposure (216% ± 15%, p < .05), and the ratio of the α1/α2 subunit of GABA R surged at 6 hr (126% ± 6%), 24 hr (127% ± 8%), and 72 hr (183% ± 22%) after sevoflurane exposure in the hippocampus (p < .05). Our study showed that sevoflurane exposure of 0.8 MAC (2.1%)/4 hr was a suitable model for 7-day-old rats. And the exposure to sevoflurane could induce the apoptosis of neurons in the early stage, which may be related to the transmission from GABA R α2 to GABA R α1.

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Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

Cited by 30 publications

References 38 publications

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABA_AR α1/GABA_AR α2 ratio

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Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

Cited by 30 publications

References 38 publications

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABAAR α1/GABAAR α2 ratio

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Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABA_AR α1/GABA_AR α2 ratio