An investigation of the mechanism of dexmedetomidine in improving postoperative cognitive dysfunction from the perspectives of alleviating neuronal mitochondrial membrane oxidative stress and electrophysiological dysfunction

Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.

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Electroacupuncture reduces astrocyte number and oxidative stress in aged rats with surgery-induced cognitive dysfunction

Journal of International Medical Research ◽

10.1177/0300060519860026 ◽

2019 ◽

Vol 47 (8) ◽

pp. 3860-3873 ◽

Cited By ~ 1

Author(s):

Pei-Rong Liu ◽

Feng Cao ◽

Yu Zhang ◽

Sheng Peng

Keyword(s):

Oxidative Stress ◽

Cognitive Function ◽

Cognitive Dysfunction ◽

Neurotrophic Factor ◽

Calcium Binding ◽

Postoperative Cognitive Dysfunction ◽

Neuron Specific Enolase ◽

Left Lobe ◽

Sprague Dawley ◽

And Oxidative Stress

Objectives To investigate the effects of electroacupuncture in regulating astrocytes and oxidative stress in a rat model of postoperative cognitive dysfunction (POCD). Methods Male aged Sprague-Dawley rats were randomized to undergo left hepatic lobe resection to induce POCD, followed by either electroacupuncture or no treatment; or similar surgery without left lobe resection or electroacupuncture (sham). Postsurgical cognitive function, hippocampal astrocyte number and oxidative stress indicators were measured. Results At days 1, 3 and 7 following surgery, escape latency was significantly shorter and platform crossing frequency was increased with electroacupuncture versus other groups. At postoperative day 1, the electroacupuncture group showed significantly fewer glial fibrillary acidic protein (GFAP)-positive hippocampal astrocytes versus the POCD model group. In POCD rats, electroacupuncture significantly decreased serum S100 calcium binding protein B and neuron-specific enolase levels, and increased brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels, at days 1, 3 and 7. Electroacupuncture significantly attenuated the hippocampal POCD-induced increase in malondialdehyde and decreased superoxide dismutase levels at day 1 following surgery. Conclusion Electroacupuncture may improve cognitive function in rats with POCD by reducing hippocampal GFAP-positive astrocyte number and suppressing oxidative stress.

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Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats

Brain Behavior and Immunity ◽

10.1016/j.bbi.2018.07.016 ◽

2018 ◽

Vol 73 ◽

pp. 661-669 ◽

Cited By ~ 26

Author(s):

Martins Back Netto ◽

Aloir Neri de Oliveira Junior ◽

Mariana Goldim ◽

Khiany Mathias ◽

Maria Eduarda Fileti ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cognitive Dysfunction ◽

Postoperative Cognitive Dysfunction

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Pathogenetic role of oxidative stress in the formation of postoperative cognitive dysfunction in otolaryngologic patients after general anaesthesia with controlled hypotension

EMERGENCY MEDICINE ◽

10.22141/2224-0586.6.101.2019.179601 ◽

2019 ◽

Vol 0 (6.101) ◽

pp. 72-77

Author(s):

O.I. Datsyuk ◽

R.A. Bondar ◽

A.V. Kostiuchenko ◽

N.V. Titarenko

Keyword(s):

Oxidative Stress ◽

General Anaesthesia ◽

Cognitive Dysfunction ◽

Postoperative Cognitive Dysfunction ◽

Controlled Hypotension ◽

Pathogenetic Role

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SIRT3 Protects Against Cognitive Dysfunction Induced by Sepsis-associated Encephalopathy Via JNK/p66Shc-Regulated Mitochondrial Apoptosis in Mice

10.21203/rs.3.rs-895666/v2 ◽

2021 ◽

Author(s):

Zhuochen Lyu ◽

Shiyuan Luo ◽

Yinjiao Li ◽

Liangfang Yao ◽

Feng Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Dysfunction ◽

Mitochondrial Membrane ◽

Synaptic Dysfunction ◽

Lysine Acetylation ◽

Mitochondrial Apoptosis ◽

Wild Type ◽

Ht22 Cells ◽

Mptp Opening ◽

Cyt C

Abstract Background: Sepsis-associated encephalopathy (SAE) is one of the severe central nervous system complications. Oxidative stress and synaptic dysfunction were involved in cognitive impairment induced by SAE. The mitochondrial nicotinamide adenine dinucleotide (NAD+) dependent deacetylase, sirtuin3 (SIRT3), plays a critical role in regulating mitochondrial function. The aim of this study was to evaluate the effect of SIRT3 in cognitive dysfunction induced by SAE.Methods: Mice were treated with lipopolysaccharide (LPS, 10 mg/kg, i.p.). Contextual and cue memory were evaluated by fear conditioning test in wild-type (WT) and SIRT3-deficient (SIRT3-/-) mice. Synapse-associated proteins and mitochondrial apoptosis-associated protein were examined by western blotting. In vitro studies, acetylation levels of cyclophilin D (CypD) were detected with different SIRT3 deacetylase activity in HT22 cells after LPS-induced microglia supernatant (Mi-sup) exposure. Oxidative stress was detected by reactive oxygen species (ROS) staining, and mitochondrial membrane potential (MMP) was detected by JC-1 staining, and mitochondrial membrane permeability transition pore (MPTP) opening was detected by Calcein and Co2+ staining. Furthermore, the phosphorylation levels of mitochondrial p66Shc and JNK were evaluated by western blotting.Results: SIRT3 expression was diminished in hippocampus of mice after LPS treatment. SIRT3-deficiency contributed to more severe contextual memory loss and synaptic dysfunction, decreased ratio of Bcl-2/Bax and increased Cyt C release to cytoplasm in hippocampus compared with wild-type controls. In HT22 cells, lysine acetylation levels of CypD were significantly increased after Mi-sup exposure and further enhanced with 3-TYP (SIRT3 deacetylation inhibitor) pretreatment, in association with the accumulation of ROS, declined MMP and increased MPTP opening, as well as the increased mitochondrial Cyt C release and phosphorylation levels of mitochondrial JNK and p66Shc-Ser36. SIRT3 overexpression restored CypD lysine acetylation levels and MPTP opening in HT22 cells after Mi-sup exposure and reduced mitochondrial JNK and p66Shc activation. Conclusions: Taken together, our results showed that SIRT3-mediated CypD deacetylation was involved in LPS-induced hippocampal synaptic dysfunction, via ROS accumulation, declined MMP, increased MPTP opening, mitochondrial Cyt C release and mitochondrial apoptosis of hippocampal neuron via JNK/p66Shc pathway. Our results revealed that SIRT3 may be a promising therapeutic and diagnostic target for cognitive dysfunction induced by SAE.

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SIRT3 Protects Against Cognitive Dysfunction Induced by Sepsis-Associated Encephalopathy via JNK/p66Shc-Regulated Mitochondrial Apoptosis in Mice

10.21203/rs.3.rs-895666/v1 ◽

2021 ◽

Author(s):

Zhuochen Lyu ◽

Shiyuan Luo ◽

Yinjiao Li ◽

Liangfang Yao ◽

Feng Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Dysfunction ◽

Mitochondrial Membrane ◽

Synaptic Dysfunction ◽

Lysine Acetylation ◽

Mitochondrial Apoptosis ◽

Wild Type ◽

Ht22 Cells ◽

Mptp Opening ◽

Cyt C

Abstract Background Sepsis-associated encephalopathy (SAE) is one of the severe central nervous system complications. Oxidative stress and synaptic dysfunction were involved in cognitive impairment induced by SAE. The mitochondrial nicotinamide adenine dinucleotide (NAD+) dependent deacetylase, sirtuin3 (SIRT3), plays a critical role in regulating mitochondrial function. The aim of this study was to evaluate the effect of SIRT3 in cognitive dysfunction induced by SAE. Methods Mice were treated with lipopolysaccharide (LPS, 10 mg/kg, i.p.). Contextual and cue memory were evaluated by fear conditioning test in wild-type (WT) and SIRT3-deficient (SIRT3-/-) mice. Synapse-associated proteins and mitochondrial apoptosis-associated protein were examined by western blotting. In vitro studies, acetylation levels of cyclophilin D (CypD) were detected with different SIRT3 deacetylase activity in HT22 cells after LPS-induced microglia supernatant (Mi-sup) exposure. Oxidative stress was detected by reactive oxygen species (ROS) staining, and mitochondrial membrane potential (MMP) was detected by JC-1 staining, and mitochondrial membrane permeability transition pore (MPTP) opening was detected by Calcein and Co2+ staining. Furthermore, the phosphorylation levels of mitochondrial p66Shc and JNK were evaluated by western blotting. Results SIRT3 expression was diminished in hippocampus of mice after LPS treatment. SIRT3-deficiency contributed to more severe contextual memory loss and synaptic dysfunction, decreased ratio of Bcl-2/Bax and increased Cyt C release to cytoplasm in hippocampus compared with wild-type controls. In HT22 cells, lysine acetylation levels of CypD were significantly increased after Mi-sup exposure and further enhanced with 3-TYP (SIRT3 deacetylation inhibitor) pretreatment, in association with the accumulation of ROS, declined MMP and increased MPTP opening, as well as the increased mitochondrial Cyt C release and phosphorylation levels of mitochondrial JNK and p66Shc-Ser36. SIRT3 overexpression restored CypD lysine acetylation levels and MPTP opening in HT22 cells after Mi-sup exposure and reduced mitochondrial JNK and p66Shc activation. Conclusion Taken together, our results showed that SIRT3-mediated CypD deacetylation was involved in LPS-induced hippocampal synaptic dysfunction, via ROS accumulation, declined MMP, increased MPTP opening, mitochondrial Cyt C release and mitochondrial apoptosis of hippocampal neuron via JNK/p66Shc pathway. Our results revealed that SIRT3 may be a promising therapeutic and diagnostic target for cognitive dysfunction induced by SAE.

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