A Mitochondrion-Targeted Antioxidant Ameliorates Isoflurane-Induced Cognitive Deficits in Aging Mice

Wu, Jing; Li, Huihui; Sun, Xiaoru; Zhang, Hui; Hao, Shuangying; Ji, Mu‐Huo; Yang, Jianjun; Li, Kuanyu

doi:10.1371/journal.pone.0138256

Cited by 38 publications

(60 citation statements)

References 41 publications

(35 reference statements)

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“…Mitochondrial dysfunction has been previously shown to link to the earliest pathogenesis of GA-induced cognitive impairments in developing or aged mammalian brain [17,29]. On the one hand, we confirmed our previous findings including the mitochondrial dysfunction after GA exposure [43]; on the other hand, we observed that pretreatment with DFP prior to GA exposure significantly attenuated GAinduced effects on mitochondrial function and dynamics. This means that GA-induced impairment of mitochondria is directly associated with iron accumulation, which is consistent with the previous studies in other ironoverload models [44].…”

Section: Discussionsupporting

confidence: 91%

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Yang

Cao

et al. 2020

J Neuroinflammation

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Background: Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. Methods: We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. Results: Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine-or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. Conclusion: We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.

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Section: Discussionsupporting

confidence: 91%

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Yang

Cao

et al. 2020

J Neuroinflammation

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“…SS-31 improves outcomes in animal models of age-associated diseases including Parkinson’s disease (50), brain ischemia and Alzheimer’s disease (51, 52). Preservation of cardiolipin by SS-31 protects mitochondria from ischemia-reperfusion injury in a variety of tissue and disease contexts including myocardial and renal ischemia (25, 53–56).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Sweetwyne

Pippin

Eng

et al. 2017

Kidney International

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Although age-associated changes in kidney glomerular architecture have been described in mice and man, the mechanisms are unknown. It is unclear if these changes can be prevented or even reversed by systemic therapies administered at advanced age. Using light microscopy and transmission electron microscopy, our results showed glomerulosclerosis with injury to mitochondria in glomerular epithelial cells in mice aged 26 month (equivalent to a 79 year old human). To test the hypothesis that reducing mitochondrial damage in late age would result in lowered glomerulosclerosis, we administered the mitochondrial targeted peptide, SS-31 to aged mice. Baseline (24 month-old) mice were randomized to receive 8 weeks of SS-31, or saline, and sacrificed at 26 months of age. SS-31 treatment improved age-related mitochondrial morphology and glomerulosclerosis. Assessment of glomeruli revealed that SS-31 reduced senescence (p16, senescence-associated-β-Gal) and increased the density of parietal epithelial cells. However, SS-31 treatment reduced markers of parietal epithelial cell activation (Collagen IV, pERK1/2 and α-smooth muscle actin). SS-31 did not impact podocyte density, but reduced markers of podocyte injury (desmin), and improved cytoskeletal integrity (synaptopodin). This was accompanied by higher glomerular endothelial cell density (CD31). Thus, despite initiating therapy in late-age mice, a short course of SS-31 has protective benefits on glomerular mitochondria, accompanied by temporal changes to the glomerular architecture. This systemic pharmacological intervention in old-aged animals limits glomerulosclerosis and senescence, reduces parietal epithelial cell activation, and improves podocyte and endothelial cell integrity.

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“…55 SS-31 has also been reported to attenuate inflammasome activation in alveolar cells in response to mechanical ventilation, 56 and in the brain of aging mice in response to isoflurane. 57 Several inhibitors of IL-1b and IL-18 are in clinical development, as well as inhibitors of the NLRP3 inflammasome and caspase-1. 58,59 Targeting upstream of the inflammasome might prove more effective than single anticytokine therapies and carry less risk.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1β and IL-18 and Arrests CKD

Szeto¹,

Liu²,

Soong³

et al. 2016

JASN

127

101

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The innate immune system has been implicated in both AKI and CKD. Damaged mitochondria release danger molecules, such as reactive oxygen species, DNA, and cardiolipin, which can cause NLRP3 inflammasome activation and upregulation of IL-18 and IL-1 It is not known if mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation. We conducted a 9-month study in Sprague-Dawley rats after 45 minutes of bilateral renal ischemia. We detected glomerular and peritubular capillary rarefaction, macrophage infiltration, and fibrosis at 1 month. Transmission electron microscopy revealed mitochondrial degeneration, mitophagy, and deformed foot processes in podocytes. These changes progressed over the study period, with a persistent increase in renal cortical expression of IL-18, IL-1, and TGF-, despite a gradual decline in TNF- expression and macrophage infiltration. Treatment with a mitoprotective agent (SS-31; elamipretide) for 6 weeks, starting 1 month after ischemia, preserved mitochondrial integrity, ameliorated expression levels of all inflammatory markers, restored glomerular capillaries and podocyte structure, and arrested glomerulosclerosis and interstitial fibrosis. Further, helium ion microscopy vividly demonstrated the restoration of podocyte structure by SS-31. The protection by SS-31 was sustained for ≥6 months after treatment ended, with normalization of IL-18 and IL-1 expression. These results support a role for mitochondrial damage in inflammasome activation and CKD and suggest mitochondrial protection as a novel therapeutic approach that can arrest the progression of CKD. Notably, SS-31 is effective when given long after AKI and provides persistent protection after termination of drug treatment.

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A Mitochondrion-Targeted Antioxidant Ameliorates Isoflurane-Induced Cognitive Deficits in Aging Mice

Cited by 38 publications

References 41 publications

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1β and IL-18 and Arrests CKD

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