Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons

et al. 2020

J Neuroinflammation

101

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.

Section: Discussionsupporting

confidence: 62%

Section: Nmdar-mediated Iron Transport Pathway Is Involved In Ga-indumentioning

confidence: 99%

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

et al. 2020

J Neuroinflammation

101

“…Evidence proved that NMDAR upregulation could promote iron overload and iron-induced neurotoxicity by enhancing RASD1-DMT1-mediated iron uptake [8]and iron releasing from lysosome [9]. In present study, we provided direct evidence that ketamine or sevoflurane exposure caused an upregulation of NMDAR subunits, which might be a compensatory upregulation of NMDAR subunits [34][35][36]. Accompanying with that, both ketamine and sevoflurane induced upregulation of RASD1, which could form a ternary complex with PAP7 and DMT1, thus enhance the ability of NMDAR to activate DMT1 for iron uptake [8,37] .…”

Section: Discussionsupporting

confidence: 59%

Section: Nmdar-mediated Iron Transport Pathway Is Involved In Ga-indumentioning

confidence: 99%

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

et al. 2020

Preprint

Background: Increasing evidence suggests that multiple or long-time exposure to general anesthesia (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 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 GAs-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.

“…NMDAR is one of the two main targets to the GAs. Previous experiments revealed that ketamine or sevoflurane induced a compensatory upregulation of NMDAR expression [32,33], which promoted iron uptake through DMT1 action [8,34]. Here we found increased expression of NMDAR1 (NR1) and NMDAR2A (NR2A), as well as RASD1 and DMT1, after 6 h ketamine or sevoflurane treatment (Fig.…”

Section: Nmdar-rasd1-dmt1 Pathway Is Involved In Ga-induced Iron Oversupporting

confidence: 66%

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

et al. 2019

Preprint

Background Increasing evidence suggests that exposure to general anesthesia (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 brain is a hallmark of neuroinflammation and is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits has not been studied.Methods We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacts 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 GAs-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, result from a novel regulated iron-dependent cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunctions, 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 insights into a potential novel therapy for prevention in GA-associated neurological disorders.