Ferroptosis Contributes to Isoflurane Neurotoxicity.
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ABSTRACT:
SUBMITTER: Xia Y
PROVIDER: S-EPMC6333734 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Ferroptosis Contributes to Isoflurane Neurotoxicity.
Xia Yimeng Y Sun Xiaoyun X Luo Yan Y Stary Creed M CM
Frontiers in molecular neuroscience 20190109
The underlying mechanisms of isoflurane neurotoxicity in the developing brain remain unclear. Ferroptosis is a recently characterized form of programmed cell death distinct from apoptosis or autophagy, characterized by iron-dependent reactive oxygen species (ROS) generation secondary to failure of glutathione-dependent antioxidant defenses. The results of the present study are the first to demonstrate <i>in vitro</i> that ferroptosis is a central mechanism contributing to isoflurane neurotoxicit ...[more]
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Project description:BackgroundCognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats.MethodsFlutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30).ResultsFlutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s).ConclusionsVulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.Editor’s perspective
| S-EPMC7695485 | biostudies-literature
Project description:IntroductionNeurotoxicity induced by early developmental exposure to volatile anesthetics is a characteristic of organisms across a wide range of species, extending from the nematode C. elegans to mammals. Prevention of anesthetic-induced neurotoxicity (AIN) will rely upon an understanding of its underlying mechanisms. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. By characterizing such pathways, we may identify mechanisms to eliminate isoflurane induced AIN in mammals.MethodsChemotaxis in adult C. elegans after larval exposure to isoflurane was used to measure AIN. We initially compared changes in chemotaxis indices between classical mutants known to affect nervous system development adding mutants in response to data. Activation of specific genes was visualized using fluorescent markers. Animals were then treated with rapamycin or preconditioned with isoflurane to test effects on AIN.ResultsForty-four mutations, as well as pharmacologic manipulations, identified two pathways, highly conserved from invertebrates to humans, that regulate AIN in C. elegans. Activation of one stress-protective pathway (DAF-2 dependent) eliminates AIN, while activation of a second stress-responsive pathway (endoplasmic reticulum (ER) associated stress) causes AIN. Pharmacologic inhibition of the mechanistic Target of Rapamycin (mTOR) blocks ER-stress and AIN. Preconditioning with isoflurane prior to larval exposure also inhibited AIN.DiscussionOur data are best explained by a model in which isoflurane acutely inhibits mitochondrial function causing activation of responses that ultimately lead to ER-stress. The neurotoxic effect of isoflurane can be completely prevented by manipulations at multiple points in the pathways that control this response. Endogenous signaling pathways can be recruited to protect organisms from the neurotoxic effects of isoflurane.
| S-EPMC5367966 | biostudies-literature
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| S-EPMC7494633 | biostudies-literature
Project description:BackgroundVolatile anesthetic exposure during development leads to long-term cognitive deficits in rats which are dependent on age and sex. Female rats are protected relative to male rats for the same exposure on postnatal day 7. Here we test our hypothesis that androgens can modulate chloride cotransporter expression to alter the susceptibility to neurotoxicity from GABAergic drugs using female rats with exogenous testosterone exposure.MethodsFemale rats were injected with testosterone (100 μg/animal) or vehicle on postnatal days 1 to 6. On postnatal day 7, the animals were randomized to either isoflurane exposure or sham. Spatial memory was assessed with the Barnes maze starting on postnatal day 41. Western blots were run from testosterone treated postnatal day 7 animals to measure levels of chloride cotransporters sodium-potassium-chloride symporter (NKCC1) and chloride-potassium symporter 5 (KCC2).ResultsExogenous testosterone modulated isoflurane anesthetic neurotoxicity in female rats based on poor performance in the probe trial of the Barnes Maze. By contrast, females with vehicle and isoflurane exposure were able to differentiate the goal position. These behavioral differences corresponded to differences in the protein levels of NKCC1 and KCC2 after exogenous testosterone exposure, with NKCC1 increasing ( P <0.001) and KCC2 decreasing ( P =0.003) relative to female controls.ConclusionsThe expression of chloride cotransporters, NKCC1 and KCC2, is altered by testosterone in female rats and corresponds to a cognitive deficit after isoflurane exposure. This confirms the role of androgens in perinatal anesthetic neurotoxicity and supports our hypothesis that the developing GABAergic system plays a critical role in the underlying mechanism.
| S-EPMC8671561 | biostudies-literature
Project description:BackgroundThe aim of this study was to assess different amyloid beta subspecies' effects on behaviour and cognition in mice and their interaction with isoflurane anaesthesia.MethodsAfter governmental approval, cannulas were implanted in the lateral cerebral ventricle. After 14 days the mice were randomly intracerebroventricularly injected with Aβ 1-40 (Aβ40), Aβ 1-42 (Aβ42), 3NTyr10-Aβ (Aβ nitro), AβpE3-42 (Aβ pyro), or phosphate buffered saline. Four days after the injection, 30 mice (6 animals per subgroup) underwent general anaesthesia with isoflurane. A "sham" anaesthetic procedure was performed in another 30 mice (6 animals per subgroup, 10 subgroups in total). During the next eight consecutive days a blinded assessor evaluated behavioural and cognitive performance using the modified hole-board test. Following the testing we investigated 2 brains per subgroup for insoluble amyloid deposits using methoxy staining. We used western blotting in 4 brains per subgroup for analysis of tumour-necrosis factor alpha, caspase 3, glutamate receptors NR2B, and mGlu5. Data were analysed using general linear modelling and analysis of variance.ResultsAβ pyro improved overall cognitive performance (p = 0.038). This cognitive improvement was reversed by isoflurane anaesthesia (p = 0.007), presumably mediated by decreased exploratory behaviour (p = 0.022 and p = 0.037). Injection of Aβ42 was associated with increased anxiety (p = 0.079). Explorative analysis on a limited number of brains did not reveal insoluble amyloid deposits or differences in the expression of tumour-necrosis factor alpha, NR2B, mGlu5, or caspase 3.ConclusionsTesting cognitive performance after intracerebroventricular injection of different amyloid beta subspecies revealed that Aβ pyro might be less harmful, which was reversed by isoflurane anaesthesia. There is minor evidence for Aβ42-mediated neurotoxicity. Preliminary molecular analysis of biomarkers did not clarify pathophysiological mechanisms.
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Project description:Parkinson's disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.
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Project description:Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. Growing evidence suggests that soluble tau aggregates trigger neurodegenerative phenotypes. However, the nature of the tau species and interactors involved in its aggregation and spreading remains unclear. By using size exclusion chromatography, mass spectrometry, and bioinformatic analysis, we identified Bassoon protein (BSN) as a significant tau interactor in PS19 mice, as well as in human AD and PSP cases. We also found that overexpression of BSN triggers the aggregation of tau and increase the tau seeding activity in vitro, and also exacerbates the degenerative phenotype in a Fly model for tauopathy. Knockdown of BSN significantly reduced tau spreading in PS19 mouse brains and destabilized the tau aggregates, leading to a reduction in the tau pathology in this model. Furthermore, BSN downregulation was able to restore the neurodegenerative phenotype in PS19 mice, observed in electrophysiology and behavioral tests. Our results identify BSN as a key interactor of tau spread and aggregation in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.
2023-03-11 | PXD027451 | Pride
Project description:Neurodegenration is a pathological hallmark of Alzheimer's disease (AD), but the underlying molecular mechanism remains elusive. Here, we present evidence that reveals a crucial role of Wnt5a signaling in this process. We showed that Wnt5a and its receptor Frizzled-5 (Fz5) were up-regulated in the AD mouse brain, and that beta-amyloid peptide (Aβ), a major constituent of amyloid plaques, stimulated Wnt5a and Fz5 expression in primary cortical cultures; these observations indicate that Wnt5a signaling could be aberrantly activated during AD pathogenesis. In support of such a possibility, we observed that inhibition of Wnt5a signaling attenuated while activation of Wnt5a signaling enhanced Aβ-evoked neurotoxicity, suggesting a role of Wnt5a signaling in AD-related neurodegeneration. Furthermore, we also demonstrated that Aβ-induced neurotoxicity depends on inflammatory processes, and that activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures. Our findings collectively suggest that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation.
| S-EPMC3157339 | biostudies-literature
Project description:BackgroundPeriodontitis has emerged as a potential risk factor for chronic obstructive pulmonary disease (COPD). However, the precise mechanism through which periodontitis influences the progression of COPD requires further investigation. Ferroptosis is one of the crucial pathogenesis of COPD and recent researches suggested that periodontitis was associated with ferroptosis. Nonetheless, the relationship among periodontitis, COPD and ferroptosis remains unclear. This study aimed to elucidate whether periodontitis contributes to COPD exacerbation and to assess the potential impact of ferroptosis on periodontitis affecting COPD.MethodsThe severity of COPD was assessed using Hematoxylin and eosin (H&E) staining and lung function tests. Iron assays, malondialdehyde (MDA) measurement and RT-qPCR were used to investigate the potential involvement of ferroptosis in the impact of periodontitis on COPD. Co-cultures of periodontitis associated pathogen Phophyromonas gingivalis (P. gingivalis) and lung tissue cells were used to evaluate the effect of P. gingivalis on inducing the ferroptosis of lung tissue via RT-qPCR analysis. Clinical Bronchoalveolar Lavage Fluid (BALF) samples from COPD patients were collected to further validate the role of ferroptosis in periodontal pathogen-associated COPD.ResultsPeriodontitis aggravated the COPD progression and the promotion was prolonged over time. For the first time, we demonstrated that periodontitis promoted the ferroptosis-associated iron accumulation, MDA contents and gene expressions in the COPD lung with a time-dependent manner. Moreover, periodontitis-associated pathogen P. gingivalis could promote the ferroptosis-associated gene expression in single lung tissue cell suspensions. Clinical BALF sample detection further indicated that ferroptosis played essential roles in the periodontal pathogen-associated COPD.ConclusionPeriodontitis could contribute to the exacerbation of COPD through up-regulating the ferroptosis in the lung tissue.
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Project description:Anesthetic sevoflurane induces mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in young mice, but the underlying mechanism remains to be determined. Cyclophilin D (CypD) is a modulatory factor for the mitochondrial permeability transition pore (mPTP). We, therefore, set out to evaluate the role of CypD in these sevoflurane-induced changes in vitro and in young mice. Wild-type (WT) and CypD knockout (KO) young (postnatal day 6, 7, and 8) mice received 3% sevoflurane 2 h daily and the neural progenitor cells (NPCs) harvested from the WT or CypD KO mice received 4.1% sevoflurane. We used immunohistochemistry and immunocytochemistry imaging, flow cytometry, Western blot, RT-PCR, co-immunoprecipitation, and Morris Water Maze to assess the interaction of sevoflurane and CypD on mitochondria function, neurogenesis, and cognition in vitro and in WT or CypD KO mice. We demonstrated that the sevoflurane anesthesia induced accumulation of CypD, mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in WT mice or NPCs harvested from WT mice, but not in CypD KO mice or NPCs harvested from CypD KO mice. Furthermore, the sevoflurane anesthesia reduced the binding of CypD with Adenine nucleotide translocator, the other component of mPTP. These data suggest that the sevoflurane anesthesia might induce a CypD-dependent mitochondria dysfunction, impairment of neurogenesis, and cognitive impairment in young mice and NPCs.
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