Deferoxamine deconditioning increases neuronal vulnerability to hemoglobin.
Ontology highlight
ABSTRACT:
SUBMITTER: Peng D
PROVIDER: S-EPMC7301423 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Previously we reported that several microRNAs (miRNA) are upregulated following experimentally induced traumatic brain injury (TBI) using both in vivo and in vitro approaches. Specific miRNAs were found to be sensitive to therapeutic hypothermia and may therefore be important targets for neuroprotective strategies. In this study we developed plasmid constructs that overexpress temperature sensitive miRNAs: miR-34a, miR-451, and miR-874. These constructs were transfected into cultured cortical neurons that were subjected to stretch injury using a cell injury controller device. Levels of expression of genes associated with stress, inflammation, apoptosis and transcriptional regulation were measured by qRT-PCR. mRNA levels of cytokines interleukin 1-β (IL1-β) and tumor necrosis factor alpha (TNF-α) as well as heat shock protein 70 (HSP70) and Caspase 11 were found to be increased up to 24 fold higher than controls in cells overexpressing these miRNAs. After moderate stretch injury, the expression of IL1-β, TNF-α, HSP70 and Caspase 11 all increased over control levels found in uninjured cells suggesting that overexpression of these miRNAs increases cellular vulnerability. miR-34a directly inhibits Bcl2 and XIAP, both anti-apoptotic proteins. The observed increase in Caspase 11 with over-expression of miR-34a indicates that miR-34a may be inducing apoptosis by reducing the levels of anti-apoptotic proteins. miR-34a is predicted to inhibit Jun, which was seen to decrease in cells overexpressing this miRNA along with Fos. Over expression of several miRNAs found to be induced by TBI in vivo (miR-34a, miR-451 and miR-874) leads to increased vulnerability in transfected neurons. Therapeutic hypothermia blunts the expression of these miRNAs in vivo and antisense silencing could be a potential therapeutic approach to targeting the consequences of TBI.
| S-EPMC3829616 | biostudies-literature
Project description:Since accumulating evidence suggests the application of anesthetics may increase the risk of Alzheimer's disease (AD), we investigated the cytotoxicity of inhaled general anesthesia in neurons and its underlying mechanism. Using primary cultured rat hippocampal neurons as the study model, here we show that isoflurane increases vulnerability to intracellular or extracellular amyloid ? with or without serum deprivation. This isoflurane-induced effect is mediated by the downregulation of miR-214 level that lead to an elevated expression of Bax, a prominent target for miR-214. We conclude that isoflurane increases cell death in the presence of amyloid ? by increasing Bax level through downregulating miR-214. Our data provide a new insight for inhaled anesthetics toxicity and indicate a possible mechanistic link between anesthetic application and neurodegenration in AD.
| S-EPMC3568119 | biostudies-literature
Project description:The global decline in the abundance and diversity of insect pollinators could result from habitat loss, disease, and pesticide exposure. The contribution of the neonicotinoid insecticides (e.g., clothianidin and imidacloprid) to this decline is controversial, and key to understanding their risk is whether the astonishingly low levels found in the nectar and pollen of plants is sufficient to deliver neuroactive levels to their site of action: the bee brain. Here we show that bumblebees (Bombus terrestris audax) fed field levels [10 nM, 2.1 ppb (w/w)] of neonicotinoid accumulate between 4 and 10 nM in their brains within 3 days. Acute (minutes) exposure of cultured neurons to 10 nM clothianidin, but not imidacloprid, causes a nicotinic acetylcholine receptor-dependent rapid mitochondrial depolarization. However, a chronic (2 days) exposure to 1 nM imidacloprid leads to a receptor-dependent increased sensitivity to a normally innocuous level of acetylcholine, which now also causes rapid mitochondrial depolarization in neurons. Finally, colonies exposed to this level of imidacloprid show deficits in colony growth and nest condition compared with untreated colonies. These findings provide a mechanistic explanation for the poor navigation and foraging observed in neonicotinoid treated bumblebee colonies.
| S-EPMC4415021 | biostudies-literature
Project description:Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.
| S-EPMC5564322 | biostudies-other
Project description:Somatostatin (SST) deficits are common pathological features in depression and other neurological disorders with mood disturbances, but little is known about the contribution of SST deficits to mood symptoms or causes of these deficits. Here we show that mice lacking SST (Sst(KO)) exhibit elevated behavioral emotionality, high basal plasma corticosterone and reduced gene expression of Bdnf, Cortistatin and Gad67, together recapitulating behavioral, neuroendocrine and molecular features of human depression. Studies in Sst(KO) and heterozygous (Sst(HZ)) mice show that elevated corticosterone is not sufficient to reproduce the behavioral phenotype, suggesting a putative role for Sst cell-specific molecular changes. Using laser capture microdissection, we show that cortical SST-positive interneurons display significantly greater transcriptome deregulations after chronic stress compared with pyramidal neurons. Protein translation through eukaryotic initiation factor 2 (EIF2) signaling, a pathway previously implicated in neurodegenerative diseases, was most affected and suppressed in stress-exposed SST neurons. We then show that activating EIF2 signaling through EIF2 kinase inhibition mitigated stress-induced behavioral emotionality in mice. Taken together, our data suggest that (1) low SST has a causal role in mood-related phenotypes, (2) deregulated EIF2-mediated protein translation may represent a mechanism for vulnerability of SST neurons and (3) that global EIF2 signaling has antidepressant/anxiolytic potential.
| S-EPMC4355106 | biostudies-literature
Project description:This study examined whether neuronal hemoglobin (Hb) is present in rats. It then examined whether cerebral ischemia or ischemic preconditioning (IPC) affects neuronal Hb levels in vivo and in vitro. In vivo, male Sprague-Dawley rats were subjected to either 15 mins of transient middle cerebral artery occlusion (MCAO) with 24 h of reperfusion, an IPC stimulus, or 24 h of permanent MCAO (pMCAO), or IPC followed 3 days later by 24 h of pMCAO. In vitro, primary cultured neurons were exposed to 2 h of oxygen-glucose deprivation (OGD) with 22 h of reoxygenation. Results showed that Hb is widely expressed in rat cerebral neurons but not astrocytes. Hemoglobin expression was significantly upregulated in the ipsilateral caudate and the cortical core of the middle cerebral artery territory after IPC. Hemoglobin levels also increased more in the penumbral cortex and the contralateral hemisphere 24 h after pMCAO, but expressions in the ipsilateral caudate and the cortical core area were decreased. Ischemic preconditioning modified pMCAO-induced brain Hb changes. Neuronal Hb levels in vitro were increased by 2 h of OGD and 22 h of reoxygenation. These results indicate that Hb is synthesized in neurons and can be upregulated by ischemia.
| S-EPMC2683405 | biostudies-literature
Project description:Glycosphingolipid (GSL) accumulation is implicated in the neuropathology of several lysosomal conditions, such as Krabbe disease, and may also contribute to neuronal and glial dysfunction in adult-onset conditions such as Parkinson's disease, Alzheimer's disease and multiple sclerosis. GSLs accumulate in cellular membranes and disrupt their structure; however, how membrane disruption leads to cellular dysfunction remains unknown. Using authentic cellular and animal models for Krabbe disease, we provide a mechanism explaining the inactivation of lipid raft (LR)-associated IGF-1-PI3K-Akt-mTORC2, a pathway of crucial importance for neuronal function and survival. We show that psychosine, the GSL that accumulates in Krabbe disease, leads to a dose-dependent LR-mediated inhibition of this pathway by uncoupling IGF-1 receptor phosphorylation from downstream Akt activation. This occurs by interfering with the recruitment of PI3K and mTORC2 to LRs. Akt inhibition can be reversed by sustained IGF-1 stimulation, but only during a time window before psychosine accumulation reaches a threshold level. Our study shows a previously unknown connection between LR-dependent regulation of mTORC2 activity at the cell surface and a genetic neurodegenerative disease. Our results show that LR disruption by psychosine desensitizes cells to extracellular growth factors by inhibiting signal transmission from the plasma membrane to intracellular compartments. This mechanism serves also as a mechanistic model to understand how alterations of the membrane architecture by the progressive accumulation of lipids undermines cell function, with potential implications in other genetic sphingolipidoses and adult neurodegenerative conditions. This article has an associated First Person interview with the first author of the paper.
| S-EPMC6550048 | biostudies-literature
Project description:The effect of preconception drinking by the mother on the life-long health outcomes of her children is not known, and therefore, in this study using an animal model, we determined the impact of preconception alcohol drinking of the mother on offspring stress response during adulthood. In our preconception alcohol exposure model, adult female rats were fed with 6.7% alcohol in their diet for 4 weeks, went without alcohol for 3 weeks and were bred to generate male and female offspring. Preconception alcohol-exposed offsprings' birth weight, body growth, stress response, anxiety-like behaviors, and changes in stress regulatory gene and protein hormone levels were evaluated. In addition, roles of epigenetic mechanisms in preconception alcohol effects were determined. Alcohol feeding three weeks prior to conception significantly affected pregnancy outcomes of female rats, with respect to delivery period and birth weight of offspring, without affecting maternal care behaviors. Preconception alcohol negatively affected offspring adult health, producing an increased stress hormone response to an immune challenge. In addition, preconception alcohol was associated with changes in expression and methylation profiles of stress regulatory genes in various brain areas. These changes in stress regulatory genes were normalized following treatment with a DNA methylation blocker during the postnatal period. These data highlight the novel possibility that preconception alcohol affects the inheritance of stress-related diseases possibly by epigenetic mechanisms.
| S-EPMC5026748 | biostudies-literature
Project description:Hemoglobin (Hb) is the major protein in erythrocytes and carries oxygen (O2) throughout the body. Recently, Hb has been found synthesized in atypical sites, including the brain. Hb is highly expressed in A9 dopaminergic (DA) neurons of the substantia nigra (SN), whose selective degeneration leads to Parkinson's disease (PD). Here we show that Hb confers DA cells' susceptibility to 1-methyl-4-phenylpyridinium (MPP+) and rotenone, neurochemical cellular models of PD. The toxic property of Hb does not depend on O2 binding and is associated with insoluble aggregate formation in the nucleolus. Neurochemical stress induces epigenetic modifications, nucleolar alterations and autophagy inhibition that depend on Hb expression. When adeno-associated viruses carrying ?- and ?-chains of Hb are stereotaxically injected into mouse SN, Hb forms aggregates and causes motor learning impairment. These results position Hb as a potential player in DA cells' homeostasis and dysfunction in PD.
| S-EPMC5386368 | biostudies-literature
Project description:Neuromelanin, a dark brown intracellular pigment, has long been associated with Parkinson's disease (PD). In PD, neuromelanin-containing neurons preferentially degenerate, tell-tale neuropathological inclusions form in close association with this pigment, and neuroinflammation is restricted to neuromelanin-containing areas. In humans, neuromelanin accumulates with age, which in turn is the main risk factor for PD. The potential contribution of neuromelanin to PD pathogenesis remains unknown because, in contrast to humans, common laboratory animals lack neuromelanin. The recent introduction of a rodent model exhibiting an age-dependent production of human-like neuromelanin has allowed, for the first time, for the consequences of progressive neuromelanin accumulation-up to levels reached in elderly human brains-to be assessed in vivo. In these animals, intracellular neuromelanin accumulation above a specific threshold compromises neuronal function and triggers a PD-like pathology. As neuromelanin levels reach this threshold in PD patients and presymptomatic PD patients, the modulation of neuromelanin accumulation could provide a therapeutic benefit for PD patients and delay brain aging. © 2019 The Author. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC7079126 | biostudies-literature