Xenon Blocks Neuronal Injury Associated with Decompression.
Ontology highlight
ABSTRACT:
SUBMITTER: Blatteau JE
PROVIDER: S-EPMC4606806 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Status epilepticus is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. ?-Aminobutyric acidergic (GABAergic) drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, which may worsen the seizures and their effects. Using a recently developed model of status epilepticus in postnatal day 7 rat pups that results in widespread neuronal injury, we found that the GABAA agonists phenobarbital and midazolam significantly increased status epilepticus-associated neuronal injury in various brain regions. Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain. Ann Neurol 2017;82:115-120.
| S-EPMC5546097 | biostudies-literature
Project description:BACKGROUND:Chemotherapy-induced peripheral neuropathy is not only one of the most common causes of dose reduction or discontinuation of cancer treatment, but it can also permanently decrease the quality of life of cancer patients and survivors. Notably, Sirt2 protects many organs from various injuries, including diabetic peripheral neuropathy. As demonstrated previously by our laboratory and others, the overexpression of Sirt2 can improve cisplatin-induced neuropathy, although the mechanism is still unclear. RESULTS:In this study, the underlying mechanism by which Sirt2 protects neurons from cisplatin-induced injury was explored using the RNAseq technique in cultured rodent neurons. Sirt2 status was modified by genetic knockout (Sirt2/KO) and was then reconstituted in Sirt2/KO cells (Sirt2/Res). We observed 323 upregulated genes and 277 downregulated genes in Sirt2-expressing cells (Sirt2/Res) compared to Sirt2-deficient cells (Sirt2/KO). Pathway analysis suggested that Sirt2 may affect several pathways, such as MAPK, TNF, and cytokine-cytokine interaction. Furthermore, cisplatin-induced changes to the transcriptome are strongly associated with Sirt2 status. Cisplatin induced distinctive transcriptome changes for 227 genes in Sirt2-expressing cells and for 783 genes in Sirt2-deficient cells, while changes in only 138 of these genes were independent of Sirt2 status. Interestingly, changes in the p53 pathway, ECM-receptor interactions, and cytokine-cytokine receptor interactions were induced by cisplatin only in Sirt2-deficient cells. CONCLUSIONS:This study demonstrated that Sirt2 regulates the transcriptome in cultured rodent neuronal cells. Furthermore, Sirt2-associated transcriptome regulation may be an important mechanism underlying the role of Sirt2 in organ protection, such as in cisplatin-induced neuronal injury. Sirt2 may be a potential target for the prevention and treatment of chemotherapy-induced neuropathy.
| S-EPMC7053098 | biostudies-literature
Project description:Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.
| S-EPMC5453710 | biostudies-literature
Project description:Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells.VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).
| S-EPMC5570662 | biostudies-literature
Project description:Symptomatic distal sensory polyneuropathy (sDSP) is common and debilitating in people with HIV/AIDS, leading to neuropathic pain, although the condition's cause is unknown. To investigate biomarkers and associated pathogenic mechanisms for sDSP, we examined plasma miRNA profiles in HIV/AIDS patients with sDSP or without sDSP in 2 independent cohorts together with assessing related pathogenic effects. Several miRNAs were found to be increased in the Discovery Cohort (sDSP, n = 29; non-DSP, n = 40) by array analyses and were increased in patients with sDSP compared with patients without sDSP. miR-455-3p displayed a 12-fold median increase in the sDSP group, which was confirmed by machine learning analyses and verified by reverse transcription PCR. In the Validation Cohort (sDSP n = 16, non-DSP n = 20, healthy controls n = 15), significant upregulation of miR-455-3p was also observed in the sDSP group. Bioinformatics revealed that miR-455-3p targeted multiple host genes implicated in peripheral nerve maintenance, including nerve growth factor (NGF) and related genes. Transfection of cultured human dorsal root ganglia with miR-455-3p showed a concentration-dependent reduction in neuronal β-III tubulin expression. Human neurons transfected with miR-455-3p demonstrated reduced neurite outgrowth and NGF expression that was reversed by anti-miR-455-3p antagomir cotreatment. miR-455-3p represents a potential biomarker for HIV-associated sDSP and might also exert pathogenic effects leading to sDSP.
| S-EPMC6328026 | biostudies-literature
Project description:Propranolol is a widely used, non-selective ?-adrenergic receptor antagonist with proven efficacy in treating cardiovascular disorders and in the prevention of migraine headaches. At plasma concentrations exceeding those required for ?-adrenergic receptor inhibition, propranolol also exhibits anti-arrhythmic ("membrane stabilizing") effects that are not fully explained by ?-blockade. Previous in vitro studies suggested that propranolol may have local anesthetic effects. We directly tested the effects of propranolol on heterologously expressed recombinant human cardiac (NaV1.5) and brain (NaV1.1, NaV1.2, NaV1.3) sodium channels using whole-cell patch-clamp recording. We found that block was not stereospecific as we observed approximately equal IC50 values for tonic and use-dependent block by R-(+) and S-(-) propranolol (tonic block: R: 21.4??M vs S: 23.6??M; use-dependent block: R: 2.7??M vs S: 2.6??M). Metoprolol and nadolol did not block NaV1.5 indicating that sodium channel block is not a class effect of ?-blockers. The biophysical effects of R-(+)-propranolol on NaV1.5 and NaV1.1 resembled that of the prototypical local anesthetic lidocaine including the requirement for a critical phenylalanine residue (F1760 in NaV1.5) in the domain 4 S6 segment. Finally, we observed that brain sodium channels exhibited less sensitivity to R-(+)-propranolol than NaV1.5 channels. Our findings establish sodium channels as targets for propranolol and may help explain some beneficial effects of the drug in treating cardiac arrhythmias, and may explain certain adverse central nervous system effects.
| S-EPMC3153018 | biostudies-literature
Project description:Glutamate receptor-mediated excitotoxicity is a common pathogenic process in many neurological conditions including epilepsy. Prolonged seizures induce elevations in extracellular glutamate that contribute to excitotoxic damage, which in turn can trigger chronic neuroinflammatory reactions, leading to secondary damage to the brain. Blocking key inflammatory pathways could prevent such secondary brain injury following the initial excitotoxic insults. Prostaglandin E2 (PGE2) has emerged as an important mediator of neuroinflammation-associated injury, in large part via activating its EP2 receptor subtype. Herein, we investigated the effects of EP2 receptor inhibition on excitotoxicity-associated neuronal inflammation and injury in vivo. Utilizing a bioavailable and brain-permeant compound, TG6-10-1, we found that pharmacological inhibition of EP2 receptor after a one-hour episode of kainate-induced status epilepticus (SE) in mice reduced seizure-promoted functional deficits, cytokine induction, reactive gliosis, blood-brain barrier impairment, and hippocampal damage. Our preclinical findings endorse the feasibility of blocking PGE2/EP2 signaling as an adjunctive strategy to treat prolonged seizures. The promising benefits from EP2 receptor inhibition should also be relevant to other neurological conditions in which excitotoxicity-associated secondary damage to the brain represents a pathogenic event.
| S-EPMC6486887 | biostudies-literature
Project description:1. Decarbomethoxyllated JW062 (DCJW), the active component of a new oxadiazine insecticide DPX-JW062 (Indoxacarb), was tested on action potentials and the inward sodium current recorded from short-term cultured dorsal unpaired median neurones of the cockroach Periplaneta americana. 2. Under whole-cell current-clamp conditions, 100 nM DCJW reduced the amplitude of action potentials and induced a large hyperpolarization of the resting membrane potential associated with a 41% increase in input resistance. 3. In voltage-clamp, DCJW resulted in a dose-dependent inhibition (IC(50) 28 nM) of the peak sodium current. Based on IC(50) values, the effect of DCJW was about 10 fold less potent than tetrodotoxin (TTX) but 1000 fold more potent than the local anaesthetic lidocaine. DCJW (100 nM) was without effect on activation properties of the sodium current, reversal potential, voltage dependence of sodium conductance and on both fast and slow steady-state inactivations. 4. TTX (2 nM) resulted in 48% inhibition of the peak inward sodium current. Co-application of TTX (2 nM) with various concentrations of DCJW produced an additional inhibition of the peak inward current, indicating that the blocking actions of DCJW and TTX were distinct. Co-application of lidocaine (IC(50) 30 microM) with various concentrations of DCJW produced a reduction of the apparent potency of DCJW, suggesting that DCJW and lidocaine acted at the same site. 5. DCJW (100 nM) did not affect inward calcium or outward potassium currents. 6. This study describes, for the first time, the action on insect neuronal voltage-dependent sodium channels of Indoxacarb, a new class of insecticides.
| S-EPMC1572588 | biostudies-other
Project description:Using long-oligo beadschip arrays, we examined the global gene expression profile in cultured hippocampal slices under the simulated ischemic condition with and without the presence of DIDS . Control-ACSF: cultured hippocampal slices were incubated with ACSF for 2 hours and were analysed on whole-genome expression chips to determine the gene expression profile. This group was used as controls for IS-treated groups and ACSF+DIDS-treated grous. IS: cultured hippocampal slices were treated wtih IS for 2 hours and the gene expression was analyzed and compared with the control group. IS+DIDS: cultured slices were treated with both IS and DIDS for 2 hours and the gene expression profile was determined. Differentially expression genes were identified by comparing with IS group. ACSF+DIDS: cultured slices were incubated with both ACSF and DIDS for 2 hours and gene expression profile was determined. This group was used as a control for IS+DIDS group. ACSF: artificial cerebral spinal fluid DIDS: 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid IS: ischemic solution
2010-05-15 | E-GEOD-12426 | biostudies-arrayexpress
Project description:Mature rat cortical neuronal networks cultured on multi-electrode arrays (MEAs) are known to show spontaneous synchronized bursts accompanied by independent single spikes. The spontaneous synchronized bursts can be inhibited by Xe gas. In this study, we adjust the Xe gas pressure to control the amount of Xe in a neuron-cultured MEA medium. We show that the synchronized bursts cease completely within several minutes by applying Xe gas at partial pressures above 0.3 MPa. After depressurizing and purging with fresh air, the synchronized bursts recover to their original frequency. Thus, we confirmed that Xe acts as a network-activity inhibitor of the cultured neuronal network on MEAs. But below 0.3 MPa, the synchronized bursts are inhibited only partially, depending on the Xe partial pressure. Based on the partial-pressure influence on the change of the neuronal network activities, we find the critical concentration of Xe for the inhibition effect to be approximately 9.5 mM, a value above which more than 90% of the synchronized burst activity is inhibited. Further systematic observations with Xe-air mixed gases show that pressurized air with a small amount of Xe suppresses the inhibition of synchronized bursts, suggesting an air component that can accelerate the synchronized bursts.
| S-EPMC6084913 | biostudies-literature