Reversal of ischemic mitochondrial dysfunction.
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Animals↗
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Results for “Mitochondria dysfunction”
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Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium.
Experimental and clinical studies have suggested an increased production of reactive oxygen species (ROS) in the failing myocardium. The present study aimed to obtain direct evidence for increased ROS and to determine the contribution of superoxide anion (*O(2)(-)), H(2)O(2), and hydroxy radical (*OH) in failing myocardial tissue. Heart failure was produced in adult mongrel dogs by rapid ventricular pacing at 240 bpm for 4 weeks. To assess the production of ROS directly, freeze-clamped myocardial tissue homogenates were reacted with the nitroxide radical, 4-hydroxy-2,2,6, 6,-tetramethyl-piperidine-N-oxyl, and its spin signals were detected by electron spin resonance spectroscopy. The rate of electron spin resonance signal decay, proportional to *OH level, was significantly increased in heart failure, which was inhibited by the addition of dimethylthiourea (*OH scavenger) into the reaction mixture. Increased *OH in the failing heart was abolished to the same extent in the presence of desferrioxamine (iron chelator), catalase (H(2)O(2) scavenger), and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron; LaMotte) (*O(2)(-) scavenger), indicating that *OH originated from H(2)O(2) and *O(2)(-). Further, *O(2)(-) produced in normal myocardium in the presence of antimycin A (mitochondrial complex III inhibitor) could reproduce the increase of H(2)O(2) and *OH seen in the failing tissue. There was a significant positive relation between myocardial ROS level and left ventricular contractile dysfunction. In conclusion, in the failing myocardium, *OH was produced as a reactive product of *O(2)(-) and H(2)O(2), which might play an important role in left ventricular failure.
Animals↗
Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium.
Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4-hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5, 5'-dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH-ubiquinone oxidoreductase (complex I) and succinate-ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P<0.01) in HF, which was due to the functional block of electron transport at complex I. The enzymatic activity of complex I decreased in HF (274+/-13 versus 136+/-9 nmol. min(-1). mg(-1) protein, P<0.01), which may thus have caused the functional uncoupling of the respiratory chain and the deleterious ROS production in HF mitochondria. The present study provided direct evidence for the involvement of ROS in the mitochondrial origin of HF myocytes, which might be responsible for both contractile dysfunction and structural damage to the myocardium.
Animals↗
Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium.
OBJECTIVES: We have shown previously that human diabetic myocardium cannot be preconditioned. Here, we have investigated the basis of this cardioprotective deficit. METHODS: Right atrial sections from four patient groups-non-diabetic, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) receiving glibenclamide, and NIDDM receiving metformin-were subjected to one of the following protocols: aerobic control, simulated ischemia/reoxygenation, ischemic preconditioning before ischemia, and pharmacological preconditioning with alpha 1 agonist phenylephrine, adenosine, the mito-K(ATP) channel opener diazoxide, the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA), or the p38 mitogen-activated protein kinase (p38MAPK) activator anisomycin. Cellular damage was assessed using creatine kinase leakage and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. In mitochondrial preparations from non-diabetic and diabetic myocardium, mitochondrial membrane potential (Psi(m)) was assessed using JC-1 dye, and production of reactive oxygen species was determined. RESULTS: Preconditioning with ischemia, phenylephrine, adenosine, or diazoxide failed to protect diabetic myocardium. However, activation of PKC or p38MAPK was still protective. In isolated non-diabetic mitochondria, diazoxide partially depolarized Psi(m), an effect not seen in diabetic mitochondria. Furthermore, diazoxide increased superoxide production in non-diabetic but not in diabetic mitochondria. CONCLUSIONS: Our results show that the cardioprotective deficit in diabetic myocardium arises upstream of PKC and p38MAPK. We suggest that mitochondrial dysfunction in diabetic myocardium, possibly dysfunctional mito-K(ATP) channels, leads to impaired depolarization and superoxide production, and that this causes the inability to respond to preconditioning.
Adenosine↗
Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders.
Mitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the beta-oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal beta-oxidation are associated with extracellular accumulation of very long-chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl-CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl-CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9 +/- 0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean +/- SEM; activity nmol/min per mg protein) was: NALD 0.55 +/- 0.02 (p < 0.01), RCDP 0.44 +/- 0.02 (P < 0.01), and controls 0.83 +/- 0.02. The acid-insoluble (long-chain and very long-chain) acyl-CoA levels (mean +/- SEM; pmol/mg protein) were: NALD 129 +/- 69 (p < 0.01), RCDP 65 +/- 15 (p < 0.05), and control 45 +/- 7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl-CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.
Acidosis, Lactic↗
Cardiomyopathy, nucleoside reverse transcriptase inhibitors and mitochondria are linked through AIDS and its therapy.
Nucleoside reverse transcriptase inhibitors (NRTIs) in highly active antiretroviral therapy (HAART) bring serious side effects to light. Mitochondrial dysfunction, mtDNA replication defects and mtDNA depletion in target tissues are observed experimentally and clinical confirmation is present in some cases. Organ-specific pathological changes, particularly in the cardiovascular system, result from and are frequently attributed to HAART where NRTIs are included. Mechanisms of mitochondrial toxicity are incompletely understood, but could reasonably relate to inhibition of DNA polymerase-gamma (the enzyme responsible for mtDNA replication in eukaryotes) by pharmacologically active NRTI triphosphates. Cellular and biological implications of the pharmacologic events are addressed.
Journal Article↗
Mitochondrial involvement in transhemispheric diaschisis following hypoxia-ischemia: Clomethiazole-mediated amelioration.
Mitochondria play a central role in both the physiological and pathophysiological regulation of cell survival/death. Increasing evidence places mitochondrial dysfunction at the center of many neuropathological conditions. The present study investigates the extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues in a rat model of hypoxia-ischemia (HI). We hypothesized that; mitochondrial dysfunction in situ may be prevented by treatment with clomethiazole (CMZ), a GABA(A) receptor agonist. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-day post-HI revealed a marked decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, small changes were seen in contralateral cortical and hippocampal tissues as well as in the cerebellum at 3-days (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V), and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed mitochondrial impairment in ipsilateral regions following HI. Complexes I, II-III, V and citrate synthase were also impaired in contralateral regions and cerebellum 3-days post-HI. Treatment with CMZ (414 mg/kg/day via minipumps) provided marked protection to all aspects of neuronal tissue assessed. Circulating cytokine (interleukin [IL]-1alpha, IL-1beta, tumor necrosis factor [TNF]-alpha, granulocyte macrophage colony-stimulating factor [GM-CSF], IL-4 and IL-10) levels were also assessed in these animals 3-days post-HI. Plasma IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels were significantly increased post-HI. Treatment with CMZ ameliorated the increases in IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels while increasing plasma IL-4 and IL-10 levels. This study provides evidence of the extent of mitochondrial damage following an HI-insult. In addition, we have shown that protection afforded by CMZ extends to preservation of mitochondrial function and integrity via anti-inflammatory mediated pathways.
Animals↗
[Melatonin recovers ischemic tolerance and decreases the sensitivity of mitochondrial permeability transition pore opening in the heart of aging rats].
The effect of the hormone of pineal gland melatonin on the ischemic tolerance and the sensitivity of mitochondrial permeability transition pore opening in old rat heart were studied. It has been shown in the Langendorf's isolated rat heart that heart contractile functional changes under ischemia and reperfusion were more pronounced in old (24-27 months) rat hearts in comparison with the adult (5-6 months) animals. A two-week's in vivo course of intraperitoneal injection of melatonin (1,5 mg/kg weight) to old rats contributed to the rehabilitation of the functional changes of isolated heart after ischemia during reperfusion and decreased the sensitivity of mitochondrial permeability transition pore opening to Ca2+ and phenilarsinoxide in comparison with old animals which did not received melatonin. It was accompanied by the significant decreasing in mRNA bax expression in old rat heart, lessening in content of the superoxide radicals and dien conjugates and twice increasing in the activity of constitutive NO-synthase in heart mitochondria of old rat after a course of melatonin injection. The protective feffect of melatonin on the mitochondrial permeability transition pore opening could be used for correction of the cardiac dysfunction with aging.
Aging↗
Implication of bax in apoptosis depends on microtubule network mobility.
Paclitaxel and vincristine sulfate, two anti-microtubule agents are known to induce apoptosis. In this study, we tried to apprehend the relationship between the regulation of apoptotic proteins such as the Bcl-2-family proteins and the cytoskeleton structure during apoptosis induction by these two drugs. Paclitaxel and vincristine sulfate were used for a 24-h incubation and resulted in EC50 of 1 micro M and 1 micro g/ml, respectively. Under these conditions, paclitaxel treatment induced microtubule network polymerization, condensation of chromatin, characteristic features of early and late apoptosis as confirmed by orange acridine and ethydium bromide double staining. However, the shape of cells was not modified, while mitochondria changed their conformation from filamentous to aggregated corpuscles located around the nucleus. In addition, pro-apoptotic Bax protein remained in the cytoplasm, the beta-tubulin polymerization induced phosphorylation and inactivation of anti-apoptotic Bcl-2 and/or BclX/L proteins leading to intense mitochondria swelling and membrane disruption that are responsible for observed cytochrome c release and apoptotic proceeding. On the contrary, after vincristine sulfate treatment we observed morphological modifications such as cell shrinkage and nucleus condensation as the result of beta-tubulin depolarization and disruption of microtubules. Bax protein was intensively translocated into mitochondria membrane, decreasing the proportion of Bax/Bcl-2 or Bax/Bcl-xL heterodimers allowing the release of cytochrome c from the mitochondria and apoptotic process. In conclusion, our study demonstrated that the two anti-microtubule agents (paclitaxel and vincristine sulfate) induced apoptosis by two different pathways. However, mitochondrial dysfunction followed by cytochrome c release are the crucial events whatever the apoptotic signal, polymerization or disruption of beta-tubulin.
Apoptosis↗
Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle.
Locomotor functional decline and loss in muscle mass with age is virtually a universal characteristic that has been documented in several species, including worms, fruit flies, rodents, non-human primates and humans. The age-related loss of muscle mass and strength (sarcopenia) represents an important risk factor for disability and mortality in older subjects and has been linked with cellular energy deficit and increased apoptosis at old age. Many key theories on aging describing the mechanisms underlying sarcopenia are now focused on the mitochondria because of their dichotomous role in controlling life and death processes within myocytes. Mitochondria represent the main producers of cellular energy in the form of adenosine triphosphate, but are also considered a key regulatory center of apoptosis. Unknown factors leading to a decrease in aerobic energy efficiency are linked with mitochondrial mutations which may result into apoptosis. Moreover, deregulation of autophagy (degradation and recycling of long-lived protein and organelles, such as the mitochondria) in post-mitotic tissue might also be responsible for the age-associated cellular energy failure. Alterations in specific signaling pathways, such as AMP-activated protein kinases, play a role in both cell survival response and apoptotic response depending on energy depletion. Evidence supports that apoptosis occurring in aging skeletal muscle may be due, in part, to the progressive decline in mitochondrial function and the resulting energy depletion within the cell. In turn, mitochondrial dysfunction is partly due to the accumulation of oxidative damage to macromolecules, including mitochondrial DNA, RNA and proteins, essential components for optimal functioning of mitochondria. Evidence concerning these series of events leading to energy depletion and apoptosis are discussed.
Aging↗
Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease.
Dysfunction of dopamine neurons has been implicated in several neuropsychiatric disorders, including Parkinson's disease, addiction, bipolar disorder and depression. Recent elucidation of gene expression profiles in dopamine neuron subpopulations has shed light on the function of different groups of dopamine neurons in the CNS and on their dysfunction in disease states. In particular, concerted differences in gene expression appear to underlie the unique properties of distinct dopamine neurons. Specifically, dopamine neurons in the substantia nigra (SN), which are prone to degenerate in Parkinson's disease, express high levels of transcripts related to energy metabolism, mitochondria and phosphate signalling pathways. In contrast, ventral tegmental area (VTA) dopamine neurons prominently express genes related to synaptic plasticity and neuropeptides, suggesting intriguing mechanisms for the involvement of VTA dysfunction in addiction and mood disorders. As new functions of dopaminergic neurotransmission become clearer, continued exploration of the transcriptional neuroanatomy of these unique neurons will be vital for producing targeted, selective, and effective therapeutic agents.
Animals↗
Surgical and anesthetic management of patients with mitochondrial dysfunction.
Mitochondrial diseases are primary defects in bio-energy metabolism. They are a heterogeneous group of diseases. The specific constellation of symptoms that will manifest in the effected individual depends on the type of genetic defect in the mitochondria. The goals of medical management, expressed in a highly simplified fashion, are to maintain a normal acid-base balance and to avoid those medical conditions and situations that add extra stress to a compromised bio-energy production system. Infection is a common stress that may cause a crisis in a patient with mitochondrial dysfunction. Treatment and avoidance of infections is a goal of both medical and surgical management. Common childhood illness such as otitis media, tonsillitis and sinusitis are example of such stress inducing infections.
Journal Article↗
Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain.
According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (betaA) directly affects neurons, leading to neurodegeneration and tau phosphorylation. In rat hippocampal culture, betaA exposure activates tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK-3beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death. To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA in mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3beta in vitro and also in betaA-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death. In cholinergic neurons, betaA impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by betaA-induced TPKI/GSK-3beta. Thus, TPKI/GSK-3beta regulates PDH and participates in energy metabolism and acetylcholine synthesis. These results suggest that TPKI/GSK-3beta plays a key role in the pathogenesis of Alzheimer disease.
Animals↗
Mitochondria play a central role in estrogen-induced neuroprotection.
Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.
Animals↗
Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells.
Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
Animals↗
Reduced oxidative power but unchanged antioxidative capacity in skeletal muscle from aged humans.
The hypothesis that the aging process is associated with mitochondrial dysfunction and oxidative stress has been investigated in human skeletal muscle. Muscle biopsy samples were taken from seven old male subjects [OS; 75 (range 61-86) years] and eight young male subjects [YS; 25 (22-31) years]. Oxidative function was measured both in permeabilised muscle fibres and isolated mitochondria. Despite matching the degree of physical activity, OS had a lower training status than YS as judged from pulmonary maximal O(2) consumption ( Vdot;O(2)max, -36%) and handgrip strength (-20%). Both maximal respiration and creatine-stimulated respiration were reduced in muscle fibres from OS (-32 and -34%, respectively). In contrast, respiration in isolated mitochondria was similar in OS and YS. The discrepancy might be explained by a biased harvest of "healthy" mitochondria and/or disruption of structural components during the process of isolation. Cytochrome C oxidase was reduced (-40%, P<0.01), whereas UCP3 protein tended to be elevated in OS ( P=0.09). Generation of reactive oxygen species by isolated mitochondria and measures of antioxidative defence (muscle content of glutathione, glutathione redox status, antioxidative enzymes activity) were not significantly different between OS and YS. It is concluded that aging is associated with mitochondrial dysfunction, which appears to be unrelated to reduced physical activity. The hypothesis of increased oxidative stress in aged muscle could not be confirmed in this study.
Adult↗
Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets.
Uncoupling protein 2 (UCP2) negatively regulates insulin secretion. UCP2 deficiency (by means of gene knockout) improves obesity- and high glucose-induced beta cell dysfunction and consequently improves type 2 diabetes in mice. In the present study, we have discovered that the small molecule, genipin, rapidly inhibits UCP2-mediated proton leak. In isolated mitochondria, genipin inhibits UCP2-mediated proton leak. In pancreatic islet cells, genipin increases mitochondrial membrane potential, increases ATP levels, closes K(ATP) channels, and stimulates insulin secretion. These actions of genipin occur in a UCP2-dependent manner. Importantly, acute addition of genipin to isolated islets reverses high glucose- and obesity-induced beta cell dysfunction. Thus, genipin and/or chemically modified variants of genipin are useful research tools for studying biological processes thought to be controlled by UCP2. In addition, these agents represent lead compounds that comprise a starting point for the development of therapies aimed at treating beta cell dysfunction.
Adenosine Triphosphate↗
Attenuation of staurosporine-induced apoptosis, oxidative stress, and mitochondrial dysfunction by synthetic superoxide dismutase and catalase mimetics, in cultured cortical neurons.
Neuronal apoptosis induced by staurosporine (STS) involves multiple cellular and molecular events, such as the production of reactive oxygen species (ROS). In this study, we tested the efficacy of two synthetic superoxide dismutase/catalase mimetics (EUK-134 and EUK-189) on neuronal apoptosis, oxidative stress, and mitochondrial dysfunction produced by STS in primary cortical neuronal cultures. Exposure of cultures to STS for 24 h increased lactate dehydrogenase (LDH) release, the number of apoptotic cells, and decreased trypan blue exclusion. Pretreatment with 20 microM EUK-134 or 0.5 microM EUK-189 significantly attenuated STS-induced neurotoxicity, as did pretreatment with the caspase-1 inhibitor, Ac-YVAD-CHO, but not the caspase-3 inhibitor, Ac-DEVD-CHO. Posttreatment (1-3 h following STS exposure) with 20 microM EUK-134 or 0.5 microM EUK-189 significantly reduced STS-induced LDH release, in a time-dependent manner. Exposure of cultures to STS for 1 h produced an elevation of ROS, as determined by increased levels of 2,7-dichlorofluorescein (DCF). This rapid elevation of ROS was followed by an increase in lipid peroxidation, and both the increase in DCF fluorescence and in lipid peroxidation were significantly blocked by pretreatment with EUK-134. STS treatment for 3-6 h increased cytochrome c release from mitochondria into the cytosol, an effect also blocked by pretreatment with EUK-134. These results indicate that intracellular oxidative stress and mitochondrial dysfunction are critically involved in STS-induced neurotoxicity. However, there are additional cellular responses to STS, which are insensitive to treatment with radical scavengers that also contribute to its neurotoxicity.
Animals↗