Publications by authors named "Anita Greco"

18 Publications

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NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

National Center for Research and Preclinical and Clinical Evaluation of Drugs, Istituto Superiore di Sanità, 00161 Rome, Italy.

An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.
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http://dx.doi.org/10.3390/ijms21197216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583077PMC
September 2020

Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.

J Neuroinflammation 2016 06 14;13(1):149. Epub 2016 Jun 14.

Section of Experimental Neurology, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161, Rome, Italy.

Background: Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. Oxidative stress and dysregulated immune responses are implicated in both organophosphate neurodevelopmental effects and ASD etiopathogenesis. BTBR T+tf/J mice, a well-studied model of idiopathic autism, show several behavioral and immunological alterations found in ASD children, and we recently showed that CPF gestational exposure strengthened some of these autistic-like traits. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile.

Methods: Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70).

Results: At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21.

Conclusions: These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long-lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.
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http://dx.doi.org/10.1186/s12974-016-0617-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908699PMC
June 2016

Nonenzymatic oxygenated metabolites of α-linolenic acid B1- and L1-phytoprostanes protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-γ activation.

Free Radic Biol Med 2014 Aug 2;73:41-50. Epub 2014 May 2.

Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, UM I, UM II, ENSCM, Montpellier, France.

Phytoprostanes (PhytoP's) are formed in higher plants from α-linolenic acid via a nonenzymatic free radical-catalyzed pathway and act as endogenous mediators capable of protecting cells from damage under various conditions related to oxidative stress. Humans are exposed to PhytoP's, as they are present in relevant quantities in vegetable food and pollen. The uptake of PhytoP's through the olfactory epithelium of the nasal mucosa, upon pollen grain inhalation, is of interest as the intranasal pathway is regarded as a direct route of communication between the environment and the brain. On this basis, we sought to investigate the potential activities of PhytoP's on immature cells of the central nervous system, which are particularly susceptible to oxidative stress. In neuroblastoma SH-SY5Y cells, used as a model for undifferentiated neurons, B1-PhytoP's, but not F1-PhytoP's, increased cell metabolic activity and protected them from oxidant damage caused by H2O2. Moreover, B1-PhytoP's induced a moderate depolarization of the mitochondrial inner membrane potential. These effects were prevented by the PPAR-γ antagonist GW9662. When SH-SY5Y cells were induced to differentiate toward a more mature phenotype, they became resistant to B1-PhytoP activities. B1-PhytoP's also influenced immature cells of an oligodendroglial line, as they increased the metabolic activity of oligodendrocyte progenitors and strongly accelerated their differentiation to immature oligodendrocytes, through mechanisms at least partially dependent on PPAR-γ activity. However, B1-PhytoP's did not protect oligodendrocyte progenitors against oxidant injury. Taken together, these data suggest that B1-PhytoP's, through novel mechanisms involving PPAR-γ, can specifically affect immature brain cells, such as neuroblasts and oligodendrocyte progenitors, thereby conferring neuroprotection against oxidant injury and promoting myelination.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.04.025DOI Listing
August 2014

Early-life sex-dependent vulnerability to oxidative stress: the natural twining model.

J Matern Fetal Neonatal Med 2013 Feb 19;26(3):259-62. Epub 2012 Oct 19.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Objectives: Twins represent a unique natural model for studying fetal adaptation to a suboptimal supply of nutrients in utero, the most likely cause of reduced fetal growth, which has been associated with cardiovascular risk. The proposed developmental origin of cardiovascular diseases may offer new venues for investigating the molecular basis of the well-known gender disparity in cardiovascular disease pathogenesis and progression. Early sex differences in oxidative stress, a mechanism of injury associated with both reduced fetal growth and cardiovascular diseases, have been so far poorly investigated. Thus, we aimed at evaluating oxidative stress in newborn twins by measuring oxidative stress biomarkers in cord blood.

Methods: Blood samples were collected from umbilical cord of 80 premature twins. The oxidative stress biomarker15-F(2t)-isoprostane and the total antioxidant capacity (tAOC) were measured in cord plasma.

Results: Males had higher levels of plasma 15-F(2t)-isoprostane than females. 15-F(2t)-isoprostane values remained greater in males than in females when considering like-sex or unlike sex pairs. No difference was found in tAOC levels.

Conclusions: Our data suggest that sex-based differences in oxidant injury vulnerability occurring early in life could represent a biological mechanism contributing to gender disparity later in life.
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http://dx.doi.org/10.3109/14767058.2012.733751DOI Listing
February 2013

Isoprostanes in clinically isolated syndrome and early multiple sclerosis as biomarkers of tissue damage and predictors of clinical course.

Mult Scler 2013 Apr 23;19(4):411-7. Epub 2012 Aug 23.

Department of Neurology and Psychiatry, Sapienza University, Rome, Italy.

Background: Isoprostanes (IsoP) are sensitive biomarkers of oxidative stress. Their cerebrospinal-fluid (CSF) level is increased in several neurological conditions, including multiple sclerosis (MS). In particular, in relapsing-remitting MS, IsoP have been proposed as an index of neurodegenerative processes. The mechanisms leading to neuroaxonal damage in MS are not fully understood but oxidative mechanisms play a substantial role. Although axonal loss is present in MS patients since their first clinical symptoms, IsoP levels at this early stage have not been evaluated yet.

Objectives: The objectives of this study were (a) to assess IsoP levels in CSF of patients with a first clinical attack suggestive of MS; (b) to correlate IsoP levels with magnetic resonance imaging (MRI) measures of brain damage and (c) to assess IsoP value in predicting disease clinical evolution.

Methods: Thirty-nine patients with a first clinical attack suggestive of MS underwent neurological examination, lumbar puncture with IsoP levels quantification and conventional/spectroscopic-MRI. Patients were followed up for 24 months.

Results: CSF IsoP levels were higher in patients than controls (mean ± standard deviation (SD) 123.4 ± 185.8 vs 4.5 ± 2.9 pg/ml; p<0.0001) and inversely correlated to normalized brain volume (p=0.04) and N-acetylaspartate/choline (NAA/Cho) (p=0.01). The risk of experiencing clinical relapses differed according to IsoP level: subjects with levels higher than 95 pg/ml (a cut-off value resulting from ROC analysis) were more likely to relapse than patients with levels equal or lower than 95 pg/ml (59% vs 27% respectively; p=0.03).

Conclusions: CSF IsoP might be useful biomarkers of tissue damage in MS with a predictive value of disease course.
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http://dx.doi.org/10.1177/1352458512457721DOI Listing
April 2013

Oxidative stress in twin neonates is influenced by birth weight and weight discordance.

Clin Biochem 2011 Jun 22;44(8-9):654-8. Epub 2011 Feb 22.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Objectives: To evaluate the extent of oxidative stress in neonates born from multiple gestation pregnancies who are at high risk of prematurity and growth abnormalities.

Design And Methods: Blood samples were collected from umbilical cord of 72 twins, born at gestational age of 28-38 weeks, and 20 consecutive control singletons. Oxidative stress parameters (15-F(2t)-isoprostane, a marker of lipid peroxidation, and total antioxidant capacity, tAOC), were measured in cord plasma.

Results: Levels of 15-F(2t)-isoprostane showed a moderate negative correlation with birth weight and were higher in small co-twins of discordant pairs; tAOC was positively correlated with birth weight but no significant difference was found between co-twins.

Conclusions: Oxidative stress levels in twins are mainly influenced by birth weight and weight discordance. We suggest that evaluation of cord blood 15-F(2t)-isoprostane might be of clinical value as maker of pre- and perinatal distress in twinning.
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http://dx.doi.org/10.1016/j.clinbiochem.2011.02.005DOI Listing
June 2011

Non-Steroidal Anti-Inflammatory Drugs and Brain Inflammation: Effects on Microglial Functions.

Pharmaceuticals (Basel) 2010 Jun 14;3(6):1949-1965. Epub 2010 Jun 14.

Experimental Neurology Section, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

The term NSAID refers to structurally diverse chemical compounds that share the ability to inhibit the activity of the prostaglandin (PG) biosynthetic enzymes, the cyclooxygenase (COX) isoforms 1 and 2. The suppression of PG synthesis at sites of inflammation has been regarded as primarily responsible for the beneficial properties of NSAIDs, but several COX-independent effects have been described in recent years. Epidemiological studies indicate that NSAIDs are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown. Microglial cells play a major role in brain inflammation and are often viewed as major contributors to the neurodegeneration. Therefore, microglia represent a likely target for NSAIDs within the brain. In the present review, we focused on the direct effects of NSAIDs and selective COX-2 inhibitors on microglial functions and discuss the potential efficacy in controlling brain inflammation.
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http://dx.doi.org/10.3390/ph3061949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033961PMC
June 2010

Plasma levels of 15-F(2t)-isoprostane in newborn infants are affected by mode of delivery.

Clin Biochem 2007 Dec 21;40(18):1420-2. Epub 2007 Sep 21.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy.

Objective: To investigate how the mode of delivery affects the level oxidative stress in newborns.

Design And Methods: 15-F(2t)-isoprostane, as index of oxidative stress, was measured in umbilical cord plasma samples from 37 infants born after vaginal delivery or caesarian section, using specific immuno-affinity extraction and immunoassay.

Results: 15-F(2t)-isoprostane levels were higher in infants born after vaginal delivery (n=18) compared to those delivered by elective caesarian section (n=19).

Conclusions: 15-F(2t)-isoprostane is a sensitive biomarker of fetal oxidative stress during labor.
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http://dx.doi.org/10.1016/j.clinbiochem.2007.09.004DOI Listing
December 2007

Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration.

J Neuropathol Exp Neurol 2007 May;66(5):363-71

From the Departments of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.

Inhibition of adenosine A2A receptors (A2ARs) is neuroprotective in several experimental models of striatal diseases. However, the mechanisms elicited by A2AR blockade are only partially known, and critical aspects about the potential beneficial effects of A2AR antagonism in models of neurodegeneration still await elucidation. In the present study, we analyzed the influence of the selective A2AR antagonist SCH 58261 in a rat model of striatal excitotoxicity obtained by unilateral intrastriatal injection of quinolinic acid (QA). We found that SCH 58261 differently affected the expression of cyclooxygenase-2 (COX-2) induced by QA in cortex and striatum. The antagonist enhanced COX-2 expression in cortical neurons and prevented it in striatal microglia-like cells. Similarly, SCH 58261 differently regulated astrogliosis and microglial activation in the 2 brain regions. In addition, the A2AR antagonist prevented the QA-induced increase in striatal brain-derived neurotrophic factor levels. Because COX-2 activity has been linked to excitotoxic processes and because brain-derived neurotrophic factor depletion has been observed in mouse models as well as in patients with Huntington disease, we suggest that the final outcome of A2AR blockade (namely neuroprotection vs neurodegeneration) is likely to depend on the balance among its various and region-specific effects.
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http://dx.doi.org/10.1097/nen.0b013e3180517477DOI Listing
May 2007

Peripheral reductive capacity is associated with cognitive performance and survival in Alzheimer's disease.

J Neuroinflammation 2006 Mar 3;3. Epub 2006 Mar 3.

Department of Cell Biology and Neurosciences, Section of Degenerative and Inflammatory Neurological Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.

Background: Oxidative stress is believed to be an early event and a key factor in Alzheimer's disease (AD) pathogenesis and progression. In spite of an intensive search for surrogate markers to monitor changes related to oxidative stress in the brain, there is as yet no consensus about which markers to use in clinical studies. The measurement of peripheral anti-oxidants is an alternative way of evaluating the involvement of oxidative stress in the course of the disease. Given the complexity of peripheral anti-oxidant defence, variations in the levels of individual anti-oxidant species may not fully reflect the overall capacity to fight oxidant conditions. We therefore chose to evaluate the total reductive capacity (herein defined as anti-oxidant capacity, AOC) in serum from control subjects and AD patients in order to study the association between peripheral anti-oxidant defence, cognitive impairment and patient survival.

Methods: We measured the levels of AOC in serum samples from 26 cognitively normal controls and 25 AD patients (12 post-mortem confirmed) who completed the Cambridge Cognitive Assessment. Cognitive decline was assessed in a subgroup of 19 patients who underwent a second cognitive assessment 2 years after the initial visit.

Results: Serum AOC levels were lower in AD patients than in controls and were correlated with their cognitive test scores, although AOC levels were unrelated to cognitive decline assessed two years later. On the other hand, AOC levels were predictive of the length of patients' survival, with higher levels giving longer survival.

Conclusion: This study indicates that peripheral anti-oxidant defences are depleted in AD patients. The results suggest that serum AOC is a good index of the general health status and prognosis of patients but does not necessarily reflect the extent to which vulnerable neuronal populations are protected from oxidant processes. Further studies are required to establish whether peripheral AOC measurements may be useful in identifying asymptomatic individuals or those with early symptoms at high risk of developing significant cognitive impairment or dementia.
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http://dx.doi.org/10.1186/1742-2094-3-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1420275PMC
March 2006

Isoprostanes as biomarkers and mediators of oxidative injury in infant and adult central nervous system diseases.

Curr Neurovasc Res 2004 Oct;1(4):341-54

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Isoprostanes are a family of prostaglandin-like compounds that are generated in vivo by free radical attack of esterified arachidonic acid and then released in free form in biological fluids. Since their discovery in 1990, they have been extensively used as biomarkers of lipid peroxidation and oxidative damage in an increasing number of human diseases. Few members of the isoprostane family are biologically active and could contribute to the functional consequences of oxidant injury. The present review summarises the current knowledge on formation and biological activities of these lipid peroxidation products, focusing on their role as valuable biomarkers to investigate the involvement of oxidative stress in the pathogenesis of infant and adult central nervous system diseases. In addition to isoprostanes, a new class of free radical-mediated peroxidation products, named neuroprostanes, is discussed. Neuroprostanes derive from peroxidation of docosahexaenoic acid, a polyunsatured fatty acid particularly abundant in neurons, and may represent a more selective index of brain oxidant injury than isoprostanes. In spite of some discrepancies in the results reported in different studies, isoprostane and neuroprostane levels in human biological fluids, as well as in experimental models of brain diseases, appear to be valuable indicators not only to monitor the occurrence and the causal role of oxidative stress in brain pathologies, but also for critical selection and evaluation of appropriate antioxidant therapies.
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http://dx.doi.org/10.2174/1567202043362036DOI Listing
October 2004

Cyclo-oxygenase-1 and -2 differently contribute to prostaglandin E2 synthesis and lipid peroxidation after in vivo activation of N-methyl-D-aspartate receptors in rat hippocampus.

J Neurochem 2005 Jun;93(6):1561-7

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

Using intracerebral microdialysis, we reported previously that acute in vivo activation of NMDA glutamate receptors triggers rapid and transient releases of prostaglandin E2 (PGE2) and F2-isoprostane 15-F(2t)-IsoP in the hippocampus of freely moving rats. The formation of the two metabolites--produced through cyclo-oxygenase (COX) enzymatic activity and free radical-mediated peroxidation of arachidonic acid (AA), respectively,--was prevented by the specific NMDA antagonist MK-801, and was largely dependent on COX-2 activity. Here, we demonstrate that besides COX-2, which is the prominent COX isoform in the brain and particularly in the hippocampus, the constitutive isoform, COX-1 also contributes to prostaglandin (PG) synthesis and oxidative damage following in vivo acute activation of hippocampal NMDA glutamate receptors. The relative contribution of the two isoforms is dynamically regulated, as the COX-2 selective inhibitor NS398 immediately prevented PGE2 and 15-F(2t)-IsoP formation during the application of NMDA, whereas the COX-1 selective inhibitor SC560 was effective only 1 h after agonist infusion. Our data suggest that, although COX-2 is the prominent isoform, COX-1 activity may significantly contribute to excitotoxicity, particularly when considering the amount of lipid peroxidation associated with its catalytic cycle. We suggest that both isoforms should be considered as possible therapeutic targets to prevent brain damage caused by excitotoxicity.
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http://dx.doi.org/10.1111/j.1471-4159.2005.03150.xDOI Listing
June 2005

Minocycline in phenotypic models of Huntington's disease.

Neurobiol Dis 2005 Feb;18(1):206-17

Laboratory of Neurophysiology, ULB-Erasme, Brussels, Belgium.

Minocycline has been shown to be neuroprotective in various models of neurodegenerative diseases. However, its potential in Huntington's disease (HD) models characterized by calpain-dependent degeneration and inflammation has not been investigated. Here, we have tested minocycline in phenotypic models of HD using 3-nitropropionic acid (3NP) intoxication and quinolinic acid (QA) injections. In the 3NP rat model, where the development of striatal lesions involves calpain, we found that minocycline was not protective, although it attenuated the development of inflammation induced after the onset of striatal degeneration. The lack of minocycline activity on calpain-dependent cell death was also confirmed in vitro using primary striatal cells. Conversely, we found that minocycline reduced lesions and inflammation induced by QA. In cultured cells, minocycline protected against mutated huntingtin and staurosporine, stimulations known to promote caspase-dependent cell death. Altogether, these data suggested that, in HD, minocycline may counteract the development of caspase-dependent neurodegeneration, inflammation, but not calpain-dependent neuronal death.
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http://dx.doi.org/10.1016/j.nbd.2004.09.017DOI Listing
February 2005

Cerebrospinal fluid isoprostanes are not related to inflammatory activity in relapsing-remitting multiple sclerosis.

J Neurol Sci 2004 Sep;224(1-2):23-7

Department of Cell Biology and Neuroscience, Instituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.

Oxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterised by inflammatory as well as degenerative phenomena. We previously found that cerebrospinal fluid (CSF) levels of isoprostane 8-epi-PGF2alpha, a marker of free radical damage and lipid peroxidation in vivo, were elevated in MS patients. Such levels were correlated with the degree of disability and reduced in subjects under steroid therapy. Here we investigated weather the CSF isoprostane levels correlated with disease inflammatory activity. To this aim, we enrolled 41 relapsing-remitting (RR) MS patients who underwent at the same time full neurological examination, NMR-imaging brain scan and diagnostic CSF test. No evidence of correlation was found between 8-epi-PGF2alpha levels and the presence of gadolinium (Gd)-enhancing NMR lesions or the time elapsed since the last relapse. We suggest that isoprostanes are not useful as surrogate inflammatory markers in MS. However, they may represent a sensitive index of degenerative phenomena, which can persist also in the absence of inflammatory activity.
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http://dx.doi.org/10.1016/j.jns.2004.05.016DOI Listing
September 2004

Increased brain levels of F2-isoprostane are an early marker of behavioral sequels in a rat model of global perinatal asphyxia.

Pediatr Res 2004 Jan 15;55(1):85-92. Epub 2003 Oct 15.

Section of Comparative Psychology, Laboratorio di Fisiopatologia, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Roma, Italy.

Perinatal asphyxia is a major cause of immediate and postponed brain damage in the newborn. It may be responsible for several delayed neurologic disorders and, in this respect, early markers of brain injury would be relevant for therapeutic intervention as well as for identification of infants at high risk for developmental disabilities. Biochemical measurements (brain F2-isoprostane levels) and behavioral tests (ultrasonic vocalization pattern on postnatal days (pnd) 5, 8, and 11, spontaneous motor behaviors on pnd 7 and 12, and homing response on pnd 10) were performed in a rat model of global perinatal asphyxia in the immature neonate. Caesarean section was performed in rats and the pups, still in uterus horns, were placed into a water bath at 37 degrees C for either 10 or 20 min. Caesarean delivered pups were used as controls. Pups experiencing severe (20 min), in contrast to those undergoing the 10 min, asphyctic insult presented with detectable abnormalities including early (two hours after the insult) increase in brain F2-isoprostane (a direct marker of oxidative injury) without detectable changes in PGE2, COX-2 and iNOS levels, and delayed physical (reduced weight gain on pnd 5 and thereafter) and behavioral disturbances (alterations in ultrasound emission on pnd 11 and spontaneous motricity levels mainly). These findings suggest that increased brain F2-isoprostane levels shortly after the asphyctic insult are predictive of delayed behavioral disturbances in the newborn rat. The present 20-min asphyxia model might serve for the assessment of preventive and curative strategies to treat neurologic/behavioral disturbances associated with perinatal asphyxia.
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http://dx.doi.org/10.1203/01.PDR.0000099774.17723.D4DOI Listing
January 2004

Differential lipid peroxidation, Mn superoxide, and bcl-2 expression contribute to the maturation-dependent vulnerability of oligodendrocytes to oxidative stress.

J Neuropathol Exp Neurol 2003 May;62(5):509-19

Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Rome, Italy.

To understand the basis of oligodendrocyte (OL) susceptibility to oxidative injury, purified rat OL cultures at different stages of maturation were exposed to nitric oxide (NO) donors with fast or slow kinetics of release and to tert-butyl-hydroperoxide, a membrane-permeant organic hydroperoxide. OL precursors (pre-OL) displayed the highest vulnerability to both oxygen or nitrogen reactive species, whereas mature OLs were uniquely vulnerable to long-lasting levels of NO. Cell death occurred by necrosis as well as apoptosis associated with increased caspase-3 activity and, only in the case of pre-OLs, with a decreased expression of the anti-apoptotic protein bcl-2. Pre-OLs were also more susceptible than mature OLs to lipid peroxidation, as measured by F2-isoprostane content in culture media. Finally, pre-OLs, but not mature OLs, expressed high levels of the mitochondrial scavenging enzyme Mn superoxide dismutase, suggesting that pre-OLs may efficiently convert anion superoxide into hydrogen peroxide and, paradoxically, be more predisposed than mature OLs to a toxic imbalance between hydrogen peroxide production and detoxification processes. These data suggest that susceptibility to lipid peroxidation, expression of the scavenging enzyme Mn superoxide dismutase and of the anti-apoptotic protein bcl-2, may contribute to the maturation-dependent vulnerability of OLs to oxidant injury.
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http://dx.doi.org/10.1093/jnen/62.5.509DOI Listing
May 2003

Paracetamol effectively reduces prostaglandin E2 synthesis in brain macrophages by inhibiting enzymatic activity of cyclooxygenase but not phospholipase and prostaglandin E synthase.

J Neurosci Res 2003 Mar;71(6):844-52

Laboratory of Pathophysiology, Istituto Superiore di Sanità, Rome, Italy.

Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown. Given their well-known adverse effects, which of the NSAIDs is the best for neurodegenerative disease management remains a matter of debate. Paracetamol is a widely used analgesic/antipyretic drug with low peripheral adverse effects, possibly related to its weak activity as inhibitor of peripheral cyclooxygenase (COX), the main target of NSAIDs. As microglia play an important role in CNS inflammation and pathogenesis of neurodegenerative diseases, we investigate the effect of paracetamol on rat microglial cultures. Although less potent than other NSAIDs, (indomethacin approximately NS-398 > flurbiprofen approximately piroxicam > paracetamol approximately acetylsalicylic acid), paracetamol completely inhibited the synthesis of prostaglandin E(2) (PGE(2)) in lipopolysaccharide-stimulated microglia, when used at concentrations comparable to therapeutic doses. The drug did not affect the expression of the enzymes involved in PGE(2) synthesis, i.e., COX-1, COX-2, and microsomal PGE synthase, or the release of the precursor arachidonic acid (AA). Paracetamol inhibited the conversion of exogenous AA, but not PGH(2), into PGE(2) indicating that the target of the drug is COX activity. Consistently, paracetamol inhibited with similar IC(50) the synthesis of PGF(2alpha) and thromboxane B(2), two other COX metabolites. Finally, none of the NSAIDs affected the productions of nitric oxide and tumor necrosis factor(alpha), two inflammatory mediators released by activated microglia. As paracetamol was reported to inhibit PG synthesis in peripheral macrophages with an IC(50) at least three orders of magnitude higher than in microglia, we suggest that this drug represents a good tool for treating brain inflammation without compromising peripheral PG synthesis.
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http://dx.doi.org/10.1002/jnr.10543DOI Listing
March 2003

Modulation of aspirin-insensitive eicosanoid biosynthesis by 6-methylprednisolone in unstable angina.

Circulation 2003 Jan;107(1):55-61

Department of Medicine and Aging, University of Chieti G. D'Annunzio School of Medicine, Chieti, Italy.

Background: The evidence that inflammation plays a pivotal role in the pathophysiology of acute coronary syndromes prompted us to investigate the effects of glucocorticoid treatment on leukotriene (LT) C4 and thromboxane (TX) A2 biosynthesis in unstable angina.

Methods And Results: Urinary LTE4 and 11-dehydro-TXB2 were significantly higher in 12 patients with unstable angina than in 12 patients with stable angina and 12 patients with nonischemic chest pain. Furthermore, we randomized the unstable angina patients to receive intravenous 6-methylprednisolone (6-MP; 1 mg/kg BID for 2 days) or matching placebo and collected 12 consecutive 6-hour urine samples before and during the infusions. LTE4 excretion showed a time-dependent decrease in the 6-MP group but did not decrease during placebo. Furthermore, during myocardial ischemia, LTE4 was significantly higher before 6-MP infusion than during steroid therapy. In contrast, 11-dehydro-TXB2 did not differ significantly during 6-MP versus placebo. Myocardial ischemia elicited by stress test in the stable angina patients was not accompanied by any change in LTE4 and 11-dehydro-TXB2, thus ruling out a role of ischemia per se in the induction of increased eicosanoid production.

Conclusions: Increased production of vasoactive LT and TX may occur in unstable angina despite conventional antithrombotic and antianginal treatment. Glucocorticoids can suppress LTC4 biosynthesis in the short term and may provide an interesting tool to explore the pathophysiological significance of inflammatory cell activation in this setting.
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http://dx.doi.org/10.1161/01.cir.0000043260.82447.62DOI Listing
January 2003