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Domenico Praticò

Publications and source records attributed to Domenico Praticò.

At least 19 recordsLinked to original sources
PubMed2006

Elevated cerebrospinal fluid F2-isoprostane levels indicating oxidative stress in healthy siblings of multiple sclerosis patients.

Lipid peroxidation has been implicated in the pathogenesis of multiple sclerosis (MS). Isoprostanes, isomers of prostaglandins, are produced by free radical-mediated peroxidation of fatty acids in vivo and can be quantified in biological fluids. This study examines the levels of cerebrospinal fluid (CSF) F2-isoprostanes (F2-iPs) in MS patients (n=46), their healthy siblings (n=46) and unrelated controls (n=50). The median CSF F2-iP concentration (range) was significantly higher in siblings of MS patients, as compared to healthy controls (40.0 [7.1-68.7] and 29.1 [6.4-60.3] pg/mL, respectively, p=0.031). MS patients demonstrated F2-iP levels intermediate between siblings and controls. F2-iP levels in MS patients and siblings correlated significantly (R=0.360, p=0.012). These results suggest that siblings of MS patients have an increased oxidative stress response to environmental and/or genetic factors that may be involved in MS pathogenesis.

Adult↗
PubMed2006

Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice.

Suppression of thromboxane (Tx) A(2) biosynthesis retards atherogenesis. In this setting, the coincidental presence of nonconventional ligands for the TxA(2) receptor (TP), such as isoprostanes, could still induce a proatherogenic vascular phenotype. However, no data are available on the effect of combining suppression of TxA(2) formation with blockade of TP in atherogenesis. To this end, we tested the effect of a selective COX-1 inhibitor, SC560, a TP antagonist, BM-573, or a combination of both in low-density lipoprotein receptor-deficient mice on a high-fat diet. None of the treatments affected body weight or plasma cholesterol or triglycerides levels. Although SC-560 suppressed TxA(2) biosynthesis, BM-573 reduced its levels by 35%; in contrast, the 2 drugs, alone or in combination, did not significantly affect prostacyclin levels. At the end of the study, SC560 and BM-573 reduced atherogenesis; however, a further significant decrease was observed in mice receiving both drugs. This effect was associated with a further significant reduction of vascular inflammation, a decrease in macrophages, and an increase in the content of collagen and smooth muscle cells of the atherosclerotic lesions. These results show for the first time that the addition of a TP antagonist increases the antiatherogenic effect of COX-1-dependent TxA(2) suppression.

Animals↗
PubMed2006

The 5-lipoxygenase enzymatic pathway in the mouse brain: young versus old.

The 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism is an important source of inflammatory mediators, and is also present in the central nervous system. In this study, we assayed the expression levels and activity of 5-LO in different brain regions of young versus old C57Bl/6 mice. 5-LO mRNA was expressed in all the brain regions considered, i.e. cortex, hippocampus, and cerebellum. The highest expression level was observed in cerebellum compared with cortex and hippocampus, although it was not affected by aging. By contrast, 5-LO mRNA and protein levels were significantly increased in the hippocampus of old (25 months) versus young (3 months) mice. Finally, levels of the leukotriene B4, a metabolic product of 5-LO, were significantly increased in the hippocampus of old mice, but no difference was observed in cortex and cerebellum. These results demonstrate that the 5-LO enzymatic pathway is widely expressed in the mouse CNS, where significant changes are region-specific and age-dependent. This observation supports the hypothesis that 5-LO may be involved in diseases of the brain associated with aging.

Aging↗
PubMed2006

Altered vascular phenotype in autism: correlation with oxidative stress.

BACKGROUND: Autism is a neurologic disorder characterized by impaired communication and social interaction. Results of previous studies showed biochemical evidence for abnormal platelet reactivity and altered blood flow in children with autism. OBJECTIVE: To evaluate the vascular phenotype in children with autism. DESIGN AND MAIN OUTCOME MEASURES: Urinary levels of isoprostane F(2alpha)-VI, a marker of lipid peroxidation; 2,3-dinor-thromboxane B(2), which reflects platelet activation; and 6-keto-prostaglandin F(1alpha), a marker of endothelium activation, were measured by means of gas chromatography-mass spectrometry in subjects with autism and healthy control subjects. SETTING AND SUBJECTS: Children with a clinical diagnosis of autism attending the Pfeiffer Treatment Center. RESULTS: Compared with controls, children with autism had significantly higher urinary levels of isoprostane F(2alpha)-VI, 2,3-dinor-thromboxane B(2), and 6-keto-prostaglandin F(1alpha). Lipid peroxidation levels directly correlated with both vascular biomarker ratios. CONCLUSION: Besides enhanced oxidative stress, platelet and vascular endothelium activation also could contribute to the development and clinical manifestations of autism.

Autistic Disorder↗
PubMed2006

Coxibs and Alzheimer's disease: should they stay or should they go?

The neuropathology of Alzheimer's disease (AD) is characterized by deposits of amyloid beta (Abeta) peptides and neurofibrillary tangles, but also, among other aspects, by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. The classic target of NSAIDs is the prevention of cyclooxygenase (COX) activation. The main mechanism of action of COXs is the synthesis of prostaglandins, some of which have potent inflammatory activity. The discovery of two isoforms of this enzyme, COX-1 and COX-2, and that the latter is inducible by inflammatory cytokines supported the hypothesis that its inhibition would result in a potent antiinflammatory effect and led to the rapid development of selective COX-2 inhibitors, collectively called coxibs. Based on this rationale, some coxibs have been used in clinical trials for AD patients, but all the results obtained so far have been negative. Here, we review our knowledge in terms of COX-2 in the central nervous system, COX-2 and Abeta formation, and finally COX-2 and AD pathogenesis to understand the reasons why these drugs have failed and whether there is any scientific support to keep them as therapeutic tools for this chronic disease.

Alzheimer Disease↗
PubMed2005

Involvement of thromboxane receptor in the proatherogenic effect of isoprostane F2alpha-III: evidence from apolipoprotein E- and LDL receptor-deficient mice.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the arterial wall, where it associates with oxidative stress and formation of oxidized lipids. The lipid oxidation product isoprostane iPF2alpha-III, also known as 8-isoPGF2alpha and 15-F2t-IsoP, is elevated in patients with cardiovascular disease and present in atherosclerotic lesions. Several proatherogenic biological effects have been attributed to this isoprostane, suggesting that it could be an active factor in the pathogenesis of the disease. METHODS AND RESULTS: In this study we show that iPF2alpha-III directly promotes atherogenesis in 2 different mouse models (ie, apolipoprotein E [apoE]- and LDL receptor-deficient mice) by activating the thromboxane receptor (TP). This effect is mediated by potent proinflammatory vascular reactions but is independent of thromboxane A2 levels, changes in blood pressure, or lipid profile. Pharmacological antagonism of TP suppresses the vascular proatherogenic effects of iPF2alpha-III. Endothelial cells genetically lacking TP show reduced inflammatory responses when stimulated with this product of lipid oxidation but not other oxidized lipids. CONCLUSIONS: Our results demonstrate that in atherosclerosis iPF2alpha-III is not only a biomarker of oxidative stress but also an active mediator of its vascular phenotype. We conclude that in a clinical setting in which both thromboxane A2 and iPF2alpha-III are elevated, suppression of the first alone would not provide the most benefit for patients because the coincidental presence of the isoprostane will still have a proatherogenic effect.

Animals↗
PubMed2005

12/15-Lipoxygenase gene disruption and vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway.

Studies in mouse models of atherosclerosis using 12/15-lipoxygenase (12/15-LO) gene disruption and transgenic overexpression demonstrate a pro-oxidative, pro-atherogenic role for this pathway. Vitamin E has been shown to suppress lipid peroxidation and reduce early atherogenesis in several mouse models, although conflicting results from several clinical trials have been reported. ApoE(-/-) and apoE(-/-)/12/15-LO(-/-) mice were maintained on normal chow diet with or without Vitamin E supplement (2000 IU/kg). Plasma Vitamin E, urinary 8,12-iso-iPF(2alpha)-VI and aortic lesion quantitation were assessed. Plasma Vitamin E levels significantly increased upon Vitamin E diet supplementation. 12/15-LO gene disruption resulted in significantly reduced aortic lesions and decreased urinary 8,12-iso-iPF(2alpha)-VI levels in apoE(-/-) mice, similar to Vitamin E administration in the absence of 12/15-LO gene disruption. However, Vitamin E dietary supplementation did not afford additive or synergistic protection in apoE(-/-)/12/15-LO(-/-) mice. These results suggest that early 12/15-LO-mediated lipid peroxidation triggers ensuing non-enzymatic peroxidation that is susceptible to Vitamin E antioxidant action in a common pathway of atherogenesis.

Animals↗
PubMed2005

Stabilization of advanced atherosclerosis in low-density lipoprotein receptor-deficient mice by aspirin.

COX-1-dependent eicosanoid formation accelerates atherogenesis, and low-dose aspirin reduces early atherosclerosis. However, the role of aspirin in modulating progression of vascular atherosclerotic lesions once established is less investigated. We wished to determine the effect of low-dose aspirin on vascular inflammation, plaque composition, and progression of established atherosclerosis. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a high-fat diet for 3 months. At this time, one group of mice underwent baseline analysis. Two additional groups, while continuing the high-fat diet, were randomized to receive placebo or aspirin for additional 3 months. At the end of the study, LDLR(-/-) mice that had received aspirin had suppressed biosynthesis of thromboxane B2, the major products of COX-1 activity, reduced monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 levels compared with controls. Compared with baseline, the placebo group had significant progression of atherosclerosis. In contrast, aspirin treated mice showed a significant reduction in progression of atherosclerosis, and a significant decrease in foam cell content. These results suggest that in murine atherosclerosis, low-dose aspirin retards progression of established and advanced vascular atherosclerotic lesions by suppressing the formation of bioactive lipids and vascular inflammation.

Animals↗
PubMed2005

Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials.

Melatonin has been proposed as a treatment for Alzheimer's disease based on the demonstration of antioxidant and "anti-amyloid" effects in vitro and in vivo. Chronic melatonin therapy in old, amyloid plaque-bearing transgenic mice was studied. Tg2576 mice started melatonin treatment at 14 months of age. After 4 months of treatment, there were no differences between untreated and melatonin-treated mice in cortical levels of soluble, formic acid extracted, or histologically detectable beta amyloid (Abeta), nor in brain levels of lipid peroxidation product (total 8,12-isoprostane F(2alpha)-VI), despite marked elevations in plasma melatonin. We conclude that melatonin fails to produce anti-amyloid or antioxidant effects when initiated after the age of amyloid plaque deposition. These findings diminish the possibility that melatonin will be useful for the treatment of established Alzheimer's disease.

Aging↗
PubMed2005

Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment.

The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls. Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD. Compared with controls, there was a significant increase of both metabolites in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2005

Antioxidants and endothelium protection.

The endothelium is a complex organ system that controls the homeostasis of the vasculature by integrating signals between the vascular wall and the vessel lumen. Under physiological conditions, it maintains a normal vascular tone and blood fluidity by elaborating a variety of factors, such as nitric oxide, prostacyclin and endothelin. However, in pathological situations the endothelium can also modify its phenotype facilitating vasoconstriction, inflammation, and thrombotic events. These abnormal responses manifest in different clinical settings, such as hypercholesterolemia, hypertension, diabetes mellitus, and occur in the absence of any morphological change of the vessel. The etiology of these altered endothelial functions is multi-factorial, and the mechanisms underlying them are complex and not yet fully elucidated. Today, there is substantial evidence that many endothelial functions are sensitive to the presence of reactive oxygen species and subsequent oxidative stress. Here, I will review the increasing number of studies showing that exogenous antioxidants can modulate the endothelium-dependent vasodilation responses, the homeostatic endothelium-leukocyte interactions, the balance between pro- and anti-thrombotic properties, and the vascular apoptotic responses. Finally, the non-antioxidant activities of some antioxidant will also be described.

Animals↗
PubMed2005

Increase in peripheral oxidative stress during hypercholesterolemia is not reflected in the central nervous system: evidence from two mouse models.

In recent years oxidative stress has been widely implicated as a pathogenetic mechanism of several diseases, and a variety of indices and assays have been developed to assess this phenomenon in complex biological systems. Most of these biomarkers can be measured virtually in every biological fluid and tissue, providing us with the opportunity to assess their formation at local site of oxidative injury. However, despite their widespread use, it is still not completely clear how their peripheral formation correlates with the levels measured in the central nervous system. For this reason, we utilized two well-characterized animal models of chronic peripheral oxidative stress, low-density lipoprotein receptor (LDLR)-deficient and C57BL/6 mice on a high fat diet. After 8 weeks on the diet, we assessed isoprostane, marker of lipid peroxidation, and carbonyls, marker of protein oxidation, in several organs of these animals. Compared with animals on chow, mice on the high fat diet showed a significant increase in both biomarkers in plasma, heart, aorta and liver but not in brain tissues. This observation was confirmed by the selective accumulation of radioactivity in the peripheral organs but not in the brains of mice injected with tritiated isoprostane. Our findings indicate that in hypercholesterolemia the peripheral formation of oxidative products does not contribute to their levels found in the central nervous system.

Animals↗
PubMed2005

Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice.

The enzyme 12/15 lipoxygenase (12/15LO) has been implicated in the oxidative modification of lipoproteins and phospholipids in vivo. In addition, mice deficient in apolipoprotein E (ApoE-/-) are characterized by spontaneous hypercholesterolemia and a systemic increase in oxidative stress. Whereas the absence of 12/15LO reduces lipid peroxidation in the plasma and urine of ApoE-/- mice, the relative contribution of this enzyme to oxidative stress in the central nervous system remains unknown. Here, we provide the first in vivo evidence that 12/15LO modulates brain oxidative stress reactions using ApoE-/- mice crossbred with 12/15LO-deficient (12/15LO-/-) mice (12/15LO-/-/ApoE-/-). In chow-fed 12-month-old 12/15LO-/-/ApoE-/- mice, the amount of brain isoprostane iPF2alpha-VI, a marker of lipid peroxidation, and carbonyls, markers of protein oxidation, were significantly reduced when compared with 12/15LO-expressing controls (12/15LO+/+/ApoE-/-). These results were observed despite the fact that cholesterol, triglyceride, and lipoprotein levels were similar to those of ApoE-/- mice. These data indicate a functional role for 12/15LO in the modulation of oxidative reactions in the central nervous system, supporting the hypothesis that inhibition of this enzymatic pathway may be a novel therapeutic target in clinical settings involving increased brain oxidative stress.

Animals↗
PubMed2005

Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-beta (Abeta) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor kappaB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Abeta-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD.

Aged↗
PubMed2004

Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis.

BACKGROUND: An increasing body of evidence implicates both brain inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). The relevance of their interaction in vivo, however, is unknown. Previously, we have shown that separate pharmacological targeting of these two components results in amelioration of the amyloidogenic phenotype of a transgenic mouse model of AD-like brain amyloidosis (Tg2576). METHODS: In the present study, we investigated the therapeutic effects of a combination of an anti-inflammatory agent, indomethacin, and a natural anti-oxidant, vitamin E, in the Tg2576 mice. For this reason, animals were treated continuously from 8 (prior to Abeta deposition) through 15 (when Abeta deposits are abundant) months of age. RESULTS: At the end of the study, these therapeutic interventions suppressed brain inflammatory and oxidative stress responses in the mice. This effect was accompanied by significant reductions of soluble and insoluble Abeta1-40 and Abeta1-42 in neocortex and hippocampus, wherein the burden of Abeta deposits also was significantly decreased. CONCLUSIONS: The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis. We propose that a combination of anti-inflammatory and anti-oxidant drugs may be a useful strategy for treating AD.

Journal Article↗
PubMed2004

Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Mice lacking leukocyte type 12/15-lipoxygenase (12/15-LO) show reduced atherosclerosis in several models. 12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis. METHODS AND RESULTS: Bone marrow from 12/15-LO-/-/apoE-/- mice was transplanted into apoE-/- mice and vice versa. Deficiency of 12/15-LO in bone marrow cells protected apoE-/- mice fed a Western diet from atherosclerosis to the same extent as complete absence of 12/15-LO, although plasma 8,12-iso-iPF2alpha-IV, a measure of lipid peroxidation, remained elevated. 12/15-LO-/-/apoE-/- mice regained the severity of atherosclerotic lesion typical of apoE-/- mice after replacement of their bone marrow cells with bone marrow from apoE-/- mice. Peritoneal macrophages obtained from wild-type but not 12/15-LO-/- mice caused endothelial activation in the presence of native LDL. Absence of 12/15-LO decreased the ability of macrophages to form foam cells when exposed to LDL. CONCLUSIONS: We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation.

Animals↗