Francesca Bosetti - Academia.edu (original) (raw)

Papers by Francesca Bosetti

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to β-amyloid

Aging, Feb 3, 2009

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by β-amyloid. β-amyloid (Aβ1-42) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1-/-) and their respective wild-type (WT) mice. In COX-1-/- mice, Aβ1-42-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.

Research paper thumbnail of Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappaB pathway and downstream enzymes involved in prostaglandin biosynthesis

J Neurochem, 2006

We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downst... more We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E 2 (PGE 2 ), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A 2 enzymes (cPLA 2 and sPLA 2 ), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and ) 2) in wild type and COX-1 -/mice. We found that brain PGE 2 concentration was significantly increased, whereas thromboxane B2 (TXB 2 ) concentration was decreased in COX-1 -/mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-jB pathway, and also an increase in the upstream cPLA 2 and sPLA 2 enzymes. The mechanism of NF-jB activation in the COX-1 -/mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-jB, as well as the increased protein levels of phosphorylated IjBa and of phosphorylated IKKa/b. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE 2 production being metabolically coupled with COX-2 and TXB 2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca 2+ -dependent PLA 2 , and terminal mPGES-2, to overcome defects in brain AA cascade.

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to �-amyloid

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by beta-amyloid. beta-amyloid (Abeta(1-42)) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1(-/-)) and their respective wild-type (WT) mice. In COX-1(-/-) mice, Abeta(1-42)-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.

Research paper thumbnail of Ginkgo biloba Extracts EGb 761 and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells

Neurochemical Research, Apr 1, 2002

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of it... more In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a approximately 2-fold significant increase in NDI mRNA level, after 48 and 72 h exposure to 100 microg/ml EGb 761 and to 10 microg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

Research paper thumbnail of The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline

Cellular and Molecular Neurobiology, 2016

The World Health Organization reports that 47.5 million people are affected by dementia worldwide... more The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer's disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer's pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer's are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.

Research paper thumbnail of Cyclooxygenase‐1 and ‐2 enzymes differentially regulate the brain upstream NF‐κB pathway and downstream enzymes involved in prostaglandin biosynthesis

Journal of Neurochemistry, Aug 1, 2006

We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downst... more We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E 2 (PGE 2 ), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A 2 enzymes (cPLA 2 and sPLA 2 ), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and ) 2) in wild type and COX-1 -/mice. We found that brain PGE 2 concentration was significantly increased, whereas thromboxane B2 (TXB 2 ) concentration was decreased in COX-1 -/mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-jB pathway, and also an increase in the upstream cPLA 2 and sPLA 2 enzymes. The mechanism of NF-jB activation in the COX-1 -/mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-jB, as well as the increased protein levels of phosphorylated IjBa and of phosphorylated IKKa/b. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE 2 production being metabolically coupled with COX-2 and TXB 2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca 2+ -dependent PLA 2 , and terminal mPGES-2, to overcome defects in brain AA cascade.

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid

Aging, Jan 11, 2009

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletio...

Research paper thumbnail of Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain

The pharmacogenomics journal, 2010

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue dama... more Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(-/-), COX-2(-/-), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(-/-) and increased in COX-2(-/-) mice, compared with their respective WT controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 ...

Research paper thumbnail of Ginkgo biloba extracts EGb 761 and bilobalide increase NADH dehydrogenase mRNA level and mitochondrial respiratory control ratio in PC12 cells

Neurochemical research, 2002

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of it... more In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a approximately 2-fold significant increase in NDI mRNA level, after 48 and 72 h exposure to 100 microg/ml EGb 761 and to 10 microg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

Research paper thumbnail of The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research

Trends in Pharmacological Sciences, 2009

Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prosta... more Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.

Research paper thumbnail of Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury

The FASEB Journal, 2007

Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen spe... more Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study, the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1(-/-)) mice or wild-type (COX-1(+/+)) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty-four hours after lipopolysaccharide (LPS) injection, COX-1(-/-) mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared with COX-1(+/+) mice. COX-1(-/-) mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, inducible NOS, and NADPH oxidase. The transcriptional down-regulation of cytokines and other inflammatory markers in COX-1(-/-) mice was mediated by a reduced activation of NF-kappaB and signal transducer and activator of transcription 3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and thromboxane B(2), as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage.

Research paper thumbnail of Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism

Psychopharmacology, 2005

Rationale: When administered chronically to rats, drugs that are effective in bipolar disorder-li... more Rationale: When administered chronically to rats, drugs that are effective in bipolar disorder-lithium and the anticonvulsants, valproic acid and carbamazepine -have been shown to downregulate the expression of certain enzymes involved in brain arachidonic acid (AA) release and cyclooxygenase (COX)-mediated metabolism. Phase II clinical trials with the anticonvulsant topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] suggest that this drug may also be effective for bipolar disorder. Objectives: To see if topiramate has effects similar to those of the other three drugs, we administered topiramate to rats for 14 days at 20 mg/kg, p.o. twice daily. Results: Compared with p.o. vehicle, topiramate treatment did not significantly affect the brain activity or protein level of cytosolic phospholipase A 2 , secretory PLA 2 , or Ca 2+independent iPLA 2 . Additionally, brain protein levels of COX-1, COX-2, 5-lipoxygenase, and cytochrome P450 epoxygenase were unchanged. Conclusions: These results suggest that topiramate does not modify expression of the enzymes involved in brain AA metabolism that have been shown to be targeted by lithium, valproic acid, or carbamazepine. If topiramate proves effective in bipolar disorder, it may not act by modulating brain AA metabolism. In view of the proven anticonvulsant effect of topiramate, our results also suggest that the AA cascade is not involved in the antiseizure properties of the drug.

Research paper thumbnail of Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2

Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 2013

Inflammation is a physiological response to exogenous and endogenous stimuli and, together with d... more Inflammation is a physiological response to exogenous and endogenous stimuli and, together with demyelination and immune system activation, is one of the key features of multiple sclerosis (MS). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) and lipoxygenase (LO) enzymes leads to the production of proinflammatory eicosanoids, and stimulates cytokine production and activation of microglia and astrocytes, thereby contributing to MS pathology. Current therapies target the immune system but do not specifically target AA-related inflammatory pathway. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immunomodulatory therapies to treat flu-like adverse effects. Few clinical and mounting preclinical data in MS show that AA metabolism contributes to immune system activation, demyelination and motor disabilities, and administration of NSAIDs reduces these symptoms. The beneficial effect of NSAIDs seems to be a prerogative of COX-2 selective inhibitors and suggests that NSAIDs selective for COX-2 may be more effective than mixed COX-1/2 inhibitors.

Research paper thumbnail of The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice

The Pharmacogenomics Journal, 2009

Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used... more Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipopolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 µg) was administered into the lateral ventricle of mice and, 24 hours later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation.

Research paper thumbnail of Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Pediatric Nephrology, 2014

Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomeru... more Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown. This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC). The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-β1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/β1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP. Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.

Research paper thumbnail of Chronic lithium chloride administration to rats decreases brain protein level of epsilon (ϵ) subunit of eukaryotic initiation factor-2B

Neuroscience Letters, 2002

The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We u... more The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (e) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (e) to actin protein was significantly reduced (P , 0:01) in LiCl-fed rats, 0.86^0.06 (SE) compared to 1.2^0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B. q

Research paper thumbnail of Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Neuropsychopharmacology, 2005

Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, ... more Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A 2 (cPLA 2 ), without affecting secretory sPLA 2 or Ca 2 þ -independent iPLA 2 . We investigated whether transcription factors known to regulate cPLA 2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 a and AP-2 b but not of the AP-2 g subunits in the frontal cortex. Activating protein 1 (AP-1)binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA 2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC a and PKC e, as well as AA-dependent PKC activity. The protein levels of PKC a and PKC e were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA 2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC a and PKC e contributes to lowering the AP-2 activity.

Research paper thumbnail of Modulatory role of cyclooxygenase-2 in cerebrovascular coupling

NeuroImage, 2006

To investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling, hemodynamic ... more To investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling, hemodynamic and neuronal responses to forepaw stimulation were measured in a-chloralose-anesthetized rats (N = 18) before and after intravenous administration of Meloxicam (MEL), a preferential COX-2 inhibitor, and following a bolus of prostaglandin E 2 (PGE 2 ), a prominent vasodilatatory product of COX-2 catalyzed metabolism of arachidonic acid. The cerebral blood flow (CBF) and blood-oxygenation-level-dependent (BOLD) response was quantified using continuous arterial spin labeling magnetic resonance imaging. Neuronal activity was measured by recording somatosensory-evoked potentials (SEPs) via intracranial electrodes. Both MEL and PGE 2 had a significant effect on the activation-elicited CBF ( P < 10 À6 ) and BOLD ( P < 10 À6 ) responses, without affecting the baseline perfusion. Meloxicam decreased brain COX enzymatic activity by 57 T 14% and decreased the stimulation-induced CBF response to 32 T 2% and BOLD to 46 T 1% of their respective pre-drug amplitudes. In turn, PGE 2 bolus resulted in a partial recovery of functional hyperemia, with the CBF response recovering to 52 T 3% and the BOLD response to 56 T 2% of their values prior to MEL administration. There was no concomitant decrease in either amplitudes or latencies of SEP components. These findings suggest a modulatory role of COX-2 products in the cerebrovascular coupling and provide evidence for existence of a functional metabolic buffer. D

Research paper thumbnail of Topiramate does not Alter the Kinetics of Arachidonic or Docosahexaenoic Acid in Brain Phospholipids of the Unanesthetized Rat

Neurochemical Research, 2005

Interest in the potential therapeutic utility of topiramate for treating bipolar disorder was sti... more Interest in the potential therapeutic utility of topiramate for treating bipolar disorder was stimulated by published reports of investigator-initiated open label clinical studies. Because chronic lithium, carbamazepine and valproate decrease the turnover of arachidonic acid (AA) but not docosahexaenoic acid (DHA) in brain phospholipids of the awake rat, we tested if topiramate would produce similar results. Rats received either topiramate (20 mg/kg twice per day) or vehicle for 14 days and then while unanesthetized were infused intravenously with either [1-14 C] AA or [1-14 C] DHA for 5 min while blood was collected from the femoral artery at fixed times. Topiramate did not alter the incorporation rate of AA or DHA from their respective brain acyl-CoA pool into brain phospholipids, nor the turnover of AA and DHA in brain phospholipids. The results of our study indicate that topiramate does not possess a pharmacological property that three drugs with proven efficacy in treating bipolar disorder have in common.

Research paper thumbnail of Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E2 concentration in rat brain

Molecular Psychiatry, 2002

type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part... more type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part of the AA cascade that involves cPLA 2 and COX-2. This effect may contribute to lithium's therapeutic action in bipolar disorder.

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to β-amyloid

Aging, Feb 3, 2009

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by β-amyloid. β-amyloid (Aβ1-42) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1-/-) and their respective wild-type (WT) mice. In COX-1-/- mice, Aβ1-42-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.

Research paper thumbnail of Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappaB pathway and downstream enzymes involved in prostaglandin biosynthesis

J Neurochem, 2006

We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downst... more We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E 2 (PGE 2 ), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A 2 enzymes (cPLA 2 and sPLA 2 ), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and ) 2) in wild type and COX-1 -/mice. We found that brain PGE 2 concentration was significantly increased, whereas thromboxane B2 (TXB 2 ) concentration was decreased in COX-1 -/mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-jB pathway, and also an increase in the upstream cPLA 2 and sPLA 2 enzymes. The mechanism of NF-jB activation in the COX-1 -/mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-jB, as well as the increased protein levels of phosphorylated IjBa and of phosphorylated IKKa/b. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE 2 production being metabolically coupled with COX-2 and TXB 2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca 2+ -dependent PLA 2 , and terminal mPGES-2, to overcome defects in brain AA cascade.

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to �-amyloid

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by beta-amyloid. beta-amyloid (Abeta(1-42)) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1(-/-)) and their respective wild-type (WT) mice. In COX-1(-/-) mice, Abeta(1-42)-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.

Research paper thumbnail of Ginkgo biloba Extracts EGb 761 and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells

Neurochemical Research, Apr 1, 2002

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of it... more In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a approximately 2-fold significant increase in NDI mRNA level, after 48 and 72 h exposure to 100 microg/ml EGb 761 and to 10 microg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

Research paper thumbnail of The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline

Cellular and Molecular Neurobiology, 2016

The World Health Organization reports that 47.5 million people are affected by dementia worldwide... more The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer&amp;amp;#39;s disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer&amp;amp;#39;s pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer&amp;amp;#39;s are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.

Research paper thumbnail of Cyclooxygenase‐1 and ‐2 enzymes differentially regulate the brain upstream NF‐κB pathway and downstream enzymes involved in prostaglandin biosynthesis

Journal of Neurochemistry, Aug 1, 2006

We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downst... more We have recently reported that cyclooxygenase (COX)-2deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E 2 (PGE 2 ), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX-1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX-2 and phospholipase A 2 enzymes (cPLA 2 and sPLA 2 ), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES-1, and ) 2) in wild type and COX-1 -/mice. We found that brain PGE 2 concentration was significantly increased, whereas thromboxane B2 (TXB 2 ) concentration was decreased in COX-1 -/mice. There was a compensatory up-regulation of COX-2, accompanied by the activation of the NF-jB pathway, and also an increase in the upstream cPLA 2 and sPLA 2 enzymes. The mechanism of NF-jB activation in the COX-1 -/mice involved the up-regulation of protein expression of the p50 and p65 subunits of NF-jB, as well as the increased protein levels of phosphorylated IjBa and of phosphorylated IKKa/b. Overall, our data suggest that COX-1 and COX-2 play a distinct role in brain PG biosynthesis, with basal PGE 2 production being metabolically coupled with COX-2 and TXB 2 production being preferentially linked to COX-1. Additionally, COX-1 deficiency can affect the expression of reciprocal and coupled enzymes, COX-2, Ca 2+ -dependent PLA 2 , and terminal mPGES-2, to overcome defects in brain AA cascade.

Research paper thumbnail of Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid

Aging, Jan 11, 2009

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-infla... more Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletio...

Research paper thumbnail of Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain

The pharmacogenomics journal, 2010

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue dama... more Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(-/-), COX-2(-/-), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(-/-) and increased in COX-2(-/-) mice, compared with their respective WT controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 ...

Research paper thumbnail of Ginkgo biloba extracts EGb 761 and bilobalide increase NADH dehydrogenase mRNA level and mitochondrial respiratory control ratio in PC12 cells

Neurochemical research, 2002

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of it... more In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a approximately 2-fold significant increase in NDI mRNA level, after 48 and 72 h exposure to 100 microg/ml EGb 761 and to 10 microg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

Research paper thumbnail of The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research

Trends in Pharmacological Sciences, 2009

Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prosta... more Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.

Research paper thumbnail of Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury

The FASEB Journal, 2007

Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen spe... more Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study, the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1(-/-)) mice or wild-type (COX-1(+/+)) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty-four hours after lipopolysaccharide (LPS) injection, COX-1(-/-) mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared with COX-1(+/+) mice. COX-1(-/-) mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, inducible NOS, and NADPH oxidase. The transcriptional down-regulation of cytokines and other inflammatory markers in COX-1(-/-) mice was mediated by a reduced activation of NF-kappaB and signal transducer and activator of transcription 3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and thromboxane B(2), as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage.

Research paper thumbnail of Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism

Psychopharmacology, 2005

Rationale: When administered chronically to rats, drugs that are effective in bipolar disorder-li... more Rationale: When administered chronically to rats, drugs that are effective in bipolar disorder-lithium and the anticonvulsants, valproic acid and carbamazepine -have been shown to downregulate the expression of certain enzymes involved in brain arachidonic acid (AA) release and cyclooxygenase (COX)-mediated metabolism. Phase II clinical trials with the anticonvulsant topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] suggest that this drug may also be effective for bipolar disorder. Objectives: To see if topiramate has effects similar to those of the other three drugs, we administered topiramate to rats for 14 days at 20 mg/kg, p.o. twice daily. Results: Compared with p.o. vehicle, topiramate treatment did not significantly affect the brain activity or protein level of cytosolic phospholipase A 2 , secretory PLA 2 , or Ca 2+independent iPLA 2 . Additionally, brain protein levels of COX-1, COX-2, 5-lipoxygenase, and cytochrome P450 epoxygenase were unchanged. Conclusions: These results suggest that topiramate does not modify expression of the enzymes involved in brain AA metabolism that have been shown to be targeted by lithium, valproic acid, or carbamazepine. If topiramate proves effective in bipolar disorder, it may not act by modulating brain AA metabolism. In view of the proven anticonvulsant effect of topiramate, our results also suggest that the AA cascade is not involved in the antiseizure properties of the drug.

Research paper thumbnail of Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2

Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 2013

Inflammation is a physiological response to exogenous and endogenous stimuli and, together with d... more Inflammation is a physiological response to exogenous and endogenous stimuli and, together with demyelination and immune system activation, is one of the key features of multiple sclerosis (MS). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) and lipoxygenase (LO) enzymes leads to the production of proinflammatory eicosanoids, and stimulates cytokine production and activation of microglia and astrocytes, thereby contributing to MS pathology. Current therapies target the immune system but do not specifically target AA-related inflammatory pathway. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immunomodulatory therapies to treat flu-like adverse effects. Few clinical and mounting preclinical data in MS show that AA metabolism contributes to immune system activation, demyelination and motor disabilities, and administration of NSAIDs reduces these symptoms. The beneficial effect of NSAIDs seems to be a prerogative of COX-2 selective inhibitors and suggests that NSAIDs selective for COX-2 may be more effective than mixed COX-1/2 inhibitors.

Research paper thumbnail of The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice

The Pharmacogenomics Journal, 2009

Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used... more Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipopolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 µg) was administered into the lateral ventricle of mice and, 24 hours later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation.

Research paper thumbnail of Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Pediatric Nephrology, 2014

Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomeru... more Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown. This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC). The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-β1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/β1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP. Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.

Research paper thumbnail of Chronic lithium chloride administration to rats decreases brain protein level of epsilon (ϵ) subunit of eukaryotic initiation factor-2B

Neuroscience Letters, 2002

The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We u... more The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (e) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (e) to actin protein was significantly reduced (P , 0:01) in LiCl-fed rats, 0.86^0.06 (SE) compared to 1.2^0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B. q

Research paper thumbnail of Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

Neuropsychopharmacology, 2005

Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, ... more Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A 2 (cPLA 2 ), without affecting secretory sPLA 2 or Ca 2 þ -independent iPLA 2 . We investigated whether transcription factors known to regulate cPLA 2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 a and AP-2 b but not of the AP-2 g subunits in the frontal cortex. Activating protein 1 (AP-1)binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA 2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC a and PKC e, as well as AA-dependent PKC activity. The protein levels of PKC a and PKC e were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA 2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC a and PKC e contributes to lowering the AP-2 activity.

Research paper thumbnail of Modulatory role of cyclooxygenase-2 in cerebrovascular coupling

NeuroImage, 2006

To investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling, hemodynamic ... more To investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling, hemodynamic and neuronal responses to forepaw stimulation were measured in a-chloralose-anesthetized rats (N = 18) before and after intravenous administration of Meloxicam (MEL), a preferential COX-2 inhibitor, and following a bolus of prostaglandin E 2 (PGE 2 ), a prominent vasodilatatory product of COX-2 catalyzed metabolism of arachidonic acid. The cerebral blood flow (CBF) and blood-oxygenation-level-dependent (BOLD) response was quantified using continuous arterial spin labeling magnetic resonance imaging. Neuronal activity was measured by recording somatosensory-evoked potentials (SEPs) via intracranial electrodes. Both MEL and PGE 2 had a significant effect on the activation-elicited CBF ( P < 10 À6 ) and BOLD ( P < 10 À6 ) responses, without affecting the baseline perfusion. Meloxicam decreased brain COX enzymatic activity by 57 T 14% and decreased the stimulation-induced CBF response to 32 T 2% and BOLD to 46 T 1% of their respective pre-drug amplitudes. In turn, PGE 2 bolus resulted in a partial recovery of functional hyperemia, with the CBF response recovering to 52 T 3% and the BOLD response to 56 T 2% of their values prior to MEL administration. There was no concomitant decrease in either amplitudes or latencies of SEP components. These findings suggest a modulatory role of COX-2 products in the cerebrovascular coupling and provide evidence for existence of a functional metabolic buffer. D

Research paper thumbnail of Topiramate does not Alter the Kinetics of Arachidonic or Docosahexaenoic Acid in Brain Phospholipids of the Unanesthetized Rat

Neurochemical Research, 2005

Interest in the potential therapeutic utility of topiramate for treating bipolar disorder was sti... more Interest in the potential therapeutic utility of topiramate for treating bipolar disorder was stimulated by published reports of investigator-initiated open label clinical studies. Because chronic lithium, carbamazepine and valproate decrease the turnover of arachidonic acid (AA) but not docosahexaenoic acid (DHA) in brain phospholipids of the awake rat, we tested if topiramate would produce similar results. Rats received either topiramate (20 mg/kg twice per day) or vehicle for 14 days and then while unanesthetized were infused intravenously with either [1-14 C] AA or [1-14 C] DHA for 5 min while blood was collected from the femoral artery at fixed times. Topiramate did not alter the incorporation rate of AA or DHA from their respective brain acyl-CoA pool into brain phospholipids, nor the turnover of AA and DHA in brain phospholipids. The results of our study indicate that topiramate does not possess a pharmacological property that three drugs with proven efficacy in treating bipolar disorder have in common.

Research paper thumbnail of Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E2 concentration in rat brain

Molecular Psychiatry, 2002

type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part... more type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part of the AA cascade that involves cPLA 2 and COX-2. This effect may contribute to lithium's therapeutic action in bipolar disorder.