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cox and mitochondrial f1f0-atpase activities in platelets and brain from patients with alzheimer disease
No full textCuprizone induced-demyelination in mice alters brain expression of genes involved in arachidonic acid metabolism .
Full text linkChronic feeding with the copper chelator cuprizone in mice
causes oligodendrocyte death and subsequent reversible
demyelination. Although the mechanism of demyelination is
unknown, activation of glia is integral to the process. Since
metabolism of arachidonic acid (AA) is involved in glial
activation, we hypothesized that cuprizone exposure would
alter expression of AA cascade genes. Mice were fed 0.2 %
cuprizone in the diet for 6 weeks and then returned to a normal
diet. Histochemistry with the myelin stains Black Gold and
Fluoromyelin demonstrated that frank demyelination and
influx of glial cells into the corpus collosum begins at week 3
and peaks at week 5. A decrease in myelin and oligodendrocyte
markers, accompanied by increased expression of markers of
microglia (CD11b) and astrocytes (glial acidic fibrillary
protein), was evident at week one. Gene expression of
cyclooxygenase-2 and 15-lipoxygenase (LOX) was also changed
at week one, suggesting that these genes are either involved
in or respond to early demyelination. Expression of 5-LOX was
not changed during early demyelination but it peaked during
week 5, when glial markers and frank demyelination also
reached their peak, suggesting that 5-LOX expression is a
consequence of the massive influx of inflammatory cells into
the area of demyelination. Our study is the first to demonstrate
that multiple enzymes involved in arachidonic acid metabolism are altered in the cuprizone model of demyelination and
remyelination. These data may help to develop new therapeutic
targets to treat human demyelinating diseases, such as multiple
sclerosis.
Supported by the Intramural Research Program of the NIH,
NIA
Selective downregulation of brain cytosolic phospholipase A2 activity and protein in rats treated chronically with carbamazepine
No full textCOX AND MITOCHONDRIAL F1F0-ATPASE (ATP SYNTHASE) ACTIVITIES IN PLATELETS AND BRAIN FROM PATIENTS WITH ALZHEIMER'S DISEASE
No full textEvidence suggests that mitochondrial dysfunction is prominent in Alzheimer's disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Chronic carbamazepine decreases the expression and the activity of cytosolic phospholipase A2 in rat brain
No full textChronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain
No full textBACKGROUND: Carbamazepine is a mood stabilizer used as monotherapy or as an adjunct to lithium in the treatment of acute mania or the prophylaxis of bipolar disorder. Based on evidence that lithium and valproate, other mood stabilizers, reduce brain arachidonic acid turnover and its conversion via cyclooxygenase to prostaglandin E(2) in rat brain, one possibility is that carbamazepine also targets the arachidonic acid cascade.
METHODS: To test this hypothesis, carbamazepine was administered to rats by intraperitoneal injection at a daily dose of 25 mg/kg for 30 days.
RESULTS: Carbamazepine decreased brain phospholipase A(2) activity and cytosolic phospholipase A(2) protein and messenger RNA levels without changing significantly protein and activity levels of calcium-independent phospholipase A(2) or secretory phospholipase A(2). Cyclooxygenase activity was decreased in carbamazepine-treated rats without any change in cyclooxygenase-1 or cyclooxygenase-2 protein levels. Brain prostaglandin E(2) concentration also was reduced. The protein levels of other arachidonic acid metabolizing enzymes, 5-lipoxygenase and cytochrome P450 epoxygenase, were not significantly changed nor was the brain concentration of the 5-lipoxygenase product leukotriene B(4).
CONCLUSIONS: Carbamazepine downregulates cytosolic phospholipase A(2)-mediated release of arachidonic acid and its subsequent conversion to prostaglandin E(2) by cyclooxygenase. These effects may contribute to its therapeutic actions in bipolar disorder
Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism
No full textRATIONALE: 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 A2, secretory PLA2, or Ca2+-independent iPLA2. 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 anti-seizure properties of the drug
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