Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease.

Typically, cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX), enzymes that generate biologically active lipid molecules termed eicosanoids, are considered inflammatory. Hence, their putative role in Alzheimer's disease (AD) has been explored in the framework of possible inflammatory mechanisms of AD pathobiology. More recent data indicate that these enzymes and the biologically active lipid molecules they generate could influence the functioning of the central nervous system and the pathobiology of neurodegenerative disorders such as AD via mechanisms different from classical inflammation.

Benefits of neuropsychiatric phenomics: example of the 5-lipoxygenase-leptin-Alzheimer connection.

Phenomics is a systematic study of phenotypes on a genomewide scale that is expected to unravel, as of yet, unsuspected functional roles of the genome. It remains to be determined how to optimally approach and analyze the available phenomics databases to spearhead innovation in neuropsychiatry. By serendipitously connecting two unrelated phenotypes of increased blood levels of the adipokine leptin, a molecule that regulates appetite, in 5-lipoxygenase- (5-LOX) deficient mice and patients with a lower risk for Alzheimer's disease (AD), we postulated a leptin-mediated basis for beneficial effects of ALOX5 (a gene encoding 5-LOX) gene-deficiency in AD.

Depression with panic episodes and coronary vasospasm.

Variant (Prinzmetal's) angina is an uncommon cause of precordial pain caused by coronary vasospasm and characterized by transient ST elevation and negative markers of myocardial necrosis. This is the case of a female patient with a prior history of depression and panic attacks who presented with recurrent symptoms including chest pain. A cardiac event monitor positively documented coronary vasospasm associated with anxiety-provoking chest pain, whereas the coronary arteries were angiographically normal.

Interactions with GluR1 AMPA receptors could influence the therapeutic usefulness of minocycline in ALS.

Despite the beneficial effects of minocycline seen in animal models of ALS, initial clinical trials of minocycline in ALS patients failed to support its expected therapeutic usefulness. Here we discuss new results from recent preclinical studies of the molecular neuronal effects of minocycline pertinent for better understanding of the therapeutic potential of this antibiotic.

Minocycline increases phosphorylation and membrane insertion of neuronal GluR1 receptors.

The tetracycline antibiotic minocycline beneficially affects neuronal functioning and also inhibits the enzyme 5-lipoxygenase (5-LOX). We hypothesized that similar to 5-LOX inhibitors, minocycline may increase phosphorylation and membrane insertion of the glutamate receptor GluR1. The experiments were performed in primary cultures of mouse striatal neurons and in the prefrontal cortex and striatum of minocycline-treated mice.

Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice.

A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX, 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment.

Caffeic acid attenuates the decrease of cortical BDNF transcript IV mRNA induced by swim stress in wild-type but not in 5-lipoxygenase-deficient mice.

Caffeic acid is a natural compound that inhibits 5-lipoxygenase (5-LOX). In mice, caffeic acid produces antidepressant-like effects and attenuates the decrease in cortical brain-derived neurotrophic factor (BDNF) mRNA induced by forced swimming. We used wild-type and 5-LOX-deficient mice and found that swimming reduced the cortical content of BDNF exon IV but not exon I mRNA.

Possible role for interactions between 5-lipoxygenase (5-LOX) and AMPA GluR1 receptors in depression and in antidepressant therapy.

Emerging evidence suggests that 5-lipoxygenase (5-LOX) plays a role in central nervous system functioning. It has been shown that 5-LOX metabolic products can decrease the phosphorylation of the glutamate receptor subunit GluR1, and that this effect can be antagonized by 5-LOX inhibitors. Recent concepts about the pathobiological mechanisms of depression and the molecular mechanisms of antidepressant activity postulate a significant role for glutamatergic neurotransmission and the GluR1 receptor.

5-Lipoxygenase inhibitor MK-886 increases GluR1 phosphorylation in neuronal cultures in vitro and in the mouse cortex in vivo.

Modifications of AMPA glutamate receptor GluR1 phosphorylation are critical for neuroplastic mechanisms. Previous in vitro studies in brain slices employed MK-886, a functional inhibitor of the enzyme 5-lipoxygenase (5-LOX), and found increased GluR1 phosphorylation. Since slice preparations have accompanying postmortem phosphorylation changes, e.

The pattern of melatonin receptor expression in the brain may influence antidepressant treatment.

The pineal hormone melatonin produces most of its biological effects via G protein-coupled receptors MT1 and MT2. In mammals, these receptors are expressed in various tissues and organs including in the brain. Recent research points to a putative role of MT1/MT2 dimerization as a mechanism that could determine the receptor-mediated biological effects of melatonin.

Could treatment with arundic acid (ONO-2506) increase vulnerability for depression?

Arundic acid (ONO-2506) is believed to be neuroprotective because of its actions on glia cells; i.e., its inhibitory effects on the synthesis of a calcium-binding protein S100B.

Nomen est Omen: do antidepressants increase p11 or S100A10?

Occasionally, multiple names are given to the same gene/protein. When this happens, different names can be used in subsequent publications, for example in different research areas, sometimes with little or no awareness that the same entity known under a different name may have a major role in another field of science. Recent reports about the protein p11 presented findings that this protein, commonly known as S100A10, may play a crucial role in depression and antidepressant treatment mechanisms.

5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease.

We first hypothesized in 2000 that a polymorphism of the human gene encoding the enzyme 5-lipoxygenase (5-LOX) might be associated with Alzheimer's disease. Only a little progress has been made in directly testing our proposal. However, additional important new data lead us to hypothesize that genetic variability not only in the 5-LOX gene, i.

Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STAR*D.

Objective: To determine the frequency and demographic and clinical characteristics of depression with atypical features in a broadly representative sample of outpatients.

Method: Data derived from the first 1500 patients with DSM-IV major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression trial at 41 primary care and nonresearch psychiatric outpatient clinics. An algorithm based on the 30-item Inventory of Depressive Symptomatology-Clinician Rating (IDS-C30) determined presence or absence of depression with atypical features.

5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders.

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid.

The meaning of mammalian adult neurogenesis and the function of newly added neurons: the "small-world" network.

Adult neurogenesis has been observed in mammalian brain including human but a question remains: how do new neurons become functional in the adult brain? We propose that the random addition of only a few new neurons functions as a maintenance system for the brain's "small-world" networks. In popular parlance, the small-world network phenomenon is described by the concept of "six degrees of separation", which postulates that everyone in the world is connected to everyone else through a chain of at most six mutual acquaintances. Randomly added to an orderly network, new links enhance signal propagation speed and synchronizability.

Both aging and chronic fluoxetine increase S100B content in the mouse hippocampus.

S100B is a cytokine with neurotrophic and neurite-extending activity that has been implicated in the mechanism of action of anti-depressants and in the pathobiology of aging associated disorders such as Alzheimer's disease. The antidepressant fluoxetine increases hippocampal S100B content in young adult rats. In humans, brain levels of S100B mRNA and protein increase with advancing age.