Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the presence of prostaglandin PGF(2?) has been demonstrated in the central nervous system in the mid sixties, it has taken a rather long time to pinpoint a role of certain metabolites of arachidonic acid in the regulation of neural activity. The modern family of bioactive compounds known as "prostanoids" or "eicosanoids" includes the classical end-products of the cyclooxygenase pathway (prostaglandins, prostacyclin and thromboxane), as well as the molecules formed after the activation of 5- and/or 15-lipoxygenases (leucotrienes and lipoxines), 12-lipoxygenase (hepoxilins) or of epoxygenase (epoxides). Although the brain levels of arachidonic acid-the precursor generating prostaglandins from the series 2-are very low, a plethora of stimuli appears to trigger its release from membrane phospholipids mainly by activation of phospholipase A(2) or subordinately phospholipase C; furthermore, its reesterification can also be subtly regulated by endogenous metabolic processes. Numerous prostanoids have now been detected in the nervous system, namely in neurons, astrocytes, cerebrospinal fluid and cerebral vascular endothelium. Efforts have been oriented at the elucidation of the roles of prostanoids in some physiological conditions (for example sleep regulation) or pathological situations (fever, migraine, epilepsy, schizophrenia). Moreover, several investigators have examined the localization of neuronal membrane receptors for prostanoids and searched for the mechanisms of signal transduction or the identity of second messengers. Those embody cyclic nucleotides (cAMP and cGMP) and calcium. There is also compelling evidence for a modulation by prostanoids of the release of noradrenaline, serotonin and vasoactive intestinal peptide (VIP) as well as of several hormones of the hypothalamic-hypophyseal tract. In addition, neurotransmitters can influence prostanoid synthesis; this has been demonstrated in particular for noradrenaline and more recently for acetylcholine. Prostanoids can also amplify neurotransmitter-mediated signals. Thus, ?(1)-adrenergic agonists, H(1)-histaminergic agonists as well as adenosine potentiate cAMP formation elicited by the VIP, through a concomitant generation of prostaglandins mediated by a direct coupling with phospholipase A(2). Baclofen (a GABA(B)-receptor agonist) exerts a similar potentiation mediated in part by the increased activity of 5-lipoxygenase. Furthermore, eicosanoids generated by 12-lipoxygenase are involved in the histamine- or FMRFamide-induced hyperpolarization (opening of K(+) channels) that has been demonstrated in identified sensory neurons of Aplysia. Finally, the stimulation of N- methyl - d - aspartate receptors (a subclass of glutamate receptors) leads to a release of arachidonic acid as well as of 11- and 12-hydroxyeicosatetraenoic acids in cultured striatal neurons. Arachidonic acid and a large number of its classical or recently discovered metabolites therefore display various effects in the central nervous system, both at the level of integrated processes and of the fine synaptic circuitry, where they can act as intracellular or extracellular local messengers triggering new cascades of short term or long term cellular events.
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PMID:Prostanoids and their role in cell-cell interactions in the central nervous system. 2050 6

Arachidonic acid (AA), an essential polyunsaturated fatty acid, is one of the major components of neural membranes, which show an altered phospholipid composition in schizophrenia. Arachidonate 12-lipoxygenase (ALOX12), an important enzyme, metabolizes AA to 12-HPETE, which affects catecholamine synthesis. However, research has yet to show the genetic association between ALOX12 and schizophrenia. Therefore, we investigated single nucleotide polymorphisms (SNP) of the ALOX12 gene in schizophrenia, recruiting patients with schizophrenia (n = 289) and normal controls (n = 306) from a Korean population. We selected three SNPs (rs1126667, rs434473, and rs1042357) of the ALOX12 gene and genotyped them by direct sequencing. We reviewed the schizophrenic patients' medical records and assessed them clinically using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Operational Criteria Checklist (OPCRIT). Then we statistically analyzed the genetic associations between the SNPs and schizophrenia, finding a genetic association between both rs1126667 and rs1042357 and schizophrenia, in the recessive model (p = 0.015 and 0.015, respectively). We also found an association between rs434473 and negative symptoms, defined through a factor analysis of the OPCRIT data (p = 0.040). Consequently, we suggest that SNPs of the ALOX12 gene might be associated with schizophrenia and negative symptoms in this Korean population. These weak positives require additional study.
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PMID:Association between polymorphisms of arachidonate 12-lipoxygenase (ALOX12) and schizophrenia in a Korean population. 2062 12

ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.
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PMID:ALOX12 in human toxoplasmosis. 2468 56