Localization of MPP+ binding sites in the brain of various mammalian species

Summary The distribution and density of³H-MPP⁺ binding sites were studied by in vitro quantitative autoradiography in the brain of the mouse, rat and monkey. The highest levels of³H-MPP⁺ specific binding were observed in rat brain. The substantia nigra in rat and monkey, and the anterior caudate-putamen formation in mouse and monkey showed the lowest density of autoradiographic grains. The presence of a relatively high density of MPP⁺ sites in the hippocampus of all species studied could be of interest to explain some effects of MPTP administration on convulsions caused by chemoconvulsants.The finding of a 60–70% reduction of³H-MPP⁺ binding sites in the rat caudate-putamen, on the side of quinolinic acid infusion and no changes after 6-hydroxydopamine lesion of dopaminergic nigrostriatal neurons suggests the presence of these sites mainly on striatal cells.The results suggest that the distribution of MPP⁺ binding sites in brain would not seem to be related to MPTP toxicity.     

Novel integrative genomic tool for interrogating lithium response in bipolar disorder

We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.     

The PDLIM5 gene and lithium prophylaxis: An association and gene expression analysis in Sardinian patients with bipolar disorder

A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score相似文献   

Dopamine genes and migraine

Migraine is a common chronic disorder with an etiology still mostly unknown. Several neurotransmitters such as dopamine and serotonin are considered to be involved in the pathogenesis of the disease and the study of their systems is crucial in the understanding of migraine. Dopaminergic receptors are variously represented in human CNS and periphery. The hypothesis that a hypersensitivity of the dopaminergic system may have a role in migraine is based on clinical and genetic data. Genetic data are represented by association studies using dopaminergic genes as candidate genes which show that the D2 receptor gene appears to be involved in the pathogenesis of migraine.     

Interacting genes in lithium prophylaxis: Preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients

Lithium represents the first-choice and most effective drug in the treatment of bipolar disorder (BD). While its mechanism of action is far from being totally understood, a large amount of evidence pointed to a role of second messengers mediated pathways and elements of the circadian system in modulating its mood stabilizing effect. In the present paper, we tested the possible association and interaction effect of the nuclear receptor subfamily 1, group D, member 1 (NR1D1) gene and the Diacylglycerol kinase eta (DGKH) gene with the therapeutic response to lithium prophylaxis. Single nucleotide polymorphisms (SNPs) rs12941497 and rs939347 at NR1D1 gene and SNPs rs9315885, rs1012053 and rs1170191 at DGKH gene were genotyped in a sample of 199 Sardinian BD patients characterized for the response to lithium therapy. Genotype and allele frequency distributions did not differ significantly between groups of patients Full Responders and partial/not responders to lithium prophylaxis. Moreover, no significant differences were identified between groups of patients when divided considering the improvement in symptoms after lithium treatment. The interaction analysis did not show a significant effect on these outcomes. While negative, our findings do not exclude an involvement of DGKH and NR1D1 in lithium prophylaxis. Moreover, the lack of statistic interaction might not necessarily correspond to a lack of biologic interaction between the genes studied.     

A reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is formed in rat brain in vitro by type B monoamine oxidase

The formation of a reactive intermediate in the oxidative metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that can covalently bind to monoamine oxidase or other cellular macromolecules has been postulated by several authors. We report here direct in vitro evidence that MPTP is converted by monoamine oxidase, predominantly type B, to a reactive metabolite, which binds irreversibly to proteins in rat brain. Rat brain homogenates were incubated at 37 degrees C with 1-[methyl-3H]MPTP and the perchloric acid precipitates were washed exhaustively with organic solvents and counted for radioactivity. The amount of recovered radioactivity was enzyme-related: it was time- and temperature-dependent and did not occur with preboiled tissue. This metabolic activity required oxygen; it was concentrated in the crude mitochondrial fraction and varied in different brain regions. Pargyline and deprenyl prevented the radioactivity binding, whereas clorgyline was less potent, indicating that monoamine oxidase, predominantly of type B, is the enzyme responsible for the production of the reactive metabolite. Glutathione and, to a lesser extent, cysteine and dithiothreitol, but not ascorbic acid, inhibited the irreversible protein binding, suggesting that sulfhydryl groups may react with the metabolite possibly leading to SH-conjugates. 1-Methyl-4-phenyl-2,3-dihydropyridinium increased the irreversible protein binding, indicating that the reactive metabolite of MPTP may not be identified as the dihydropyridinium compound. This chemically reactive intermediate might play a role in MPTP neurotoxicity.