No abstract

Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.

Our results indicate that ACCN1 gene is a potential candidate for response to lithium treatment that would serve as a genetic marker of lithium efficacy for BD patients.

Bipolar disorder (BD) and cluster headache (CH) are distinct conditions with important similarities such as a temporal pattern of disturbances, dysregulation of the sleep-wake cycle, and response to lithium treatment in a proportion of patients. Aiming to identify common transcription signatures in these two disorders, we carried out an exploratory microarray gene expression analysis in lymphoblasts from 8 CH and 10 BD I patients selected for positive response to lithium and 10 healthy controls (CO). Gene expression levels of BD and CH were compared with CO to create two lists of differentially expressed genes. We then matched the two lists and focus on genes showing statistically significant difference and same change direction in both disorders. RNA binding motif protein 3 (RBM3) was the most significantly altered gene in the list (3.17 × 10(-13) in BD, 9.44 × 10(-14) in CH). Pathway analysis identified protein processing in endoplasmic reticulum as the most significantly enriched. For validation with quantitative reverse transcription PCR (qRT-PCR) using the same samples, we selected seven genes. Among these, we were able to validate the RBM3, nuclear receptor subfamily 1, group D, member 1 (NR1D1), and tryptophan hydroxylase 1 (TPH1). These genes encode for elements involved in circadian rhythm regulation (RBM3 and NR1D1) and in serotonin synthesis (TPH1), processes previously involved in both disorders, and in the mechanism of action of lithium.

To assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample. Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine. The TNF-alpha and TNF-ss genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis. We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls. Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the two groups. These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.

A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.

No abstract

Several lines of evidence point to a role for dopamine in mood disorders and, in particular, in bipolar disorders. In line with a considerable amount of evidence, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorders. Several studies did not find any association between bipolar 1 patients and DRD1. In this study, we investigate a possible association between BP disorder and -48A/G polymorphism of the DRD1. We genotyped 107 bipolar 1 patients and 129 healthy control subjects of exclusively Sardinian descent. A statistically significant difference in genotype (chi2 = 6.29, df = 2, P = 0.042) and allele (chi2 = 5.46, df=1, P = 0.019; OR = 1.53, 95% CI = 1.08-2.16) frequencies was found, suggesting an association between the DRD1 gene and bipolar I disorder (BP I) in the Sardinian population.