[Heritability of bipolar affective disorder--family study].

BACKGROUND/AIM: Bipolar affective disorder is mental disorder with polygenic type of heredity. Heritability--relation between genetic and environmental variance is used to estimate the level of influence of genetic variance to phenotype variance. Study results show decreasing trend in the value of heritability of bipolar affective disorder, thus indicating that this disorder is a complex behavioral threshold characteristic. Therefore, the aim of this study was to estimate the contribution of genetic variance to phenotype variance of bipolar affective disorder, i.e. to estimate heritability of this disorder. METHODS: By the use of a questionnaire, 80 patients with over crossed threshold for bipolar affective disorder were asked for functional information about the members of their families belonging to the first degree of relation (fathers, mothers and full-sibs). By using "Applet for calculating heritability for threshold traits (disease)", and regression analysis, heritability of bipolar affective disorder as well as its statistical significance, were estimated (chi2 test). RESULTS: Heritability and relationship of genetic and environmental variance of bipolar affective disorder is 0.2 with statistically significant difference from zero (p < 0.001). CONCLUSION: The estimated contribution of genetic variance to phenotype variance of bipolar affective disorder is low being 20%, while the contribution of environmental variance is 80%. This result contributes to the understanding of bipolar affective disorder as a complex behavioral threshold trait.

Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein.

PURPOSE: The sedating effect of first generation H(1)-antihistamines has been associated with their ability to penetrate the blood-brain barrier (BBB) and lack of efflux by P-glycoprotein (Pgp). Second generation H(1)-antihistamines are relatively free of sedation and their limited brain penetration has been suggested to arise from Pgp-mediated efflux. The objective of this work was to evaluate the role of Pgp in brain penetration of first and second generation antihistamines. METHODS: Potential of antihistamines to be Pgp substrates was tested in vitro using Madin Darby canine kidney cells transfected with human Pgp. The role of Pgp in limiting brain penetration of antihistamines was tested by using the in situ brain perfusion technique. RESULTS: Majority of antihistamines were Pgp substrates in vitro. Following in situ brain perfusion, the first generation antihistamines substantially penetrated into rat brain independently from Pgp function. The second generation antihistamines terfenadine and loratadine, achieved substantial brain penetration, which was further enhanced by Pgp inhibition by cyclosporin A (CSA). In contrast, fexofenadine and cetirizine, penetrated brain poorly regardless of CSA administration. CONCLUSIONS: Antihistamines greatly differ in their ability to cross the BBB as well as in the role of Pgp in limiting their transport into the CNS in vivo.

Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction.

The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P(app)) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R(2) = 0.82) between P and P(app), whereas the uptake of more lipophilic compounds seems to be influenced by both P(app) and brain free fraction. A nonlinear relationship is observed between logP(oct) and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.

Chronic ethanol consumption increases plasma leptin levels and alters leptin receptors in the hypothalamus and the perigonadal fat of C57BL/6 mice.

BACKGROUND: Leptin, a protein secreted from adipocytes, and leptin receptors, expressed in the hypothalamus and fat tissue, regulate energy balance and adiposity. Leptin receptors exist as several forms that are delineated by the length of their cytoplasmic domains. Only the longest form is physiologically active through stimulation of the signal transducers and activators of transcription (STAT) second messenger system. Previous studies demonstrated that chronic ethanol consumption increases body adiposity and circulating leptin levels. This study examined the effect of chronic alcohol intake on the expression of leptin receptors and associated STAT second messengers in the hypothalamus and fat tissue. METHODS: Female C57BL/6 mice were given water or 20% w/v ethanol and Purina 5001 laboratory chow ad libitum for 2 or 5 weeks. Plasma leptin levels were determined by radioimmunoassay and body adiposity was evaluated by measuring the amount of perigonadal fat. Expression of leptin receptors as well as STAT molecules in whole-cell lysates of the hypothalamus and the perigonadal fat were assayed by Western blot analysis. RESULTS: Plasma leptin and perigonadal fat were increased after 5 weeks. The overall expression of leptin receptors was increased while the expression of the physiologically active long form of leptin receptor was decreased in the hypothalamus and the perigonadal fat of ethanol-consuming mice. Ethanol consumption also decreased hypothalamic expression of STAT3, a protein associated with leptin receptor activation in this region of the brain. In contrast, STAT1, a protein associated with leptin receptor activation in adipose tissue, was significantly elevated in the perigonadal fat of ethanol-consuming mice. CONCLUSIONS: Chronic ethanol consumption increases the circulating level of leptin, and this is accompanied by altered expression of leptin-sensing molecules in the hypothalamus and peripheral adipose tissue. These results suggest that chronic ethanol intake affects metabolism by altering the leptin system that regulates energy balance.

Leptin and cellular and innate immunity in abstinent alcoholics and controls.

BACKGROUND: Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity. METHODS: Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2)-stimulated NK activity, and concanavalin A-stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n = 27) and age- and gender-matched controls (n = 34). RESULTS: As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p = 0.055). In the total sample, leptin predicted NK activity (beta = 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n = 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone. CONCLUSIONS: These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.