[Drug therapy and the most common drugs for childhood psychiatric disorders]. / Lasten psykiatristen häiriöiden lääkehoito ja tavallisimmat lääkkeet.

Psychotropic drugs are more commonly prescribed for children, although scientific evidence about psychotrophic medication and long-term effects thereof in children is scarce. The drugs are often used off-label. ADHD drugs, antipsychotics and antidepressants and melatonin are the most commonly used drugs. ADHD medication possesses the most established status. Antipsychotic drugs are utilized for the treatment of psychoses, bipolar disorder, and conduct disorder symptoms in particular. Antidepressants are utilized for the treatment of childhood depression and anxiety disorders, melatonin for the treatment of children's sleep problems. Drug therapy should always be carried out as part of other psychiatric therapy.

A water-alcohol extract of Citrus grandis whole fruits has beneficial metabolic effects in the obese Zucker rats fed with high fat/high cholesterol diet.

Epidemiological studies suggest that citrus fruits and compounds such as flavonoids, limonoids and pectins have health promoting effects. Our aim was to study the effects of Citrus grandis (L.) Osbeck var. tomentosa hort. fruit extract on the energy metabolism. A whole fruit powder from dry water and alcohol extracts of C. grandis containing 19% naringin flavonoid was prepared. The effects of the citrus extract were followed in the obese Zucker rats fed with the HFD. The circulatory levels of GLP-1 decreased significantly by the extract in comparison to the HFD group, whereas the decreased ghrelin levels were reversed. The levels of PYY were decreased in all HFD groups. The leptin amounts decreased but not significantly whereas insulin and amylin were unchanged. The cholesterol and glucose levels were somewhat but not systematically improved in the HFD fed rats. Further studies are needed to identify the active compounds and their mechanisms.

Distinct effects of calorie restriction and resveratrol on diet-induced obesity and Fatty liver formation.

The potential of resveratrol to mimic beneficial effects of calorie restriction (CR) was investigated. We compared the effects of both CR (70% of ad libitum energy intake) or resveratrol (2 g/kg or 4 g/kg food) on high-fat diet-induced obesity and fatty liver formation in C57Bl/6J mice, and we examined their effects on calorimetry, metabolic performance, and the expressions of inflammatory genes and SIRT proteins. We found that resveratrol with 4 g/kg dose partially prevented hepatic steatosis and hepatocyte ballooning and induced skeletal muscle SIRT1 and SIRT4 expression while other examined parameter were unaffected by resveratrol. In contrast, CR provided superior protection against diet-induced obesity and fatty liver formation as compared to resveratrol, and the effects were associated with increased physical activity and ameliorated adipose tissue inflammation. CR increased expressions of SIRT3 in metabolically important tissues, suggesting that the beneficial effects of CR are mediated, at least in part, via SIRT3-dependent pathways.

Sample purification improves the analysis of nonviral in vivo gene transfection.

Nonviral gene delivery has gained a lot of interest as a promising approach for gene therapy. Despite intensive studies and much progress the outcome of nonviral vectors has remained significantly weaker than that of viral vectors. A weak transfection efficiency of nonviral gene transfection is still limiting their in vivo use. We have tested the possibility to improve the measurement of transfection efficiency by increasing the sensitivity of analysis with sample purification. The BPVlacZ and CMVlacZ plasmids were transfected by i.v. infusion of the PEI/DNA complexes in the rats. An adenovirus lacZ vector was used as a reference. The transfection efficiency was analysed from the lungs and brain. Tissue samples were minced and homogenized for preparation of crude homogenates and for further purification of crude homogenates with a DEAE anion exchange chromatography. The beta-galactosidase activity was measured using a luminometric assay. The obtained activity of beta-galactosidase was higher in the purified than nonpurified samples and the analysis of transfection efficiency as beta-galactosidase activity was improved more than 1000-fold by the purification of samples from perfused target tissues. An increased sensitivity of analysis by sample preparation may be a useful and inexpensive strategy to detect and estimate a low transfection efficiency or transgene expression often associated with a nonviral in vivo gene delivery.

Lack of robust protective effect of quercetin in two types of 6-hydroxydopamine-induced parkinsonian models in rats and dopaminergic cell cultures.

In the present study, we examined the ability of a flavonoid quercetin to prevent 6-hydroxydopamine (6-OHDA)-induced oxygen radical formation and cytotoxicity in vitro and neurotoxicity in vivo. Quercetin (10-100 microM) had an acute significant antioxidant effect against the 6-OHDA-induced (30 microM) oxygen radical formation in catecholaminergic SH-SY5Y neuroblastoma cells. Moreover, in these cells, quercetin at 10-50 microM had a significant protective effect against 6-OHDA though at 100 microM it was itself harmful to the cells. The possible effect of quercetin in preventing neurotoxicity in unilateral medial forebrain bundle (full nigral lesion) or striatal (partial lesion) 6-OHDA rat lesion models of Parkinson's disease was studied in three treatment schedules: a 7-day pre- or post-treatment or their combination. Rotational responses to apomorphine (0.1 mg/kg, subcutaneously) and d-amphetamine (2.5 mg/kg, intraperitoneally) were assessed at weeks 1 and 2 post-lesion. Quercetin had no consistent neuroprotective effect in either model at 50-200 mg/kg once a day or 100 mg/kg twice a day. Furthermore, no protection was observed in tyrosine hydroxylase positive nigral cell numbers, striatal fiber density or in striatal levels of dopamine. These in vitro and in vivo results cast doubt on the theory that quercetin exerts reliable neuroprotective effects against 6-OHDA-induced toxicity. In vitro, quercetin seems to be protective at low doses but damaging at high doses.

Neuroanatomical mapping of juvenile rat brain regions with prominent basal signal in [(35)S]GTPgammaS autoradiography.

[(35)S]GTPgammaS autoradiography represents a powerful functional approach to detect receptor-dependent G(i/o) protein activity in anatomically defined brain structures. Inherent to this technique, however, is the notable basal signal evident in several brain regions in the absence of receptor stimulation by exogenously added agonist. In the rat brain, much of this basal labelling derives from tonic activation of adenosine A(1) and lysophosphatidic acid LPA(1) receptors in the gray and white matter regions, respectively. Despite the elimination of the two receptor activities, prominent basal [(35)S]GTPgammaS labelling is still evident in discrete brain structures, possibly reflecting regional enrichment of G(i/o) and/or constitutive receptor activity or the presence of still unknown endogenous ligands activating their orphan receptors. Here, the anatomical distribution of the enhanced basal signal was systematically mapped in brain sections of 4-week-old male Wistar rats. Regions with prominent basal [(35)S]GTPgammaS labelling represented neuroanatomically distinct structures, in particular various thalamic and hypothalamic nuclei. For instance, the paraventricular thalamic nucleus, the bed nucleus of the stria terminalis and the subfornical organ were highly labelled, as were the periaqueductal gray and the nucleus of the solitary tract. Pre-treatment with N-ethylmaleimide (NEM), an alkylating agent preventing all known receptor-driven G protein activity in cryostat sections markedly decreased the basal binding in all examined regions. In preliminary screening, selective antagonists for various brain-enriched G(i/o)-coupled receptors failed to suppress the basal signal in any of the studied regions.

Increased leptin expression in the dorsal vagal complex suppresses adiposity without affecting energy intake and metabolic hormones.

OBJECTIVE: Increased leptin transgene expression locally in hypothalamic sites suppresses weight and energy intake, enhances thermogenic energy expenditure, and differentially modulates metabolic hormones for an extended period. We evaluated whether a similar localized expression of leptin transgene in the dorsal vagal complex (DVC) in the caudal brain stem that also displays the biologically relevant leptin receptor would reproduce these varied responses and thus demonstrate functional connectivity between the hypothalamus and DVC. RESEARCH METHODS AND PROCEDURES: Adult female rats were microinjected with a recombinant adeno-associated virus encoding either rat leptin or green fluorescent protein gene (control) in the DVC. Food intake and body weight were monitored weekly, and metabolic variables were analyzed at the end of 10 weeks. RESULTS AND DISCUSSION: Increased leptin transgene expression in the DVC suppressed the time-related increase in body weight accompanied by a transient decrease in food intake at week 1 post-injection and little effect on thermogenic energy expenditure. That suppression of weight was due to decreased adiposity is shown by the markedly suppressed white adipose tissue-derived hormones, leptin and adiponectin. Circulating concentrations of pancreatic insulin, gastric ghrelin, and glucose levels were unchanged. This segregation of the varied effects of leptin expression in hypothalamic sites vs. DVC endorses the view that among the various endocrine organs under sympathetic nervous system control, only those leptin-activated neural circuits in the hypothalamus that suppress weight and adiposity on a long-term basis transverse through DVC en route to white adipose tissue.

Suppression of fat deposition for the life time with gene therapy.

Unexpended energy is stored as fat in the body and increased rate of fat accretion culminates in obesity. Obesity increases the risks of many diseases several folds and shortens life span. A progressive deficit in the central feedback effects of leptin, a peptide produced by fat cells and hypothalamus, results in increased weight gain and obesity. This article summarizes our experimental findings to show that a stable increase in leptin availability in the hypothalamus alone with the aid of leptin gene therapy suppresses fat accretion and metabolic hormones for nearly the lifetime of laboratory rodents. Consequently, central leptin gene therapy is a novel modality that offers a viable therapeutic option to reduce fat depots and attendant metabolic sequelae implicated in obesity-related illnesses.

Perigestational suppression of weight gain with central leptin gene therapy results in lower weight F1 generation.

The efficacy of central leptin therapy on weight homeostasis through various phases of reproduction, pregnancy outcome and postnatal, prepubertal and pubertal growth of offspring was assessed. Enhanced leptin transgene expression after a single intracerebroventricular injection of recombinant adeno-associated virus vector encoding the leptin gene (rAAV-lep) decreased calorie intake and weight in adult nulliparous female rats. rAAV-lep treated rats conceived normally, displayed unremarkable pregnancy rate, parturition and delivered normal sized litters. Significantly lower weight was maintained through gestation, lactation, and post-lactation periods. The maintenance of a modest weight reduction was accompanied by voluntarily reduced calorie intake, increased thermogenic energy expenditure, decreased adiposity as reflected by drastically reduced leptin levels, and suppressed insulin and insulin-like growth factor 1 levels through lactation and post-lactation in rAAV-lep treated dams. The offspring at birth weighed significantly less than those of controls and this lower weight range was sustained during postnatal, prepubertal, pubertal and adult (3 months old) periods, contemporaneous with metabolic circulating hormones in the normal range. For the first time we show the persistent efficacy of central leptin gene therapy to suppress weight gain through all phases of reproduction, lactation and post-lactation in dams and reveal the potential imprinting link to producing lower weight in the F1 generation.

Agonists for neuropeptide Y receptors Y1 and Y5 stimulate different phases of feeding in guinea pigs.

1. The stimulatory effect of neuropeptide Y (NPY) on food intake is well established but the roles of the receptor subtypes Y(1) and Y(5) have been difficult to define. We have studied the effects of two novel Y(1)-preferring and two Y(5)-preferring agonists on feeding in guinea pigs. 2. The Y(1)-preferring receptor agonists [Arg(6),Pro(34)]pNPY and [Phe(7),Pro(34)]pNPY had high affinity for the Y(1) receptor (K(i) values 0.07 and 0.04 nM, respectively) and nanomolar affinity for the Y(5) receptor. Administration of either compound into the third brain ventricle increased food intake equally to NPY. 3. The Y(5) agonist [Ala(31),Aib(32)]pNPY displayed a moderate affinity for the Y(5) receptor (K(i) 7.42 nM) and a low affinity for Y(1) (K(i) 1.7 micro M). This compound had only a modest effect on feeding. 4. The other Y(5)-preferring peptide [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP had a higher affinity at the Y(5) receptor (K(i) 1.32 nM) and also at the Y(1) receptor (K(i) 85 nM). It potently stimulated feeding: the food consumption after administration of this peptide was two-fold compared to NPY. 5. Our results support the view that both the receptor subtypes Y(1) and Y(5) are involved in the stimulation of feeding. As the action profiles of the Y(1) and Y(5) agonists on feeding parameters were different, it seems that they influence different phases of eating.

Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea-pig.

1. Neuropeptide Y (NPY) is one of the most potent stimulants of food intake. It has been debated which receptor subtype mediates this response. Initially Y(1) was proposed, but later Y(5) was announced as a 'feeding' receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea-pig. When infused intracerebroventricularly, NPY dose-dependently increased food intake. 2. PYY, (Leu(31),Pro(34))NPY and NPY(2 - 36) stimulated feeding, whereas NPY(13 - 36) had no effect. These data suggest that either Y(1) or Y(5) receptors or both may mediate NPY induced food intake in guinea-pigs. 3. The Y(1) receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar affinity for the Y(1) receptor (K(i) values 1.1+/-0.2 nM and 5.6+/-0.9 nM, respectively), but low affinity for the Y(2) or Y(5) receptors. When guinea-pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited. 4. The Y(5) antagonist, CGP 71683A had high affinity for the Y(5) receptor (K(i) 1.3+/-0.05 nM) without having any significant activities at the Y(1) and Y(2) receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated. 5. The present study shows that NPY stimulates feeding in guinea-pigs through Y(1) and Y(5) receptors. As the guinea-pig is very distantly related to the rat and mouse, this suggests that both Y(1) and Y(5) receptors may mediate NPY-induced hyperphagia also in other orders of mammals.