Levodopa‐induced dyskinesias in tyrosine hydroxylase deficiency

The objective of this study was to characterize levodopa (l‐ dopa)–induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l‐ dopa. All 6 patients showed l ‐dopa‐induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l ‐Dopa–induced dyskinesias were precipitated by increases in the dose of l ‐dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l ‐dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l ‐Dopa–induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l‐ dopa–induced dyskinesias are frequent in a dopamine‐deficient state in the absence of nigrostriatal degeneration. Although l ‐dopa–induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinson's disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l‐ dopa–induced dyskinesias in the 2 conditions. © 2013 Movement Disorder Society     

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine‐related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5‐day withdrawal period. In addition, c‐Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c‐Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Synapse 67:553–567, 2013. © 2013 Wiley Periodicals, Inc.     

唐山市苯丙酮尿症患儿筛查及PAH基因突变情况分析

摘要：目的　分析唐山市苯丙酮尿症（PKU）患儿筛查结果及苯丙氨酸羟化酶（PAH）基因突变的情况。方法　选取2015年1月—2018年12月唐山市新生儿303 777例,通过茚三酮免疫荧光法检测新生儿足跟血中苯丙氨酸（PA）含量。再利用聚合酶链反应（PCR）和基因测序的方法对筛查出的PKU患儿PAH基因进行检测。结果　303 777例新生儿初步筛查共发现609例可疑阳性,召回其中411例（67.49%）进行复查,确诊42例（13.8/10万）。42例PKU患者的PAH基因测序显示,在84条染色体上共检测到62个（73.81%）12种突变,其中错义突变8种,无义突变2种,缺失突变1种,剪接突变1种。患者PAH基因突变分布在第2、3、6、7、9外显子上,其中第7外显子最多（35个,56.45%）,其次为第3外显子（14个,22.58%）。最常见的突变基因为Exon7-R243Q（18个,29.03%）和Exon3-R111X（10个,16.13%）、Exon7-R261Q（10个,16.13%）。筛查中发现1例典型PKU患儿,该患儿在PAH基因外显子区域同时发现2处杂合突变：c.208-210delTCT（缺失突变）和c.964G＞A（鸟嘌呤＞腺嘌呤）。结论　唐山市新生儿PKU发病率略高于全国,PAH基因突变以错义突变为主,第7外显子是唐山市患儿PAH基因高频突变位点。     

Dopaminergic projections from the VTA substantially contribute to the mesohabenular pathway in the rat

Recent evidence suggests that the lateral habenular complex (LHb) is a source of negative reward signals in midbrain dopaminergic neurons. LHb activity, in turn, is modulated by locally released dopamine, which is largely derived from the ventral tegmental area (VTA) via the mesohabenular pathway. Unfortunately, the presumed importance of this modulation has not been appreciated so far, as its intensity had been largely underestimated in previous reports. Consequently, the present study used contemporary techniques to reexamine the origin of dopaminergic fibers to the LHb. For this purpose, the retrograde tract-tracer gold-coupled wheatgerm agglutinin was injected into the LHb of fourteen rats. Four of these animals providing the most representative information were selected for detailed analysis. In total, 343 retrogradely labeled neurons were detected in the VTAs of these animals. By far most of them were found in the anterior VTA, accumulating in its ventral paramedian fields. About 47% (162) of retrogradely labeled cells displayed tyrosine hydroxylase immunoreactivity, suggesting that almost half of the mesohabenular neurons are dopaminergic. In addition, our data suggest that also incerto-hypothalamic and periventricular neurons contribute dopaminergic terminals to the LHb. The majority of LHb neurons, however, does not project to the origin of the mesohabenular pathway in the anterior VTA. Consequently, there might be no closed VTA-LHb-VTA loop. Instead, our data are in line with the idea that the anterior VTA via its projection to the medial part of the LHb may modulate the information flow from the limbic forebrain to monoaminergic midbrain nuclei.     

Distribution of serotonin 5-HT2C receptors in the ventral tegmental area

Serotonin 2C receptors (5-HT2CR) appear to exert tonic inhibitory influence over dopamine (DA) neurotransmission in the ventral tegmental area (VTA), the origin of the mesolimbic DA system, thought to be important in psychiatric disorders including addiction and schizophrenia. Current literature suggests that the inhibitory influence of 5-HT2CR on DA neurotransmission occurs via indirect activation of GABA inhibitory neurons, rather than via a direct action of 5-HT2CR on DA neurons. The present experiments were performed to establish the distribution of 5-HT2CR protein on DA and GABA neurons in the VTA of male rats via double-label immunofluorescence techniques. The 5-HT2CR protein was found to be co-localized with the GABA synthetic enzyme glutamic acid decarboxylase (GAD), confirming the presence of the 5-HT2CR on GABA neurons within the VTA. The 5-HT2CR immunoreactivity was also present in cells that contained immunoreactivity for tyrosine hydroxylase (TH), the DA synthetic enzyme, validating the localization of 5-HT2CR to DA neurons in the VTA. While the degree of 5-HT2CR+GAD co-localization was similar across the rostro-caudal levels of VTA subnuclei, 5-HT2CR+TH co-localization was highest in the middle relative to rostral and caudal levels of the VTA, particularly in the paranigral, parabrachial, and interfascicular subnuclei. The present results suggest that the inhibitory influence of the 5-HT2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT2CR control of the output of both GABA and DA neurons within this region.     

Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease

Introduction: In the last decade, concerns have been raised around the use of erythropoiesis-stimulating agents (ESAs) and intravenous iron in chronic kidney disease (CKD) patients, especially when given at high doses. Moreover, treatment with ESA is expensive.

Areas covered: We searched PubMed for original articles, reviews, and editorials having as a topic anemia, CKD, hypoxia inducible factor, hepcidin, iron, and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI). HIF-PHI are a new class of small molecules activating HIF-alfa isoforms (the main mediators of the effects of hypoxia on the body). This causes the secretion of endogenous erythropoietin and increased iron availability. Differing from ESA, HIF-PHI are administered orally. Preliminary data from phase-II clinical studies have shown their efficacy and safety in the short term.

Expert Opinion: HIF-PHI are a new promising class of drugs. The results of large, phase-III clinical studies are awaited to prove their efficacy and safety on cardiovascular events and cancer development in the long term. Their capability of penetrating the ESA market in the future will be influenced also by their selling price. The oral administration of HIF-PHI will be weighed to the ‘intra-lines’ infusion of ESA in hemodialysis or to the infrequent subcutaneous injections of long-acting ESA.     

Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3–4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs.

Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT_1A receptor), (2) the effect of dimerization of 5-HT₇ and 5-HT_1A receptors on the internalization and functioning of 5-HT_1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI.

Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.     

Bile synthesis in rat models of inflammatory bowel diseases

BACKGROUND: A broad spectrum of hepatobiliary disorders are found in patients with inflammatory bowel diseases. The aim of the present work was to study interactions between gut and liver in experimental rat models of colitis and small bowel inflammation. MATERIALS AND METHODS: Colitis was induced either by trinitrobenzene sulphonic acid or dextran sodium sulphate. Small-bowel inflammation was induced by indomethacin. Bile acid secretion, bile acid pool, and cholesterol 7-alpha hydroxylase were studied. Cholesterol 7-alpha hydroxylase protein expression was analysed in the microsomal liver fraction. As portal mediators released form the inflamed gut we measured lipopolysaccharide, tumour necrosis factor-alpha and interleukin-1beta in portal serum. The hepatic inflammatory response was evaluated by binding activity of nuclear factor-kappaB, activator protein-1 and alpha-2-macroglobulin. RESULTS: Increased bile acid secretion, total bile acid content in gut and liver (bile acid pool size), and hepatic cholesterol 7-alpha hydroxylase protein and mRNA levels were found in the two colitis models associated with only a minor hepatic acute phase and cytokine response. In contrast, during indomethacin-induced small-bowel inflammation bile acid secretion, pool size, and cholesterol 7-alpha hydroxylase decreased in parallel to a strong hepatic cytokine and acute phase response. CONCLUSIONS: Colitis without portal cytokine release and acute phase reaction shows an induction of bile acid secretion, pool size, and cholesterol 7-alpha hydroxylase. In contrast, intestinal inflammation after indomethacin treatment is associated with an acute phase response and a repression of bile acid synthesis.     

Association of HTR2A-1438G/A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease

Introduction

Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease (COPD). Serotonin levels have been associated with COPD and smoking has been as a significant modulator. Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence, thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin.