Efficacy of serotonin inhibition in mouse models of bone loss

In a proof‐of‐concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy‐induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy‐induced bone loss in aged mice. It also cures the low bone mass of Lrp5‐deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone‐loss disorders. © 2011 American Society for Bone and Mineral Research     

TPH2 in the ventral tegmental area of the male rat brain

This study surveyed the distribution of tryptophan hydroxylase 2 (TPH2) mRNA, protein, and enzymatic activity throughout the male Sprague-Dawley rat brain.TPH2 is the genetic isoform of TPH that catalyzes the rate-limiting step in serotonin biosynthesis within the central nervous system. Although cell bodies of serotonergic neurons are located mainly in the raphe, serotonin-containing axons innervate many regions of the brain. In the present study, we assessed the levels of mRNA, protein expression, and enzyme activity of TPH2 in the rat raphe, ventral tegmental area (VTA), substantia nigra, hippocampus, cerebellum, dorsal striatum, nucleus accumbens, amygdala, and medial prefrontal cortex to more fully understand the distribution of this enzyme throughout the central nervous system. The pineal gland was used as a control tissue that expresses TPH1 (the peripheral enzyme), but not TPH2. As expected, the raphe showed the highest brain TPH2 activity and protein expression. In the contrast to other reports, however, the VTA followed the raphe as the region with the second-highest amount of TPH2 activity, mRNA and protein expression. There were significantly lower TPH activities and levels of TPH2 protein in the other regions. In addition, TPH2 immunocytochemistry demonstrated the presence of TPH-positive cell bodies within the VTA. The results of this study indicate that TPH2 and serotonergic signaling may play an important role in the mesolimbic/mesocortical reward pathway.     

支链氨基酸对腹部术后疲劳综合征大鼠模型TPH mRNA表达的影响

目的探讨补充支链氨基酸(BCAA)对术后疲劳综合征(POFS)大鼠脑干色氨酸羟化酶(TPH) mRNA表达的影响。方法采用肝切除法建立大鼠腹部手术术后疲劳综合征模型。将72只雄性成年Sprague-Dawley(SD)大鼠按体重随机分为假手术组、试验对照组和BCAA治疗组。BCAA治疗结束后,断头取脑,冰上分离出脑干,半定量RT-PCR法检测TPH mBNA的表达。结果1 d和3 d试验对照组未明显改变大鼠脑干TPH mRNA的表达,与假手术组比较差异无统计学意义(P>0.05);而7 d和10 d后TPH mRNA表达量大幅度增加,与其他各组相比差异有统计学意义(P<0.01)。补充BCAA与未补充BCAA组比较,大鼠脑干TPH mRNA的表达水平未见明显变化。结论一定时间的疲劳可以引起大鼠脑干TPH mRNA的表达上调,但补充一定剂量的支链氨基酸并不能改变疲劳对大鼠脑干TPH mRNA的表达。     

支链氨基酸对大鼠TPH mRNA表达的影响

目的　探讨补充支链氨基酸 (branched -chainaminoacids,BCAA)对睡眠剥夺 (sleepdeprivation ,SD)大鼠脑干色氨酸羟化酶 (Tryptophanhydroxylase ,TPH)mRNA表达的影响。方法　采用小站台水环境 (flower- pot)睡眠剥夺模型对大鼠进行睡眠剥夺。将 5 6只雄性成年Sprague-Dawley大鼠按体重随机分为C(对照组 ,自由睡眠 )、2 4hSD(剥夺睡眠 2 4h)、2 4hSDB(睡眠剥夺 2 4h ,进食添加 3%BCAA的饲料 )、4 8hSD、4 8hSDB、72hSD和 72hSDB组 ,每组 8只。睡眠剥夺结束后 ,断头取脑 ,冰上分离出脑干 ,半定量RT -PCR法检测TPH mBNA的表达。结果　 2 4和 4 8h睡眠剥夺未明显改变大鼠脑干TPH mRNA的表达 ,与对照组比较差异无统计学意义 (P >0 . 0 5 ) ;而 72h睡眠剥夺后TPHmRNA表达量大幅度增加 ,与其它各组相比差异有统计学意义 (P <0 . 0 1)。补充BCAA与未补充BCAA组比较 ,大鼠脑干TPHmRNA的表达水平末见明显变化。结论　一定时间的睡眠剥夺可以引起大鼠脑干TPH mRNA的表达上调 ,但补充一定剂量的支链氨基酸并不能改变睡眠剥夺大鼠脑干TPHmRNA的表达。     

Hopelessness, a potential endophenotpye for suicidal behavior, is influenced by TPH2 gene variants

Objectives

Hopelessness is one of the strongest risk factors for suicidal behavior but relevant genetic studies are poorly available. Tryptophan hydroxylase (TPH) is widely considered to be a good candidate for genetic association studies on depression and suicide, however, investigations on these complex, multifactorial phenotypes have resulted in conflicting data. We hypothesized that hopelessness could be a mediating phenotype between TPH2 gene, depression and suicidal behavior.

Methods

Depressive phenotype and suicidal risk were investigated of 760 individuals from general population by Zung Self Rating Depression Scale (ZDS), Beck's Hopelessness Scale (BHS) and a detailed background questionnaire. All participants' DNA samples were genotyped for 7 tag SNPs in TPH2 gene. Generalized linear models were performed for single marker association studies and p-values were corrected by Bonferroni criteria. In haplotype analyses score tests were used and permutated p-values were computed.

Results

Four SNPs of TPH2 gene showed association with hopelessness but only rs6582078 had a significant effect on the BHS scores after Bonferroni's correction; GG individuals had significantly higher BHS scores, while GT and TT had intermediate and lower BHS scores respectively (p = 0.0047). Compared with other genotypes, homozygous GG individuals also had almost three times greater estimated suicidal risk, as did carriers of the AA genotype of rs6582078 (OR = 2.87; p = 0.005) and also of rs1352250 (OR = 2.86; p = 0.006). A risk and a protective haplotype of TPH2 gene were also identified in association with hopelessness. ZDS scores have not shown any association with TPH2 gene.

Conclusions

We found that hopelessness, with its allied increased suicidal risk was strongly associated with TPH2 gene variants in multiple tests. These findings suggest that TPH2 gene confers risk for suicidal behavior while hopelessness can be a potential endophenotype for suicidal vulnerability.     

Potential peripheral biological predictors of suicidal behavior in major depressive disorder

Previous studies have shown that dysfunctions in the serotonin system and hypothalamic-pituitary-adrenal axis (HPA) are associated strongly with suicidal behavior and suicide, especially among individuals with major depressive disorder. Suicidal behavior has been explained using both the stress-diathesis model and the state-trait interaction model. Specifically, diatheses, or trait-dependent risk factors, are associated with dysfunctions in the serotonin system; however, stress responses, or state-dependent factors, are associated with HPA hyperactivity. Decreases in cholesterol and brain-derived neurotrophic factor (BDNF) levels have been associated with impaired brain plasticity among individuals with suicidal behavior. Decreased serotonin functioning has been measured using cerebral spinal fluid (CSF) 5-HIAA, fenfluramine challenge studies, and platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated with the dexamethasone suppression test. Cholesterol and BDNF levels have been measured in blood serum or plasma.Nevertheless, challenges to finding promising and accessible neurobiological predictors of suicide and suicidal behavior remain. As suicide behavior is a complex phenomenon, a combined or multidimensional approach, including each of the aforementioned methods, may be required to predict suicide risk among individuals with major depressive disorder.     

Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls

Background

There is a decreased serotonergic function in impulsive aggression and borderline personality disorder (BPD), and genetic association studies suggest a role of serotonergic genes in impulsive aggression and BPD. Only one study has analyzed the association between the tryptophan-hydroxylase 2 (TPH2) gene and BPD. A TPH2 “risk” haplotype has been described that is associated with anxiety, depression and suicidal behavior.

Methods

We assessed the relationship between the previously identified “risk” haplotype at the TPH2 locus and BPD diagnosis, impulsive aggression, affective lability, and suicidal/parasuicidal behaviors, in a well-characterized clinical sample of 103 healthy controls (HCs) and 251 patients with personality disorders (109 with BPD). A logistic regression including measures of depression, affective lability and aggression scores in predicting “risk” haplotype was conducted.

Results

The prevalence of the “risk” haplotype was significantly higher in patients with BPD compared to HCs. Those with the “risk” haplotype have higher aggression and affect lability scores and more suicidal/parasuicidal behaviors than those without it. In the logistic regression model, affect lability was the only significant predictor and it correctly classified 83.1% of the subjects as “risk” or “non-risk” haplotype carriers.

Conclusions

We found an association between the previously described TPH2 “risk” haplotype and BPD diagnosis, affective lability, suicidal/parasuicidal behavior, and aggression scores.     

Association study of single nucleotide polymorphism in tryptophan hydroxylase 1 gene with adolescent idiopathic scoliosis: A meta-analysis

Background:Adolescent idiopathic scoliosis is a common spinal deformity among children and adolescents worldwide with its etiology uncertain. Over a decade, a single nucleotide polymorphism rs10488682 in tryptophan hydroxylase 1 (TPH1) gene has been investigated in several association studies. We perform this study to summarize the current evidence of TPH1 rs10488682 polymorphisms and adolescent idiopathic scoliosis (AIS).Methods:Six databases were systematically searched: PubMed, Embase, Cochrane Library, Web of Science, Chinese Biomedical Literature, and Wanfang database. Eligible case–control studies related to TPH1 and AIS were selected. Reference lists of them were reviewed for more available studies. Two authors independently screened and evaluated the literature and extracted data. The odds ratios and 95% confidence intervals were derived in association tests. Subgroup analysis was conducted by ethnicity. Sensitivity analysis was performed to examine the stability of the overall results.Results:A total of 1006 cases and 1557 controls in 3 independent studies were included for meta-analysis. Statistical significance was discovered in heterozygote model (AT vs AA: OR = 1.741, 95%Cl = 1.100–2.753, P = .018 < .05, I² = 0%), recessive model (AA vs AT + TT: OR = 0.640, 95%Cl = 0.414–0.990, P = .045 < .05, I² = 0%) and over-dominant model (AT vs AA + TT: OR = 1.366, 95%Cl = 1.115–1.673, P = .003 < .05, I² = 84.7%) in overall populations. Similar associations were also found in the Caucasian population. No significant associations were found in other genotypic comparisons and allelic comparisons.Conclusions:Statistically significant correlations were discovered between the TPH1 rs10488682 polymorphisms and AIS. Heterozygous AT genotype seems to be risky with an over-dominant effect. Ethnicity appears to modify the disease association.Registration:Not applicable.