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Biomedical subjects

Shih-Jen Tsai

Publications and source records attributed to Shih-Jen Tsai.

At least 19 recordsLinked to original sources
PubMed2006

Glatiramer acetate could be a potential antidepressant through its neuroprotective and anti-inflammatory effects.

Antidepressants that act by increasing the activity of central serotonergic or noradrenergic systems are the main biological treatments for major depressive disorder (MDD). Although these agents are generally safe and effective, they are far from ideal due to their slow onset and a substantial proportion of MDD patients do not clinically improve, despite maximal dosing. Thus, the development of new antidepressants based on novel theories may help to develop faster and more effective antidepressant agents. Over the last decade, there has been an impressive accumulation of data about non-monoamine systems that might mediate the pathogenesis of, and therapeutic mechanisms in, MDD. For example, MDD has been associated with a decreased central brain-derived neurotrophic factor (BDNF) state and activating the BDNF-signaling pathway may play an important role in the mechanisms of antidepressant therapeutic action. Glatiramer acetate (GA) is a collection of synthetic polypeptides indicated as therapy for relapsing-remitting multiple sclerosis. Both preclinical and clinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity or increase serum BDNF levels. Furthermore, MDD has been associated with an inflammatory process in the brain. Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of interleukin-10. Finally, recent animal studies have suggested that psychosocial stress reduces neurogenesis, whereas antidepressant treatment increases neurogenesis and blocks the effects of stress. Peripheral administration of GA was found to augment neurogenesis, including cell proliferation, migration, and differentiation in rodent brain. From the above evidence, GA could have antidepressant effects by increasing central BDNF, stimulating neurogenesis or through its anti-inflammatory effect. It is also suggested that immediate GA treatment after stress may prevent the development of stress-related psychiatric disorders such as MDD and post-traumatic stress disorder.

Animals↗
PubMed2006

Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression.

The family of hydroxymethylglutaryl coenzyme A reductase inhibitors, collectively known as statins, are used clinically to reduce plasma cholesterol levels. Recent reports indicate that statin therapy is associated with a reduced risk of depression, although the mechanism underlying this antidepressant effect is unknown. Evidence suggests that increasing central BDNF activity plays an important role in the treatment of major depression. In the nervous system, the proteolytic cleavage of pro-BDNF, a BDNF precursor, to BDNF through the tissue-type plasminogen activator (tPA)-plasmin pathway represents one mechanism that can regulate the action of BDNF. In vitro studies have demonstrated that statins can induce tPA and inhibit plasminogen activator inhibitor-1, the major inhibitor of tPA. It is therefore possible that statins could act through the tPA-plasminogen pathway to increase BDNF and achieve an antidepressant effect. It is suggested that statins could be of therapeutic potential for patients with major depression: especially those that have an abnormality in the tPA-plasminogen pathway or comorbidities relating to cardiovascular disease. Furthermore, BDNF dysfunction has also been implicated in several other neuropsychiatric diseases, such as Alzheimer's disease, attention-deficit hyperactivity disorder and Rett syndrome. The potential use of statins in these diseases may warrant further exploration.

Antidepressive Agents↗
PubMed2006

Semax, an analogue of adrenocorticotropin (4-10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndrome.

Psychostimulants, such as methylphenidate, are currently the most common used drug therapy for children with attention-deficit hyperactivity disorder (ADHD). However, a number of patients with ADHD either fail to respond to these drugs or experience side effects that preclude their use. The heptapeptide Semax is an analogue of the N-terminal fragment (4-10) of adrenocorticotropic hormone, but is completely devoid of any hormonal activity. It has been found to stimulate memory and attention in rodents and humans after intranasal application. Evidence from animal studies revealed that Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis. In addition, Semax could improve selective attention and modulate brain development. Since ADHD is likely to be a neurodevelopmental disorder with disturbance in dopamine and BDNF function, it is proposed in this paper that Semax may have good therapeutic potential in ADHD. Furthermore, increased BDNF activity is found to improve Rett syndrome, a severe neurodevelopmental disorder which is, in the majority of cases, caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). The potential therapeutic effect of Semax in Rett syndrome by increasing central BDNF activity may be of interest for further exploration in animal models of Rett syndrome.

Adrenocorticotropic Hormone↗
PubMed2006

Association of APOE genetic polymorphism with cognitive function and suicide history in geriatric depression.

Apolipoprotein E (APOE) has been associated with a variety of late-life neuropsychiatric disorders, including geriatric depression. This study determined whether APOE genotypes affect vulnerability to geriatric depression. We also tested the effect of the presence of the APOE epsilon4 (APOE4) allele on age of onset, suicide attempt history and cognitive function in geriatric depressed patients. We genotyped APOE in 111 elderly inpatients diagnosed as having major depression and 144 normal controls. The depressed patients were evaluated at baseline using the Hamilton Rating Scale for Depression and the Mini-Mental State Examination (MMSE) after admission. Age of onset of depression and suicide attempt history in the depressed group were evaluated by interview and medical record. We found no association between APOE genotypes and geriatric depression (p = 0.342) or APOE4 status and age of onset of depression (p = 0.281). However, compared with depressed subjects lacking the APOE epsilon4 allele, depressed subjects who were also APOE4 carriers showed significantly lower MMSE scores (p = 0.021) and an increased suicide attempt history (p = 0.012). The APOE genotype may contribute to cognitive performance and suicidality in geriatric depression, rather than being a specific risk factor for the disorder.

Aged↗
PubMed2006

Attention-deficit hyperactivity disorder may be associated with decreased central brain-derived neurotrophic factor activity: clinical and therapeutic implications.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.

Animals↗
PubMed2006

TrkB partial agonists: potential treatment strategy for major depression.

Brain-derived neurotrophic factor (BDNF) regulates a wide variety of processes in the nervous system, including neural development, function and survival, through activation of the tyrosine kinase B receptor (TrkB). Evidence suggests that low central BDNF activity, especially in the hippocampus, may play a pivotal role in the pathophysiology of major depression, and that agents that can increase BDNF-TrkB pathway signaling may be therapeutic for this disease. However, recent studies showed that increased BDNF activity in the mesolimbic region may cause a depressed state. A partial agonist is an agent that elicits a maximum response that is less than that of an agonist and acts as an antagonist in the presence of excess full agonist. Recently some small peptides have been synthesized that act as TrkB partial agonists. Since BDNF might be pro-depressive in the mesolimbic system and anti-depressive in the hippocampus region, it is proposed that these peptides or other partial TrkB agonists may provide a novel strategy for the treatment of major depression, which may be associated with BDNF-TrkB hypofunction in hippocampus and/or hyperfunction in the mesolimbic system. Furthermore, given the potential imbalance of BDNF in specific brain regions in major depression, selection of agents with maximal hippocampus/mesolimbic BDNF activation ratio could be of importance in the development of novel antidepressants.

Animals↗
PubMed2006

The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants.

Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration.

Animals↗
PubMed2006

Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: a speculative hypothesis.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impulsiveness and inattention that begins in childhood. The underlying pathogenesis of this disorder is still unknown, although pharmacological, genetic and neuroimaging studies suggest that dopamine transportation may be implicated in the pathogenesis of ADHD. Signal transducer and activator of transcription 6 (STAT6), similar to other members of the signal transducer and activator of transcription family of proteins, is an important molecule in the induction and regulation of the immune response. Animal studies have demonstrated that STAT6 is highly expressed in the CNS, especially in the developing brain. Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type. From these findings, and evidence from other studies, it can be proposed that STAT6 may be implicated in the pathogenesis of ADHD. Several proposals to test this hypothesis are suggested; attempts to prove the STAT6-ADHD hypothesis may provide a new direction that elucidates the pathogenesis of and a treatment for ADHD.

Animals↗
PubMed2006

Family-based association study between G72/G30 genetic polymorphism and schizophrenia.

Genetic variations in G72/G30 have been reported to be associated with schizophrenia and bipolar disorders in several case-control studies. This gene is located in a genomic region known to contain susceptibility genes for schizophrenia. As case-control studies carry an increased risk of confounding through population stratification, we investigate whether the rs947267 (A/C) polymorphism is associated with schizophrenia in a family-based association study. This polymorphism is located within the G72/G30 gene and has been previously associated with bipolar disorders. The sample consisted of a total of 216 Chinese families that included an affected offspring and parents. Transmission disequilibrium analysis revealed a significant association between the G72/G30 rs947267 polymorphism and schizophrenia (P=0.016), with the A allele more commonly transmitted to patients. Further analysis stratified by sex showed that the A allele was significantly more overtransmitted than nontransmitted in the trios of male probands (P=0.031), but not in the trios of female probands. Our family-based association study supports the suggestion that the G72/G30 gene may be implicated in susceptibility to schizophrenia and there may be an interaction between this gene and sex in the pathogenesis of schizophrenia.

Adult↗
PubMed2006

Increased central brain-derived neurotrophic factor activity could be a risk factor for substance abuse: Implications for treatment.

Drug addiction is a common psychiatric disorder with complex genetic, psychological and social contributing factors. While the midbrain dopaminergic system is crucial for acute reward and the initiation of addiction, evidence suggests that there are permanent neuronal changes at the cellular and molecular levels that underlie the addictive process. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family and the most abundant neurotrophins in the brain, plays a key role in the survival and differentiation of midbrain dopaminergic (DA) neurons. Evidence from animal and clinical studies suggests that increased central BDNF activity may be implicated in the pathogenesis of drug addiction. For example, BDNF infusion into rat midbrain enhances the rewarding effects of cocaine as measured by the condition place preference paradigm. In contrast, cocaine-conditioned place preference was reduced in heterozygous BDNF knockout mice. In humans, the 66Val allele of the BDNF-gene Val66Met polymorphism is associated with higher BDNF secretion in response to neuronal stimulation compared with the 66Met allele. We found higher BDNF 66Val homozygote frequency in people with drug addiction compared with normal controls. Furthermore, plasma BDNF concentrations of methamphetamine users were significantly higher than controls. The increased central BDNF activity hypothesis of drug addiction may provide new insights for improved therapeutic strategies for the prevention and treatment of drug addiction. Several strategies to decrease central BDNF activity that have potential use in the treatment of drug addiction are proposed.

Brain↗
PubMed2006

Cysteamine-related agents could be potential antidepressants through increasing central BDNF levels.

Major depressive disorder (MDD) is a common mental disease, but with an unknown etiology. Antidepressants are the main biological treatment for MDD. However, current antidepressive agents have a slow onset of effect and a substantial proportion of MDD patients do not clinically improve, despite maximal medication. Thus, the exploration for new antidepressants with novel strategies may help to develop faster and more effective antidepressant agents. Studies in the recent decades have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels and activating the BDNF-signaling pathway may play an important role in their therapeutic mechanism. Cysteamine is a natural product of cells and constitutes the terminal region of the CoA molecule. Recent work has found that cysteamine and a related agent, cystamine, have neuroprotective effects in Huntington's disease (HD) mice, through enhancing central BDNF levels. Furthermore, cystamine or cysteamine injection could increase serum BDNF levels in wild-type mice as well as HD mice. Since activation of the BDNF-dependent pathway plays an important role in the mechanism of antidepressant therapeutic action, cystamine or its derivatives could have potential antidepressant therapeutic effects. Among these agents, pantethine may be one of the most promising agents. It is a naturally occurring compound which can be administered orally with negligible side effects, and is metabolized to cysteamine. Further evaluation of the therapeutic and toxic effects of these cysteamine-related antidepressant agents in MDD animal models is needed before any clinical application.

Animals↗
PubMed2006

Lithium and antidepressants: potential agents for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females. It is caused by mutations in gene encoding methyl-CpG-binding protein 2 (MECP2) in the majority of cases. MECP2 was originally thought to be a global transcriptional repressor, but recent evidence from studies of animals suggests that it may have a role in regulating neuronal activity-dependent expression of specific genes such as Bdnf. A recent report demonstrated that deletion of Bdnf in Mecp2 mutants caused earlier onset/accelerated disease progression, whereas BDNF overexpression in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Lithium and antidepressants have been demonstrated to increase central BDNF levels or signaling in human as well as animal studies. Thus, it is proposed that these agents could have therapeutic potential for RTT subjects. Several points regarding the use of these agents in RTT are discussed. Further evaluation of the therapeutic effects of these drugs in RTT animal models is needed before clinical trials can begin.

Antidepressive Agents↗
PubMed2006

Association study of two serotonin 1A receptor gene polymorphisms and fluoxetine treatment response in Chinese major depressive disorders.

The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors. Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors (SSRIs). Recent studies, including our recent findings, have reported that a functional HTR1A C-1019G polymorphism in the promoter region, as well as a nonsynonymous polymorphism, Gly272Asp, may be associated with SSRI pharmacogenetics. In this study, we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine antidepressant effect in 222 Chinese major depressive patients. We also tested the linkage disequilibrium (LD) measurement between HTR1A Gly272Asp and C-1019G polymorphisms, and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and fluoxetine antidepressant response. The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response. The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response. This association is gender-specific and mostly arises from the effect of HTR1A C-1019G polymorphism: female patients with -1019C/C genotype showed a better response than -1019G carriers. These findings need to be confirmed in other ethnic populations.

Adult↗
PubMed2006

The brain-derived neurotrophic factor gene as a possible susceptibility candidate for Alzheimer's disease in a chinese population.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may represent a candidate gene conferring susceptibility to Alzheimer's disease (AD). This is because it has an important role in neuronal survival, and a decreased central level of BDNF is observed in AD. Some previous studies, though not all, have demonstrated that BDNF C270T polymorphisms might be associated with AD susceptibility. We examined the association of the C270T polymorphisms with sporadic AD in a Chinese cohort of 175 AD patients and 189 controls. We also tested BDNF Val66Met-C270T haplotypes for an interaction with the apolipoprotein E upsilon4 (APOE4) allele in AD. The results showed that the frequency of the 66Val allele was significantly lower in AD than controls (p = 0.031), but no significant difference in C270T allele or genotype frequencies was observed between AD cases and controls. Global case-control haplotype analysis showed that there is significant difference in haplotype distribution between both groups (p = 0.033). Stratification of the data according to the APOE status showed that in APOE4 allele bearers there was no significant difference in the frequency of haplotype 66Val-270C between AD and controls (p = 0.125), although there was a significant difference between the two groups in non-APOE4 carriers (p = 0.002). These results suggest that BDNF genetic variation may possibly affect the risk for AD, particularly in subjects who are negative for APOE4.

Alleles↗
PubMed2006

Association study of adenosine A2a receptor (1976C>T) genetic polymorphism and mood disorders and age of onset.

Evidence suggests that the adenosine A2a receptor (A2aAR) may be implicated in the pathogenesis of mood disorders. We tested the hypothesis that the A2aAR 1976C>T genetic variant confers susceptibility to mood disorders by comparing 192 mood disorder patients and 216 normal controls. The distribution of the A2aAR genotypes and alleles did not differ significantly comparing the two groups, suggesting that it is unlikely that the A2aAR 1976C>T polymorphism plays a major role in the development of mood disorders.

Age of Onset↗
PubMed2006

Polymorphisms in glycine transporter with schizophrenia.

Glycine acts as an obligatory co-agonist with glutamate on N-methyl-D-aspartate (NMDA) receptors. Brain glycine availability is determined by glycine transporters (GlyT1 or SLC6A9), which mediate glycine reuptake into nerve terminals. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, this study tests the hypothesis that GlyT1 genetic variants confer susceptibility to schizophrenia. Four GlyT1 polymorphisms were studied in a sample population of 249 people with schizophrenia and 210 normal controls. One polymorphism (rs16831541) was not informative in our Chinese population while the other three polymorphisms (rs1766967, rs2248632 and rs2248253) were analysed with chi-square tests and haplotype analysis. Significant linkage disequilibrium was obtained among the three polymorphisms. Neither single marker nor haplotype analysis revealed an association between variants at the GlyT1 locus and schizophrenia, suggesting that it is unlikely that the GlyT1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with other GIyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested.

Adult↗
PubMed2005

Association study of androgen receptor CAG repeat polymorphism and male violent criminal activity.

Androgens exert their effects primarily by stimulating androgen receptors (ARs) and androgen activity has been implicated in antisocial or violent criminal behaviour. Exon 1 of the AR gene contains a highly polymorphic glutamine (CAG) repeat sequence. We tested the hypothesis that shorter AR CAG repeat polymorphisms, which have a greater AR gene expression, are related to violent criminal activity in Chinese males using a sample of 146 extremely violent criminals and 108 normal controls. The results show no association between the AR repeat length and violent convicts, although we found that there are more violent-criminal cases than control cases with the shorter (<17) AR gene trinucleotide repeat polymorphisms (7.5% vs. 1.9%; P=0.047). No correlation was found between the AR CAG repeat length and the first criminal record age in the violent-criminal group. The mean AR repeat length is not significantly different between substance dependence cases and antisocial personality disorder diagnosis in the violent criminals and normal controls. Our findings suggest that the AR CAG repeat polymorphism does not play a major role in the susceptibility of male violent criminal activity.

Asian People↗