Changes in the Concentrations of Tetrahydrobiopterin, the Cofactor of Tyrosine Hydroxylase, in Blood under Physical Stress and in Depression

Nagatsu, T; Ohta, Tatsuro; Mizutani, M; Omura, Izumi

doi:10.1196/annals.1296.047

Cited by 25 publications

(13 citation statements)

References 15 publications

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“…Third, a significant reduction in cofactor availability, especially that of tetrahydrobiopterin (BH 4 ), in response to increased diaphragmatic activity would result in reduced NOS activity. Little is known about regulation of skeletal muscle BH 4 production; however, it is known that serum levels of BH 4 increase in response to whole body exercise (18). Furthermore, the expression of GTP cyclohydrolase I, the rate-limiting enzyme in BH 4 synthesis, is induced along with iNOS by proinflammatory cytokines such as TNF-␣ and IL-1␤ (41).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide production in the ventilatory muscles in response to acute resistive loading

Vassilakopoulos¹,

Govindaraju²,

Parthenis³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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.-The effect of muscle activation on muscle nitric oxide (NO) production remains controversial. Whereas NO release increases in in vitro activated muscles and in vivo limb muscles, diaphragmatic NO synthase (NOS) activity declines after 3 h of inspiratory resistive loading (IRL). We tested in this study the hypotheses that acute IRL decreases diaphragmatic NO derivatives levels and reduces protein expression of neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) NO synthases, as well as 3-nitrotyrosine formation. Anesthetized, tracheostomized, spontaneously breathing adult rats were subjected to IRL (50% of the maximum inspiratory pressure) for 1, 3, or 6 h. Quietly breathing rats served as controls. After 3 h of IRL, muscle eNOS and nNOS protein levels rose by 80 and 60% of control values, respectively. Whereas eNOS expression did not change any further, nNOS expression reached 550% of control values after 6 h of IRL. Strong iNOS protein expression was detected in the diaphragms after 6 h of IRL. Total NO derivatives levels in the diaphragm declined during IRL as a result of reduction in nitrate, nitrite, and nitrosothiols. Diaphragmatic protein tyrosine nitration decreased in response to IRL, and this reduction was mainly due to reduced tyrosine nitration of enolase and aldolase. We conclude that diaphragmatic NO derivatives levels decline in response to IRL and that the rise in diaphragmatic NOS protein expression may be a compensatory response designed to counterbalance the decline in NOS activity. nitrite; muscle contraction; diaphragm; nitric oxide synthases; nitrosothiols NITRIC OXIDE (NO) is synthesized inside skeletal muscle fibers by the endothelial (eNOS) and neuronal (nNOS) NO synthases (26,27,42). The eNOS isoform is localized in the mitochondria (27) and in sarcolemmal caveolae (at least in cardiac myocytes) associated with caveolin-3 (14). The nNOS isoform directly associates with the dystrophin complex and is localized in close proximity to the sarcolemma of mainly type II fibers (11). Although very low levels of the inducible NOS (iNOS) isoform may be expressed in skeletal muscles of normal mammals, the expression of this isoform in limb and ventilatory muscles rises significantly and in a transient fashion in response to proinflammatory conditions such as severe sepsis in humans (29) and bacterial endotoxemia in rodents (20). NO can promote many important processes inside skeletal muscle fibers such as Ca 2ϩ release from the sarcoplasmic reticulum, glucose metabolism, and blood flow (42). However, excessive NO production primarily by the iNOS isoform may have deleterious effects on muscle contractile performance (8) and sarcolemmal integrity (32).Resistive breathing is a clinically relevant form of acute exercise for the respiratory muscles, since it is encountered in various disease states such as upper airway obstruction, snoring, or acute asthma attacks, and exacerbations of chronic obstructive pulmonary disease. Despite the importance of NO in the regulation of muscle function, little...

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Section: Discussionmentioning

confidence: 99%

Nitric oxide production in the ventilatory muscles in response to acute resistive loading

Vassilakopoulos¹,

Govindaraju²,

Parthenis³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…and may serve as indirect biomarkers of DA synthetic capacity (Candito et al, 1994;Capuron et al, 2011;Hashimoto et al, 2004;Neurauter et al, 2008;Yokoyama et al, 2002). For example, a number of patient populations with increased inflammation, including patients with trauma, sepsis, cancer, and HIV, have been found to exhibit increased peripheral blood concentrations of phenylalanine (Hufner et al, 2015;Neurauter et al, 2008).…”

Section: Da Synthesis and Availabilitymentioning

confidence: 99%

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Felger

Treadway

2016

Neuropsychopharmacol

307

237

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Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

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“…Other studies have shown a relationship between BH 4 activity and antidepressants. [6][7][8][9][10] Several pharmacogenomic studies investigating mood-regulating drugs have shown altered expression in several components of the BH 4 pathway. [11][12][13] Together, this evidence supports a link between the BH 4 pathway and mood control, as well as in antidepressant function.…”

Section: Introductionmentioning

confidence: 99%

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

et al. 2010

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Tetrahydrobiopterin (BH 4 ) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH 4 is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis that GFRP gene (GCHFR) variants would modify response to antidepressants in subjects with major depression. Two single nucleotide polymorphisms (rs7164342 and rs7163862) in the GCHFR promoter were identified and occurred as two haplotypes (GA or TT). A multiple regression analysis revealed that homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the tricyclic antidepressant nortriptyline (P ¼ 0.037). Moreover, the TT haplotype showed a reduced transcription rate in luciferase reporter gene assays, which may impact on BH 4 -mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.

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Changes in the Concentrations of Tetrahydrobiopterin, the Cofactor of Tyrosine Hydroxylase, in Blood under Physical Stress and in Depression

Cited by 25 publications

References 15 publications

Nitric oxide production in the ventilatory muscles in response to acute resistive loading

Nitric oxide production in the ventilatory muscles in response to acute resistive loading

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants

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