Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland

Catelas, Diogo; Serrão, Paula; Soares-da-Silva, Patrı́cio

doi:10.1080/10641963.2019.1583245

Cited by 12 publications

(11 citation statements)

References 35 publications

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“…In our study, nepicastat plasma concentration was in agreement with previous reports (Bonifácio et al, 2015;Loureiro et al, 2015), and is consistent with an unbound plasma drug concentration that is pharmacologically active (Braggio et al, 2010). The dosage of 30 mg/kg used leads to maximal adrenal gland DBH enzyme inhibition between 1 and 8 h post-administration (Bonifácio et al, 2015;Loureiro et al, 2015;Catelas et al, 2020). This high inhibition of DBH activity allows to effectively elicit pharmacological effects, namely a gradual decrease in catecholamine levels in the following 24 h (Bonifácio et al, 2015;Loureiro et al, 2015), and therefore nepicastat was administered once daily.…”

Section: Discussionsupporting

confidence: 92%

“…This high inhibition of DBH activity allows to effectively elicit pharmacological effects, namely a gradual decrease in catecholamine levels in the following 24 h (Bonifácio et al, 2015;Loureiro et al, 2015), and therefore nepicastat was administered once daily. This dosage was already used in several studies, namely in hypertension (Stanley et al, 1997;Sabbah et al, 2000;Manvich et al, 2013;Bonifácio et al, 2015;Devoto et al, 2015;Loureiro et al, 2015;Catelas et al, 2020). Since we performed nepicastat treatment daily, in the first protocol from days 0-7 and in the second protocol from days 0-12, this administration was chronic.…”

Section: Discussionmentioning

confidence: 99%

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Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

Martinho

Correia

Seixas

et al. 2021

Front. Mol. Neurosci.

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Post-traumatic stress disorder (PTSD) is a common anxiety mental disorder and can be manifested after exposure to a real or perceived life-threatening event. Increased noradrenaline and adrenaline in plasma and urine have been documented in PTSD. Dopamine-β-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and consequently, DBH inhibition reduces catecholamines. Our aim was to evaluate if nepicastat treatment decreases PTSD signs in an animal model. Wild-type (129x1/SvJ) female mice were submitted to PTSD induction protocol. DBH-inhibitor nepicastat (30 mg/kg) or vehicle (0.2% HPMC) were administered once daily since day 0 until day 7 or 12. The percentage of freezing was calculated on days 0, 1, 2, and 7, and behavioral tests were performed. Quantification of nepicastat in plasma and DBH activity in the adrenal gland was evaluated. Catecholamines were quantified by HPLC with electrochemical detection. mRNA expression of Npas4 and Bdnf in hippocampus was evaluated by qPCR.Mice in the PTSD-group and treated with nepicastat showed a decrease in freezing, and an increase in the time spent and entries in open arms in elevated plus maze test. In mice treated with nepicastat, adrenal gland DBH activity was decreased, and catecholamines were also decreased in plasma and tissues. On day 7, in mice treated with nepicastat, there was an increase of Npas4 and Bdnf mRNA expression in the hippocampus.In conclusion, DBH inhibitor nepicastat has an effect consistent with a decrease in the persistence of traumatic memories and anxiety-like behavior in this PTSD mice model. The disruption of traumatic memories through interference with the formation, consolidation, retrieval, and/or expression processes may be important to decrease PTSD symptoms and signs. The increase in Npas4 and Bdnf mRNA expression in the hippocampus may be important to develop a weaker traumatic contextual memory after nepicastat treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

Martinho

Correia

Seixas

et al. 2021

Front. Mol. Neurosci.

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“…The extracted NE/octopamine can then be measured directly by chromatography methods such as HPLC with an electrochemical detector or ultra‐performance liquid chromatography with a photodiode array detector (Feilchenfeld et al ). Recent reports by Catelas et al () found very high reproducibility in the ion exchange/spectrometry method, where they observed minimal experimental variability (Catelas et al ). In 1972, Nagatsu & Udenfriend in found that octopamine can be oxidized to para‐hydroxybenzaldehyde by sodium periodate (Fig.…”

Section: Assays Of Dβh Activitymentioning

confidence: 99%

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

Gonzalez-Lopez

Vrana

2019

Journal of Neurochemistry

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Dopamine beta-hydroxylase (DbH) is an essential neurotransmitter-synthesizing enzyme that catalyzes the formation of norepinephrine (NE) from dopamine and has been extensively studied since its discovery in the 1950s. NE serves as a neurotransmitter in both the central and peripheral nervous systems and is the precursor to epinephrine synthesis in the brain and adrenal medulla. Alterations in noradrenergic signaling have been linked to both central nervous system and peripheral pathologies. DbH protein, which is found in circulation, can, therefore, be evaluated as a marker of norepinephrine function in a plethora of different disorders and diseases. In many of these diseases, DbH protein availability and activity are believed to contribute to disease presentation or select symptomology and are believed to be under strong genetic control. Alteration in the DbH protein by genetic polymorphisms may result in DbH becoming ratelimiting and directly contributing to lower NE and epinephrine levels and disease. With the completion of the human genome project and the advent of next-generation sequencing, new insights have been gained into the existence of naturally occurring DbH sequencing variants (genetic polymorphisms) in disease. Also, biophysical tools coupled with genetic sequences are illuminating structure-function relationships within the enzyme. In this review, we discuss the role of genetic variants in DbH and its role in health and disease.

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“…Dopamine is produced by dopaminergic neurons in the brain from aminoacid tyrosine, which is converted into dihydroxyphenylalanine (DOPA) by a rate-limiting enzyme, tyrosine hydroxylase (TH) (Tekin et al 2014). Dopamine β hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into catecholamine neurotransmitter noradrenaline (Catelas et al 2020). Circadian variations in the activity of tyrosine hydroxylase and dopamine β hydroxylase were observed in the rat brain stem and Per1b mutant zebrafish (Cahill and Ehret 1981;Huang 2015).…”

Section: Introductionmentioning

confidence: 99%

Dopamine adjusts the circadian gene expression of Per2 and Per3 in human dermal fibroblasts from ADHD patients

et al. 2021

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A link between dopamine levels, circadian gene expression, and attention deficit hyperactivity disorder (ADHD) has already been demonstrated. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after dopamine exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different dopamine concentrations in human dermal fibroblast (HDF) cultures, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analyzed via qRT-PCR. We found no statistical significant effect in the actigraphy of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, wake after sleep onset, and total number of wake bouts. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. Dopamine has no effect on Per3 expression in healthy controls, but produces a significant difference in the ADHD group at ZT24 and ZT28. In the ADHD group, incubation with dopamine, either 1 µM or 10 µM, resulted in an adjustment of Per3 expression to control levels. A similar effect also was found in the expression of Per2. Statistical significant differences in the expression of Per2 (ZT4) in the control group compared to the ADHD group were found, following incubation with dopamine. The present study illustrates that dopamine impacts on circadian function. The results lead to the suggestion that dopamine may improve the sleep quality as well as ADHD symptoms by adjustment of the circadian gene expression, especially for Per2 and Per3.

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Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland

Cited by 12 publications

References 35 publications

Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

Dopamine adjusts the circadian gene expression of Per2 and Per3 in human dermal fibroblasts from ADHD patients

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