Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine beta-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 microM, and 43.9 microM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 microM, and 42.5 microM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 microM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 microM and this value was higher than that of deprenyl (0.046 microM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 microM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.
Angelica* ; Antidepressive Agents ; Chalcones ; Depression ; Dopamine beta-Hydroxylase ; Inhibitory Concentration 50 ; Iproniazid ; Monoamine Oxidase ; Monoamine Oxidase Inhibitors ; Oxidoreductases* ; Selegiline

OBJECTIVEAttention deficit hyperactivity disorder (ADHD), a common behavior disorder of childhood, is a highly heterogeneous disease frequently accompanied by various mental disorders, including disruptive behavior disorder (DBD). Studies show that children suffering from ADHD with DBD are at higher risk of antisocial personality, substance abuse, and social adaptations disorder at their adulthood. The dopamine beta hydroxylase (DbetaH) is the key enzyme to ADHD since it catalyzes the conversion of dopamine to norepinephrine, and dysfunction there of is believed to be one of the causes of the disorder. To explore the association between DBH gene and ADHD complicated with or without DBD, the authors analyzed the transmission of a novel polymorphism DBH -1021C-->T, which is found associated with plasma DbetaH activity, in ADHD nuclear families using transmission disequilibrium test (TDT).

METHODSConsensus diagnoses were based on the DSM-IV. The samples included those from 292 Chinese Han nuclear families with ADHD probands. Genotypes of DBH -1021C-->T polymorphism were determined by PCR amplification, endonuclease digesting and electrophoresis. The transmission of DBH -1021C-->T polymorphism in ADHD nuclear families with or without DBD was analyzed by TDT.

RESULTSThe results showed that there was transmission disequilibrium between DBH-1021C-->T polymorphism and ADHD with or without DBD. In ADHD comorbid with DBD, T allele was preferentially transmitted (P < 0.05); and in ADHD without DBD, so was the C allele (P < 0.05). Among the three subtypes of ADHD, only ADHD-C subtype with DBD had an increased transmission of T allele (P < 0.05).

CONCLUSIONThere is an association between DBH gene and ADHD comorbid with or without DBD, but the preferential transmission alleles are different. The low activity T allele is increased to transmit in ADHD with DBD, while the high activity C allele is preferentially transmitted in ADHD without DBD. The results support the proposition that the genetic mechanism is different between ADHD comorbid with or without DBD. We also found that only ADHD-C subtype with DBD is associated with DBH -1021C-->T polymorphism in three subtypes of ADHD, which may suggest that there is a more intense relationship between DBD and ADHD-C subtype.

Alleles ; Attention Deficit and Disruptive Behavior Disorders ; genetics ; China ; Dopamine beta-Hydroxylase ; genetics ; Genotype ; Humans ; Polymerase Chain Reaction ; Polymorphism, Genetic

These studies document species differences in the distribution of the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) within the main olfactory bulb (MOB) of a number of rodents and insectivore species including the rat, wild mouse, mongolian gerbil, stripped field mouse (apodemus agrarius), hedgehog, mole, laboratory shrew (suncus murinus). TH-containing neuronal perikarya were observed in the MOB of the both species of the rodents and insectivore except the hedgehog and laboratory shrew (suncus murinus). None of these cell groups displayed either dopamine beta hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). The number of stained somata and their intensity varied such that label was most prominent in the stripped field mouse followed in decreasing order by the rat, mongolian gerbil, wild mouse and mole. The vast majority of such cells occurred in the glomerular layer as periglomerular cells surrounging the glomeruli of the stripped field mouse, rat, mongolian gerbil, wild mouse and moles. Numerous additional cells were present in the external plexiform layer (EPL) and mitral cell layer (MCL). These often displayed long ascending immunoreactive processes and appeared to correspond to tufted cells. Also a few smaller, multipolar cells were present in the internal granular layer scattered among the granule cells. However, the hedgehog and laboratory shrew displayed no perikaryal staining in the MOB. In conclusion, these data suggest that TH is present in the MOB of stripped field mouse, rat, mongolian gerbil, wild mouse and moles but is not found in the MOB of the hedgehog and laboratory shrew, or that species differences exist in the level of TH.
Animals ; Dopamine beta-Hydroxylase ; Dopaminergic Neurons* ; Gerbillinae ; Hedgehogs ; Mice ; Neurons ; Olfactory Bulb* ; Rats ; Rodentia* ; Shrews ; Tyrosine 3-Monooxygenase

Catecholamines are among the first molecules that displayed a kind of response to prolonged or repeated stress. It is well established that long-term stress leads to the induction of catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) in adrenal medulla. The aim of the present study was to evaluate the effects of ginseng on TH and DBH mRNA expression. Repeated (2 h daily, 14 days) immobilization stress resulted in a significant increase of TH and DBH mRNA levels in rat adrenal medulla. However, ginseng treatment reversed the stress-induced increase of TH and DBH mRNA expression in the immobilization-stressed rats. Nicotine as a ligand of the nicotinic acetylcholine receptor (nAChR) in adrenal medulla stimulates catecholamine secretion and activates TH and DBH gene expression. Nicotine treatment increased mRNA levels of TH and DBH by 3.3- and 3.1-fold in PC12 cells. The ginseng total saponin exhibited a significant reversal in the nicotine-induced increase of TH and DBH mRNA expression, decreasing the mRNA levels of TH and DBH by 57.2% and 48.9%, respectively in PC12 cells. In conclusion, immobilization stress induced catecholamine biosynthetic enzymes gene expression, while ginseng appeared to restore homeostasis via suppression of TH and DBH gene expression. In part, the regulatory activity in the TH and DBH gene expression of ginseng may account for the anti-stress action produced by ginseng.
Adrenal Medulla ; Animals ; Catecholamines ; Dopamine ; Dopamine beta-Hydroxylase ; Down-Regulation ; Gene Expression ; Homeostasis ; Immobilization ; Nicotine ; Panax ; PC12 Cells ; Rats ; Receptors, Nicotinic ; RNA, Messenger ; Saponins ; Tyrosine ; Tyrosine 3-Monooxygenase

Electroacupuncture (EA) is a modified form of acupuncture that utilizes electrical stimulation. We previously showed that EA stimulated rats were divided into responders that were sensitive to EA and non-responders that were insensitive to EA based on the tail flick latency (TFL) test. The dopamine beta-hydroxylase (DBH) gene was more abundantly expressed in the hypothalamus of responder rats than non-responder rats. To determine whether overexpression of DBH gene expression in the hypothalamus modulate EA analgesia, we constructed a DBH encoding adenovirus and which was then injected into the hypothalamus of SD rats. Microinjection of DBH or control GFP virus into the hypothalamus had no changes on the basal pain threshold measured by a TFL test without EA treatment. However, the analgesic effect of EA was significantly enhanced from seven days after microinjection of the DBH virus, but not after injection of the control GFP virus. DBH expression was significantly higher in the hypothalamus of DBH virus injected rat than control GFP virus or PBS injected rats. Moreover, expression of the DBH gene did not affect the body core temperature, body weight, motor function or learning and memory ability. Although the functional role of DBH in the hypothalamus in the analgesic effect of EA remains unclear, our findings suggest that expression of the DBH gene in the hypothalamus promotes EA analgesia without obvious side-effects.
Acupuncture ; Adenoviridae ; Analgesia* ; Animals ; Body Temperature ; Dopamine beta-Hydroxylase* ; Dopamine* ; Electric Stimulation ; Electroacupuncture* ; Gene Expression ; Hypothalamus* ; Learning ; Memory ; Microinjections ; Pain Threshold ; Rats* ; Viruses

BACKGROUND & OBJECTIVE: Stereotaxic injection of 6-hydroxydopamine(6OHDA) into the ventral midbrain is the most commonly used Parkinsonian animal model. In the presence of norepinephrine(NE) uptake blockers, 6OHDA is believed to be selectively toxic to the dopamine(DA) system. However, it was observed in this model that there is a massive fiber degeneration in the fornix, where there are no known DA fibers. There are NE fibers in the fornix arising from the locus ceruleus (LC) terminating in the cerebral cortex including hippocampus. The study was done to examine whether there is a change in the NE system and characterize the neurochemical nature of the previously demonstrated degenerating fornix fibers. METHODS: 6OHDA was injected stereotaxically into the unilateral ventral midbrain in desipramine pretreated rats. DA and NE were measured in the striatum, cortex, hippocampus, and LC. Silver staining was done to demonstrate degenerating neurons and nerve terminals. Immunohistochemistry using tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) was done to demonstrate catecholamine neurons and nerve fibers. RESULTS: DA was markedly depleted in the ipsilateral striatum. NE was decreased in the striatum, cortex, and hippocampus, but not in the LC. Silver staining showed massive fiber degeneration in the fornix, but did not show degenerating neurons in the LC. TH and DBH Immunohistochemistry failed to show catecholaminergic fibers in the fornix. There was no side difference on immunostaining in the LC neurons. CONCLUSION: 6OHDA Parkinson model does not make selective lesion to the DA system, and damages ascending NE fibers. Neuronal cell bodies in the LC remain intact in this model. The neurochemical nature of the degenerating fornix fibers is not clearly characterized.
Animals ; Cerebral Cortex ; Desipramine ; Dopamine beta-Hydroxylase ; Hippocampus ; Immunohistochemistry ; Locus Coeruleus ; Mesencephalon ; Models, Animal ; Models, Theoretical* ; Nerve Fibers ; Neurons ; Oxidopamine* ; Parkinsonian Disorders* ; Rats ; Silver Staining ; Tyrosine 3-Monooxygenase

Serum dopamine-beta-hydroxylase (DBH) inhibition has been reported in lead workers treated with CaNa2EDTA and in alcoholic patients repeatedly treated with the alcohol aversive drug Disulfiram. The mechanism of inhibition involves Cu++ chelation at the active site of DBH. The effect of CaNa2EDTA and Disulfiram on serum DBH has been compared to the effect of dithiocarbamate pesticides in vitro for the possible use of serum DBH determination for the biological monitoring of workers exposed to these pesticides. Most dithiocarbamates inhibit human serum DBH at micromolar concentrations (range of I50, 0.027-1.6 mumol/L). The inhibitory potency increased from methyl- and dimethyl dithiocarbamates to diethyl dithiocarbamates up to the most potent ethylene bisdithiocarbamates. The I50 of CaNa2EDTA was 3.8 mumol/L, higher than those of dithiocarbamates. Copper addition to the test system reactivated at stoichiometric concentrations dithiocarbamate-inhibited DBH indicating that both base line values and percent of inhibition can be calculated in a single blood sample. Results suggest that serum DBH determination could be useful in case of acute poisoning involving high doses of dithiocarbamate pesticides.
Alcohol Deterrents ; pharmacology ; Biomarkers ; blood ; Chelating Agents ; pharmacology ; Disulfiram ; pharmacology ; Ditiocarb ; pharmacology ; Dopamine beta-Hydroxylase ; blood ; drug effects ; Edetic Acid ; pharmacology ; Female ; Humans ; Male ; Pesticides ; blood

Disulfiram, or antabuse, is used in the treatment of chronic alcoholism since it causes an unpleasant aversive reaction to alcohol. It works by inactivating hepatic aldehyde dehydrogenase, leading to a pronounced rise in the acetaldehyde concentration when ethanol is metabolized. Acetaldehyde causes alcohol sensitivity, which involves vasodilation associated with increased skin temperature, subjective feelings of hotness and facial flushing, increased heart and respiration rates, lowered blood pressure, a drymouth or throat sensation associated with bronchoconstriction and allergy reactions, nausea, and headache. One of its metabolites, diethyldithiocarbamate (DDC) can inhibit the enzyme dopamine beta-hydroxylase (DBH) through copper chelation. This may account for the profound refractory hypotension seen with the disulfiram-ethanol reaction (DAR), resulting from norepinephrine depletion. This report is presents the case of a patient we met, who presented with severe hypotension caused by the disulfiram-alcohol reaction, and along with a brief review of the subject.
Acetaldehyde ; Alcoholism ; Aldehyde Dehydrogenase ; Blood Pressure ; Bronchoconstriction ; Copper ; Disulfiram ; Ditiocarb ; Dopamine beta-Hydroxylase ; Ethanol ; Flushing ; Headache ; Heart ; Humans ; Hypersensitivity ; Hypotension* ; Nausea ; Norepinephrine ; Pharynx ; Respiratory Rate ; Sensation ; Skin Temperature ; Vasodilation

OBJECTIVETo investigate the correlation between the polymorphism of dopamine beta hydroxylase(DBH) gene and the susceptibility of Shanghai Chinese Han population to Parkinson's disease(PD).

METHODSAssociation study was performed in 144 PD patients and 188 healthy control subjects matched for age, sex and origin. Polymorphism of DBH gene was analyzed with polymerase chain reaction-restriction fragment length polymorphism.

RESULTSThe allelic frequency of A2 allele of DBH gene was significantly higher in PD patients than in controls(P<0.01).The risk of suffering from PD increased (OR=1.82) in the individual with A2 allele. And the genotypic frequency of A2/A2 was significantly higher in PD patients(OR=2.11, P<0.01),too. On the other hand, the allelic frequency of A1 allele and the genotypic frequency of A1/A2 genotype of DBH gene in PD patients were significantly lower(A1 alleles: OR=0.54, P<0.01; A1/A2 genotypes: OR=0.45, P<0.01).

CONCLUSIONThe polymorphism in DBH gene might play an important role in the susceptibility of Shanghai Chinese Han population to PD.

Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; China ; Dopamine beta-Hydroxylase ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Parkinson Disease ; genetics ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length

OBJECTIVETo investigate the relationship between genetic polymorphism of dopamine &beta;-hydroxylase (DBH) and manganese-induced nerve injury.

METHODSIn a cross-sectional study, 402 electric welders who had worked over one year in relatively fixed sites were recruited, and the concentration of manganese in which they worked was stable. These samples was divided into high exposure group (CEI > 1) and low exposure group (CEI < 1) by CEI. Between the two groups, the groups were divided into abnormal group and normal group according to the result of neurologic check (there were 81 workers with abnormal neurological dysfunction in high exposure group and 28 workers in low exposure group, P < 0.05). Polymorphism of DBH gene was analyzed with polymerase chain reaction-restriction fragment length polymorphism.

RESULTSThe distribution of A2A2 genotype and A2 allele of DBH was significantly different. In high exposure group, the distribution of A2A2 genotype and A2 allele of DBH in abnormal group was significantly wider than in normal group (A2A2 genotype, OR = 1.248, P < 0.05, A2 allele, OR = 1.103, P < 0.05). In low exposure group, the distribution of A2 allele of DBH in abnormal group was significantly wider than in normal group (OR = 1.176, P < 0.05).

CONCLUSIONThe individuals who carry A2A2 genotype and A2 allele of DBH have increased risk of neurological dysfunction after explosion to manganese for a certain time, which suggests that polymorphism of DBH (intron 5 Taq I) would play a great role in hereditary susceptibility of neurological dysfunction cause by manganese.

Adult ; Air Pollutants, Occupational ; analysis ; toxicity ; Cross-Sectional Studies ; Dopamine beta-Hydroxylase ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Manganese ; analysis ; toxicity ; Middle Aged ; Nervous System Diseases ; genetics ; Polymorphism, Single Nucleotide ; Welding ; Young Adult