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  1. Fulltext Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes
    Himmelreich N, Bertoldi M, Alfadhel M, Alghamdi MA, Anikster Y, Bao X, et al.
    Mol Genet Metab, 2023 Jul;139(3):107624.
    PMID: 37348148 DOI: 10.1016/j.ymgme.2023.107624
    Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
    Matched MeSH terms: Dopamine/metabolism
  2. Normobaric hyperoxia treatment prevents early alteration in dopamine level in mice striatum after fluid percussion injury: a biochemical approach
    Muthuraju S, Islam MR, Pati S, Jaafar H, Abdullah JM, Yusoff KM
    Int J Neurosci, 2015;125(9):686-92.
    PMID: 25180987 DOI: 10.3109/00207454.2014.961065
    Dopamine (DA) is one of the key neurotransmitters in the striatum, which is functionally important for a variety of cognitive and motor behaviours. It is known that the striatum is vulnerable to damage from traumatic brain injury (TBI). However, a therapeutic approach has not yet been established to treat TBI. Hence, the present work aimed to evaluate the ability of Normobaric hyperoxia treatment (NBOT) to recover dopaminergic neurons following a fluid percussion injury (FPI) as a TBI experimental animal model. To examine this, mice were divided into four groups: (i) Control, (ii) Sham, (iii) FPI and (iv) FPI+NBOT. Mice were anesthetized and surgically prepared for FPI in the striatum and immediate exposure to NBOT at various time points (3, 6, 12 and 24 h). Dopamine levels were then estimated post injury by utilizing a commercially available ELISA method specific to DA. We found that DA levels were significantly reduced at 3 h, but there was no reduction at 6, 12 and 24 h in FPI groups when compared to the control and sham groups. Subjects receiving NBOT showed consistent increased DA levels at each time point when compared with Sham and FPI groups. These results suggest that FPI may alter DA levels at the early post-TBI stages but not in later stages. While DA levels increased in 6, 12 and 24 h in the FPI groups, NBOT could be used to accelerate the prevention of early dopaminergic neuronal damage following FPI injury and improve DA levels consistently.
    Matched MeSH terms: Dopamine/metabolism*
  3. Emerging role of S100B protein implication in Parkinson's disease pathogenesis
    Angelopoulou E, Paudel YN, Piperi C
    Cell Mol Life Sci, 2021 Feb;78(4):1445-1453.
    PMID: 33052436 DOI: 10.1007/s00018-020-03673-x
    The exact etiology of Parkinson's disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidence presents some contradictions, estimation of S100B in the serum and cerebrospinal fluid seems to hold a great promise as a potential PD biomarker, particularly regarding the severity of motor and non-motor PD symptoms. Furthermore, given the recent development of S100B inhibitors that are able to cross the blood brain barrier, novel opportunities are arising in the research field of PD therapeutics. In this review, we provide an update on recent advances in the implication of S100B protein in the pathogenesis of PD and discuss relevant studies investigating the biomarker potential of S100B in PD, aiming to shed more light on clinical targeting approaches related to this incurable disorder.
    Matched MeSH terms: Dopamine/metabolism
  4. The effects of metallothionein in paraquat-induced Parkinson disease model of zebrafish
    Mohamad Najib NH, Yahaya MF, Das S, Teoh SL
    Int J Neurosci, 2023 Dec;133(8):822-833.
    PMID: 34623211 DOI: 10.1080/00207454.2021.1990916
    INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. Metallothionein has been shown to act as a neuroprotectant in various brain injury. Thus, this study aims to identify the effects of full-length human metallothionein 2 peptide (hMT2) in paraquat-induced brain injury in the zebrafish.

    METHODOLOGY: A total of 80 adult zebrafish were divided into 4 groups namely control, paraquat-treated, pre-hMT2-treated, and post-hMT2-treated groups. Fish were treated with paraquat intraperitoneally every 3 days for 15 days. hMT2 were injected intracranially on day 0 (pre-treated group) and day 16 (post-treated group). Fish were sacrificed on day 22 and the brains were collected for qPCR, ELISA and immunohistochemistry analysis.

    RESULTS: qPCR analysis showed that paraquat treatment down-regulated the expression of genes related to dopamine activity and biosynthesis (dat and th1) and neuroprotective agent (bdnf). Paraquat treatment also up-regulated the expression of the mt2, smtb and proinflammatory genes (il-1α, il-1β, tnf-α and cox-2). hMT2 treatment was able to reverse the effects of paraquat. Lipid peroxidation decreased in the paraquat and pre-hMT2-treated groups. However, lipid peroxidation increased in the post-hMT2-treated group. Paraquat treatment also led to a reduction of dopaminergic neurons while their numbers showed an increase following hMT2 treatment.

    CONCLUSION: Paraquat has been identified as one of the pesticides that can cause the death of dopaminergic neurons and affect dopamine biosynthesis. Treatment with exogenous hMT2 could reverse the effects of paraquat in the zebrafish brain.

    Matched MeSH terms: Dopamine/metabolism
  5. Methanolic extract of Mitragyna speciosa Korth leaf inhibits ethanol seeking behaviour in mice: involvement of antidopaminergic mechanism
    Vijeepallam K, Pandy V, Murugan DD, Naidu M
    Metab Brain Dis, 2019 12;34(6):1713-1722.
    PMID: 31396844 DOI: 10.1007/s11011-019-00477-2
    In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75 mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100 mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75 mg/kg, p.o.) and reference drugs; acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.
    Matched MeSH terms: Dopamine/metabolism*
  6. Fulltext Kisspeptin-1 regulates forebrain dopaminergic neurons in the zebrafish
    Abdul Satar NM, Ogawa S, Parhar IS
    Sci Rep, 2020 11 09;10(1):19361.
    PMID: 33168887 DOI: 10.1038/s41598-020-75777-0
    The habenula is a phylogenetically conserved epithalamic structure, which conveys negative information via inhibition of mesolimbic dopamine neurons. We have previously shown the expression of kisspeptin (Kiss1) in the habenula and its role in the modulation of fear responses in the zebrafish. In this study, to investigate whether habenular Kiss1 regulates fear responses via dopamine neurons in the zebrafish, Kiss1 peptides were intracranially administered close to the habenula, and the expression of dopamine-related genes (th1, th2 and dat) were examined in the brain using real-time PCR and dopamine levels using LC-MS/MS. th1 mRNA levels and dopamine levels were significantly increased in the telencephalon 24-h and 30-min after Kiss1 administration, respectively. In fish administered with Kiss1, expression of neural activity marker gene, npas4a and kiss1 gene were significantly decreased in the ventral habenula. Application of neural tracer into the median raphe, site of habenular Kiss1 neural terminal projections showed tracer-labelled projections in the medial forebrain bundle towards the telencephalon where dopamine neurons reside. These results suggest that Kiss1 negatively regulates its own neuronal activity in the ventral habenula via autocrine action. This, in turn affects neurons of the median raphe via interneurons, which project to the telencephalic dopaminergic neurons.
    Matched MeSH terms: Dopamine/metabolism
  7. Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on its Association and Options of Treatment
    Rappek NAM, Sidi H, Kumar J, Kamarazaman S, Das S, Masiran R, et al.
    Curr Drug Targets, 2018;19(12):1352-1358.
    PMID: 28025939 DOI: 10.2174/1389450117666161227142947
    Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter- playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potential confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies. The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter system such as nitric oxide (NO), noradrenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome.
    Matched MeSH terms: Dopamine/metabolism
  8. Fulltext Lactobacillus plantarum DR7 Modulated Bowel Movement and Gut Microbiota Associated with Dopamine and Serotonin Pathways in Stressed Adults
    Liu G, Chong HX, Chung FY, Li Y, Liong MT
    Int J Mol Sci, 2020 Jun 29;21(13).
    PMID: 32610495 DOI: 10.3390/ijms21134608
    We have previously reported that the administration of Lactobacillus plantarum DR7 for 12 weeks reduced stress and anxiety in stressed adults as compared to the placebo group, in association with changes along the brain neurotransmitters pathways of serotonin and dopamine-norepinephrine. We now aim to evaluate the effects of DR7 on gut functions, gut microbiota compositional changes, and determine the correlations between microbiota changes and the pathways of brain neurotransmitters. The administration of DR7 prevented an increase of defecation frequency over 12 weeks as compared to the placebo (p = 0.044), modulating the increase of stress-induced bowel movement. Over 12 weeks, alpha diversity of gut microbiota was higher in DR7 than the placebo group across class (p = 0.005) and order (p = 0.018) levels, while beta diversity differed between groups at class and order levels (p < 0.001). Differences in specific bacterial groups were identified, showing consistency at different taxonomic levels that survived multiplicity correction, along the phyla of Bacteroides and Firmicutes and along the classes of Deltaproteobacteria and Actinobacteria. Bacteroidetes, Bacteroidia, and Bacteroidales which were reduced in abundance in the placebo group showed opposing correlation with gene expression of dopamine beta hydrolase (DBH, dopamine pathway; p < 0.001), while Bacteroidia and Bacteroidales showed correlation with tryptophan hydroxylase-II (TPH2, serotonin pathway; p = 0.001). A correlation was observed between DBH and Firmicutes (p = 0.002), Clostridia (p < 0.001), Clostridiales (p = 0.001), Blautia (p < 0.001), and Romboutsia (p < 0.001), which were increased in abundance in the placebo group. Blautia was also associated with TDO (p = 0.001), whereas Romboutsia had an opposing correlation with TPH2 (p < 0.001). Deltaproteobacteria and Desulfovibrionales which were decreased in abundance in the placebo group showed opposing correlation with DBH (p = 0.001), whereas Bilophila was associated with TPH2 (p = 0.001). Our present data showed that physiological changes induced by L. plantarum DR7 could be associated with changes in specific taxa of the gut microbiota along the serotonin and dopamine pathways.
    Matched MeSH terms: Dopamine/metabolism
  9. Neuroprotection of α-synuclein under acute and chronic rotenone and maneb treatment is abolished by its familial Parkinson's disease mutations A30P, A53T and E46K
    Choong CJ, Say YH
    Neurotoxicology, 2011 Dec;32(6):857-63.
    PMID: 21658409 DOI: 10.1016/j.neuro.2011.05.012
    α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). α-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of α-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial α-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type α-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant α-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type α-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type α-Syn may be protective, and such property may be lost by its familial PD mutations.
    Matched MeSH terms: Dopamine/metabolism
  10. Real time monitoring of dopamine release evoked by mitragynine (Kratom): An insight through electrochemical sensor
    Effendy MA, Yunusa S, Zain ZM, Hassan Z
    Neurosci Lett, 2021 10 15;763:136183.
    PMID: 34418508 DOI: 10.1016/j.neulet.2021.136183
    BACKGROUND: Mitragynine, the major indole alkaloid from Mitragyna speciosa has been reported previously to possess abuse liability. However, there are insufficient data suggesting the mechanism through which this pharmacological agent causes addiction.

    AIMS: In this study, we investigated the effects of mitragynine on dopamine (DA) level and dopamine transporter (DAT) expression from the rat's frontal cortex.

    METHODS: DA level was recorded in the brain samples of animals treated with acute or repeated exposure for 4 consecutive days with either vehicle or mitragynine (1 and 30 mg/kg) using electrochemical sensor. Animals were then decapitated and the brain regions were removed, snap-frozen in liquid nitrogen and immediately stored at -80 °C. DA level was quantified using Enzyme linked immunosorbent assay (ELISA) kits and DAT gene expression was determined using quantitative real time polymerase chain reaction (RT-qPCR).

    RESULTS/OUTCOME: Mitragynine (1 and 30 mg/kg) did not increase DA release following acute treatment, however, after repeated exposure at day 4, mitragynine significantly and dose dependently increased DA release in the frontal cortex. In this study, we also observed a significant increase in DAT mRNA expression at day 4 in group treated with mitragynine (30 mg/kg).

    CONCLUSION/INTERPRETATION: Data from this study indicates that mitragynine significantly increased DA release when administered repeatedly, increased in DAT mRNA expression with the highest tested dose (30 mg/kg). Therefore, the rewarding effects observed after mitragynine administration could be due to its ability to increase DA content in certain areas of the brain especially the frontal cortex.

    Matched MeSH terms: Dopamine/metabolism*
  11. The Functional Significance of Endocrine-immune Interactions in Health and Disease
    Muthusami S, Vidya B, Shankar EM, Vadivelu J, Ramachandran I, Stanley JA, et al.
    Curr Protein Pept Sci, 2020;21(1):52-65.
    PMID: 31702489 DOI: 10.2174/1389203720666191106113435
    Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.
    Matched MeSH terms: Dopamine/metabolism; Receptors, Dopamine/metabolism
  12. Effects of various nonopioid receptor antagonists on the antinociceptive activity of Muntingia calabura extracts in mice
    Zakaria ZA, Hassan MH, Nurul Aqmar MN, Abd Ghani M, Mohd Zaid SN, Sulaiman MR, et al.
    Methods Find Exp Clin Pharmacol, 2007 Oct;29(8):515-20.
    PMID: 18040526
    This study was carried out in mice to determine the nonopioid receptor signaling pathway(s) that might modulate the antinociceptive activity of the aqueous and chloroform extracts of Muntingia calabura (M. calabura) leaves, using the hot-plate test. The leaves of M. calabura were sequentially soaked [1:2 (w/v); 72 h] in distilled water (dH(2)O) and chloroform. The 50% concentration extracts were selected for this study based on the plant's previously established antinociceptive profiles. The mice (n = 7) were pretreated (s.c.) for 10 min with the selected nonopioid receptor antagonists, followed by the (s.c.) administration of the respective extract. The latency of discomfort was recorded at the interval time of 0.5, 1, 2, 3, 4 and 5 h after the extract administration. The 5 mg/kg atropine, 10 mg/kg phenoxybenzamine, 10 mg/kg yohimbine, 10 mg/kg pindolol, 1 mg/kg haloperidol and 10 mg/kg bicuculline caused significant (p < 0.05) reduction in the aqueous extract-induced antinociceptive activity. The 10 mg/kg phenoxybenzamine, 10 mg/kg yohimbine, 10 mg/kg pindolol and 10 mg/kg bicuculline caused significant (p < 0.05) reduction in the chloroform extract-induced antinociceptive activity. In conclusion, the central antinociceptive activity of M. calabura leaves appears to be involved in the modulation of various nonopioid receptor signaling pathways. Its aqueous extract antinociceptive activity is mediated via modulation of the muscarinic, alpha(1)-adrenergic, alpha(2)-adrenergic, beta-adrenergic, dopaminergic and GABAergic receptors, while its chloroform extract activity is mediated via modulation of the alpha(1)-adrenergic, alpha(2)-adrenergic, beta-adrenergic and GABAergic receptors.
    Matched MeSH terms: Receptors, Dopamine/metabolism
  13. Neurophysiological symptoms and aspartame: What is the connection?
    Choudhary AK, Lee YY
    Nutr Neurosci, 2018 Jun;21(5):306-316.
    PMID: 28198207 DOI: 10.1080/1028415X.2017.1288340
    Aspartame (α-aspartyl-l-phenylalanine-o-methyl ester), an artificial sweetener, has been linked to behavioral and cognitive problems. Possible neurophysiological symptoms include learning problems, headache, seizure, migraines, irritable moods, anxiety, depression, and insomnia. The consumption of aspartame, unlike dietary protein, can elevate the levels of phenylalanine and aspartic acid in the brain. These compounds can inhibit the synthesis and release of neurotransmitters, dopamine, norepinephrine, and serotonin, which are known regulators of neurophysiological activity. Aspartame acts as a chemical stressor by elevating plasma cortisol levels and causing the production of excess free radicals. High cortisol levels and excess free radicals may increase the brains vulnerability to oxidative stress which may have adverse effects on neurobehavioral health. We reviewed studies linking neurophysiological symptoms to aspartame usage and conclude that aspartame may be responsible for adverse neurobehavioral health outcomes. Aspartame consumption needs to be approached with caution due to the possible effects on neurobehavioral health. Whether aspartame and its metabolites are safe for general consumption is still debatable due to a lack of consistent data. More research evaluating the neurobehavioral effects of aspartame are required.
    Matched MeSH terms: Dopamine/metabolism
  14. Pharmacological evaluation of vanillic acid in rotenone-induced Parkinson's disease rat model
    Sharma N, Khurana N, Muthuraman A, Utreja P
    Eur J Pharmacol, 2021 Jul 15;903:174112.
    PMID: 33901458 DOI: 10.1016/j.ejphar.2021.174112
    In the present study, we investigated the anti-Parkinson's effect of vanillic acid (VA) (12 mg/kg, 25 mg/kg, 50 mg/kg p.o.) against rotenone (2 mg/kg s.c.) induced Parkinson's disease (PD) in rats. The continuous administration of rotenone for 35 days resulted in rigidity in muscles, catalepsy, and decrease in locomotor activity, body weight, and rearing behaviour along with the generation of oxidative stress in the brain (rise in the TBARS, and SAG level and reduced CAT, and GSH levels). Co-treatment of VA and levodopa-carbidopa (100 mg/kg + 25 mg/kg p.o.) lead to a significant (P 
    Matched MeSH terms: Dopamine/metabolism
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