Displaying publications 1 - 20 of 40 in total

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  1. The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise
    Ando S, Fujimoto T, Sudo M, Watanuki S, Hiraoka K, Takeda K, et al.
    J Physiol, 2024 Feb;602(3):461-484.
    PMID: 38165254 DOI: 10.1113/JP285173
    Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.
    Matched MeSH terms: Neurotransmitter Agents
  2. Fulltext Antinociceptive activities of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol, and its possible mechanisms of action in mice
    Ong HM, Azmi AFA, Leong SW, Abas F, Perimal EK, Farouk AAO, et al.
    Sci Rep, 2021 12 16;11(1):24121.
    PMID: 34916536 DOI: 10.1038/s41598-021-02961-1
    A novel synthetic compound from the 2-benzoyl-6-benzylidenecyclohexanone analogue, namely 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC), showed pronounced nitric oxide inhibition in IFN-γ/LPS-induced RAW 264.7 cells. Based on this previous finding, our present study aimed to investigate the antinociceptive effects of BBHC via chemical and thermal stimuli in vivo. The investigation of the antinociceptive activity of BBHC (0.1, 0.3, 1.0 and 3.0 mg/kg, i.p.) was initiated with 3 preliminary screening tests, then BBHC was subjected to investigate its possible involvement with excitatory neurotransmitters and opioid receptors. The potential acute toxicity of BBHC administration was also studied. Administration of BBHC significantly inhibited acetic acid-induced abdominal constrictions, formalin-induced paw licking activity and developed notable increment in the latency time. BBHC's ability to suppress capsaicin- and glutamate-induced paw licking activities, as well as to antagonise the effect of naloxone, had indicated the possible involvement of its antinociception with TRPV1, glutamate and opioid receptors, respectively. The antinociceptive activities of BBHC was not related to any sedative action and no evidence of acute toxic effect was detected. The present study showed that BBHC possessed significant peripheral and central antinociceptive activities via chemical- and thermal-induced nociceptive murine models without any locomotor alteration and acute toxicity.
    Matched MeSH terms: Neurotransmitter Agents
  3. Probiotic consumption relieved human stress and anxiety symptoms possibly via modulating the neuroactive potential of the gut microbiota
    Ma T, Jin H, Kwok LY, Sun Z, Liong MT, Zhang H
    Neurobiol Stress, 2021 May;14:100294.
    PMID: 33511258 DOI: 10.1016/j.ynstr.2021.100294
    Stress has been shown to disturb the balance of human intestinal microbiota and subsequently causes mental health problems like anxiety and depression. Our previous study showed that ingesting the probiotic strain, Lactobacillus (L.) plantarum P-8, for 12 weeks could alleviate stress and anxiety of stressed adults. The current study was a follow-up work aiming to investigate the functional role of the gut metagenomes in the observed beneficial effects. The fecal metagenomes of the probiotic (n = 43) and placebo (n = 36) receivers were analyzed in depth. The gut microbiomes of the placebo group at weeks 0 and 12 showed a significantly greater Aitchison distance (P 
    Matched MeSH terms: Neurotransmitter Agents
  4. Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms
    Akyuz E, Kullu I, Arulsamy A, Shaikh MF
    ACS Chem Neurosci, 2021 04 21;12(8):1281-1292.
    PMID: 33813829 DOI: 10.1021/acschemneuro.1c00083
    Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst of abnormal and excessive electrical discharges, known as seizures, in the neurons. Epilepsy is a devastating neurological condition that affects 70 million people globally. Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while others become drug resistant and may be more prone to epilepsy comorbidities such as SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and inhibitory neurotransmitters, and neuroinflammation are some of the common pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a pineal hormone that governs sleep-wake cycles, may be neuroprotective against neurological disorders and thus may be translated as an antiepileptic as well. Melatonin has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/molecule in neurodegenerative diseases, which may contribute to its antiepileptic and neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been shown to play a regulatory role in the cardiorespiratory system and sleep-wake cycles, which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the changes in melatonin release due to epilepsy and melatonin's antiepileptic role have been inconclusive and scarce, respectively. Thus, this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients, particularly those who are drug resistant.
    Matched MeSH terms: Neurotransmitter Agents
  5. Fulltext Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy
    Akyuz E, Doganyigit Z, Paudel YN, Koklu B, Kaymak E, Villa C, et al.
    Life (Basel), 2021 Mar 26;11(4).
    PMID: 33810231 DOI: 10.3390/life11040276
    Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.
    Matched MeSH terms: Neurotransmitter Agents
  6. Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities
    Angelopoulou E, Paudel YN, Piperi C, Mishra A
    J Biochem Mol Toxicol, 2021 Jan 24.
    PMID: 33491302 DOI: 10.1002/jbt.22720
    Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the TLR/NF-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored, and potential obstacles/limitations that need to be overcome, for its inclusion in experimental PD therapeutics.
    Matched MeSH terms: Neurotransmitter Agents
  7. Revisiting the role of neurotransmitters in epilepsy: An updated review
    Akyuz E, Polat AK, Eroglu E, Kullu I, Angelopoulou E, Paudel YN
    Life Sci, 2021 Jan 15;265:118826.
    PMID: 33259863 DOI: 10.1016/j.lfs.2020.118826
    Epilepsy is a neurologicaldisorder characterized by persistent predisposition to recurrent seizurescaused by abnormal neuronal activity in the brain. Epileptic seizures maydevelop due to a relative imbalance of excitatory and inhibitory neurotransmitters. Expressional alterations of receptors and ion channelsactivated by neurotransmitters can lead to epilepsy pathogenesis.

    AIMS: In this updated comprehensive review, we discuss the emerging implication of mutations in neurotransmitter-mediated receptors and ion channels. We aim to provide critical findings of the current literature about the role of neurotransmitters in epilepsy.

    MATERIALS AND METHODS: A comprehensive literature review was conducted to identify and critically evaluate studies analyzing the possible relationship between epilepsy and neurotransmitters. The PubMed database was searched for related research articles.

    KEY FINDINGS: Glutamate and gamma-aminobutyric acid (GABA) are the main neurotransmitters playing a critical role in the pathophysiology of this balance, and irreversible neuronal damage may occur as a result of abnormal changes in these molecules. Acetylcholine (ACh), the main stimulant of the autonomic nervous system, mediates signal transmission through cholinergic and nicotinic receptors. Accumulating evidence indicates that dysfunction of nicotinic ACh receptors, which are widely expressed in hippocampal and cortical neurons, may be significantly implicated in the pathogenesis of epilepsy. The dopamine-norepinephrine-epinephrine cycle activates hormonal and neuronal pathways; serotonin, norepinephrine, histamine, and melatonin can act as both hormones and neurotransmitters. Recent reports have demonstrated that nitric oxide mediates cognitive and memory-related functions via stimulating neuronal transmission.

    SIGNIFICANCE: The elucidation of the role of the main mediators and receptors in epilepsy is crucial for developing new diagnostic and therapeutic approaches.

    Matched MeSH terms: Neurotransmitter Agents/metabolism*
  8. Fulltext Emodin Derivatives as Multi-Target-Directed Ligands Inhibiting Monoamine Oxidase and Antagonizing Vasopressin V1A Receptors
    Paudel P, Shrestha S, Park SE, Seong SH, Fauzi FM, Jung HA, et al.
    ACS Omega, 2020 Oct 20;5(41):26720-26731.
    PMID: 33110998 DOI: 10.1021/acsomega.0c03649
    The brain neurotransmitter level is associated with the pathology of various neurodegenerative diseases, and age-dependent increase in the blood level of vasopressin, human brain monoamine oxidase (hMAO) level, oxidative stress, and imbalance in aminergic signaling are common disease-modifying factors leading to various neurodegenerative disorders. Based on the reports of emodin in hMAO inhibition and antagonist effect on the vasopressin V1A receptor, in this study we synthesized six emodin derivatives and evaluated their effects on MAO activity and G protein-coupled receptors. Among them, 4-hydroxyemodin and 5-hydroxyemodin were potent inhibitors of hMAO, and 2-hydroxyemodin and 5-hydroxyemodin were good V1AR antagonists. In silico molecular docking simulation revealed that the hydroxyl group at C2, C4, and C5 of the respective compounds interacted with prime residues, which corroborates the in vitro effect. Likewise, these three derivatives were predicted to have good drug-like properties. Overall, our study demonstrates that the hydroxyl derivatives of emodin are multi-target-directed ligands that may act as leads for the design and development of a therapy for central nervous system disorders.
    Matched MeSH terms: Neurotransmitter Agents
  9. Fulltext Antidepressant-Like Properties of Fish Oil on Postpartum Depression-Like Rats Model: Involvement of Serotonergic System
    Abdul Aziz NU, Chiroma SM, Mohd Moklas MA, Adenan MI, Ismail A, Hidayat Baharuldin MT
    Brain Sci, 2020 Oct 13;10(10).
    PMID: 33066310 DOI: 10.3390/brainsci10100733
    Pathophysiology of postpartum depression (PPD) has been associated with many factors, such as neuroendocrine, neuroinflammation and neurotransmitter changes. Fish oil (FO) improves PPD both in humans and animals. However, little is known with regards to its pharmacology on a PPD-like rat model. Hence, the current study aimed at investigating the effects of FO on a PPD-like rat model. Female rats were induced with PPD-like symptoms and then randomly divided into six groups (n = 6) for two experimental protocols. Protocol 1 consisted of PPD-like rats (2 mL distilled water), PPD-like + FO (9 g/kg/d) and PPD-like + Fluoxetine (FLX) (15 mg/kg/d) groups of rats, whereas Protocol 2 consisted of PPD-like rats (2 mL distilled water) + PCPA (p-chlorophenylalanine) 150 mg/kg, PPD-like + FO (9 g/kg/d) + PCPA 150 mg/kg and PPD-like + FLX (15 mg/d) + PCPA 150 mg/kg groups of rats, respectively. All treatments were administered orally for 10 days postpartum, except PCPA, which was given intraperitoneally. Prior to euthanasia, the antidepressant-like effect of the FO was evaluated using the forced swimming test (FST) and open field test (OFT) on day 10 postpartum. Biochemical analysis of serotonin, serotonin metabolite and serotonin turnover from their prefrontal cortex and hippocampus were also measured. The results showed that FO decreased immobility time and increased swimming time significantly, but not climbing time in FST. Further, it also decreased serotonin metabolite and turnover significantly in the hippocampus of the PPD-like rats. In contrast, administration with PCPA reversed all the outcomes. The antidepressant-like effects of FO were found to be similar with that of FLX. Thus, it can be concluded that FO exerts its antidepressant-like effects in PPD-like rats through modulation of serotonergic system.
    Matched MeSH terms: Neurotransmitter Agents
  10. Fulltext Orthosiphon stamineus Proteins Alleviate Pentylenetetrazol-Induced Seizures in Zebrafish
    Chung YS, Choo BKM, Ahmed PK, Othman I, Shaikh MF
    Biomedicines, 2020 Jul 02;8(7).
    PMID: 32630817 DOI: 10.3390/biomedicines8070191
    The anticonvulsive potential of proteins extracted from Orthosiphon stamineus leaves (OSLP) has never been elucidated in zebrafish (Danio rerio). This study thus aims to elucidate the anticonvulsive potential of OSLP in pentylenetetrazol (PTZ)-induced seizure model. Physical changes (seizure score and seizure onset time, behavior, locomotor) and neurotransmitter analysis were elucidated to assess the pharmacological activity. The protective mechanism of OSLP on brain was also studied using mass spectrometry-based label-free proteomic quantification (LFQ) and bioinformatics. OSLP was found to be safe up to 800 µg/kg and pre-treatment with OSLP (800 µg/kg, i.p., 30 min) decreased the frequency of convulsive activities (lower seizure score and prolonged seizure onset time), improved locomotor behaviors (reduced erratic swimming movements and bottom-dwelling habit), and lowered the excitatory neurotransmitter (glutamate). Pre-treatment with OSLP increased protein Complexin 2 (Cplx 2) expression in the zebrafish brain. Cplx2 is an important regulator in the trans-SNARE complex which is required during the vesicle priming phase in the calcium-dependent synaptic vesicle exocytosis. Findings in this study collectively suggests that OSLP could be regulating the release of neurotransmitters via calcium-dependent synaptic vesicle exocytosis mediated by the "Synaptic Vesicle Cycle" pathway. OSLP's anticonvulsive actions could be acting differently from diazepam (DZP) and with that, it might not produce the similar cognitive insults such as DZP.
    Matched MeSH terms: Neurotransmitter Agents
  11. Fulltext MDMA and the Brain: A Short Review on the Role of Neurotransmitters in Neurotoxicity
    Mustafa NS, Bakar NHA, Mohamad N, Adnan LHM, Fauzi NFAM, Thoarlim A, et al.
    Basic Clin Neurosci, 2020 07 01;11(4):381-388.
    PMID: 33613876 DOI: 10.32598/bcn.9.10.485
    N-Methyl-3, 4-methylenedioxyamphetamine (MDMA), or ecstasy is a recreational drug of abuse. It is a synthetic substance that affects the body's systems, which its mechanism of action and treatment should be more investigated. MDMA provides an immediate enjoyable feeling by stimulating the release of neurotransmitters, such as dopamine and serotonin in the brain. Unfortunately, abnormal regulation of the brain neurotransmitters, as well as the increased oxidative stress causes damage to the brain neurons after the MDMA exposure. Only a few studies have been done regarding its treatment. Thus, the treatment of MDMA complications should be further explored mainly by targeting its mechanism of action in the neurotransmitter systems. Hence, this study presents a short review regarding the recent findings on the role of neurotransmitters to cause MDMA neurotoxicity. The results will be useful for future research in elucidating the potential treatment based on the targeted mechanisms to treat the neurotoxic effects of MDMA.
    Matched MeSH terms: Neurotransmitter Agents
  12. 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: Neurotransmitter Agents/metabolism
  13. Fulltext Pilocarpine Induced Behavioral and Biochemical Alterations in Chronic Seizure-Like Condition in Adult Zebrafish
    Paudel YN, Kumari Y, Abidin SAZ, Othman I, Shaikh MF
    Int J Mol Sci, 2020 Apr 03;21(7).
    PMID: 32260203 DOI: 10.3390/ijms21072492
    Epilepsy is a devastating neurological condition exhibited by repeated spontaneous and unpredictable seizures afflicting around 70 million people globally. The basic pathophysiology of epileptic seizures is still elusive, reflecting an extensive need for further research. Developing a novel animal model is crucial in understanding disease mechanisms as well as in assessing the therapeutic target. Most of the pre-clinical epilepsy research has been focused on rodents. Nevertheless, zebrafish disease models are relevant to human disease pathophysiology hence are gaining increased attention nowadays. The current study for the very first time developed a pilocarpine-induced chronic seizure-like condition in adult zebrafish and investigated the modulation in several neuroinflammatory genes and neurotransmitters after pilocarpine exposures. Seizure score analysis suggests that compared to a single dose, repeated dose pilocarpine produces chronic seizure-like effects maintaining an average seizure score of above 2 each day for a minimum of 10 days. Compared to the single dose pilocarpine treated group, there was increased mRNA expression of HMGB1, TLR4, TNF-α, IL-1, BDNF, CREB-1, and NPY; whereas decreased expression of NF-κB was upon the repeated dose of pilocarpine administration. In addition, the epileptic group demonstrates modulation in neurotransmitters levels such as GABA, Glutamate, and Acetylcholine. Moreover, proteomic profiling of the zebrafish brain from the normal and epileptic groups from LCMS/MS quantification detected 77 and 13 proteins in the normal and epileptic group respectively. Summing up, the current investigation depicted that chemically induced seizures in zebrafish demonstrated behavioral and molecular alterations similar to classical rodent seizure models suggesting the usability of adult zebrafish as a robust model to investigate epileptic seizures.
    Matched MeSH terms: Neurotransmitter Agents/metabolism
  14. Butyrylcholinesterase: A Multifaceted Pharmacological Target and Tool
    Ha ZY, Mathew S, Yeong KY
    Curr Protein Pept Sci, 2020;21(1):99-109.
    PMID: 31702488 DOI: 10.2174/1389203720666191107094949
    Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer's disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the "hunger hormone". These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.
    Matched MeSH terms: Neurotransmitter Agents/metabolism
  15. Lactobacillus paracasei PS23 reduced early-life stress abnormalities in maternal separation mouse model
    Liao JF, Hsu CC, Chou GT, Hsu JS, Liong MT, Tsai YC
    Benef Microbes, 2019 Apr 19;10(4):425-436.
    PMID: 30882243 DOI: 10.3920/BM2018.0077
    Maternal separation (MS) has been developed as a model for inducing stress and depression in studies using rodents. The concept of the gut-brain axis suggests that gut health is essential for brain health. Here, we present the effects of administration of a probiotic, Lactobacillus paracasei PS23 (PS23), to MS mice against psychological traits including anxiety and depression. The administration of live and heat-killed PS23 cells showed positive behavioural effects on MS animals, where exploratory tendencies and mobility were increased in behavioural tests, indicating reduced anxiety and depression compared to the negative control mice (P<0.05). Mice administered with both live and heat-killed PS23 cells also showed lower serum corticosterone levels accompanied by higher serum anti-inflammatory interleukin 10 (IL-10) levels, compared to MS separated mice (P<0.05), indicating a stress-elicited response affiliated with increased immunomodulatory properties. Assessment of neurotransmitters in the brain hippocampal region revealed that PS23 affected the concentrations of dopaminergic metabolites differently than the control, suggesting that PS23 may have improved MS-induced stress levels via neurotransmitter pathways, such as dopamine or other mechanisms not addressed in the current study. Our study illustrates the potential of a probiotic in reversing abnormalities induced by early life stress and could be an alternative for brain health along the gut-brain axis.
    Matched MeSH terms: Neurotransmitter Agents
  16. Role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke exposure induced cognitive impairment in Danio rerio
    Muthuraman A, Nafisa K, Sowmya MS, Arpitha BM, Choedon N, Sandy CD, et al.
    Life Sci, 2019 Mar 04.
    PMID: 30844374 DOI: 10.1016/j.lfs.2019.03.002
    BACKGROUND: Cigarette smoke is exogenous modifiable factors to changes the neurovascular complication. The chronic exposure of cigarette smoke enhances neurocognitive dysfunction.

    AIMS: The present study is focused on evaluating the role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke-induced cognitive impairment in Danio rerio.

    MAIN METHODS: The cognitive dysfunction was developed by cigarette smoke exposure (CSE; 10 min in 25 ml of CSE per day) for five days. The selective endothelin-A receptor antagonist i.e., ambrisentan (2.5 to 5 mg/kg; i.p. for five consecutive days) was used for testing of CSE induced cognitive dysfunction. In addition, treatment of reference drug i.e., donepezil (10 mg/kg; i.p. for five consecutive days) was used for this cognitive function study. The cognitive functions were assessed by light and dark chamber; color recognition; partition preference; horizontal compartment; and T-Maze tests. Further, the CSE induced biomarkers changes of the zebrafish brain samples were estimated.

    KEY FINDINGS: The treatment of ambrisentan showed a potential ameliorative effect against the CSE induced cognitive functions along with attenuation of biochemical changes. The results are comparable to donepezil-treated groups.

    SIGNIFICANCE: Therefore, ambrisentan can be considered for the attenuation of CSE induced impairment neurocognitive functions due to its reduction of free radical scavenging and neuroinflammatory actions as well as regulation of cholinergic neurotransmitter functions.

    Matched MeSH terms: Neurotransmitter Agents
  17. The Bio-Psycho-Social Dimension in Women's Sexual Desire: 'Argumentum ad novitatem'
    Roslan NS, Jaafar NRN, Sidi H, Baharudin N, Kumar J, Das S, et al.
    Curr Drug Targets, 2019;20(2):146-157.
    PMID: 28641524 DOI: 10.2174/1389450118666170622090337
    Sexual desire includes complex motivation and drive. In the context of biological and cognitive- emotive state art of science, it is often a neglected field in medicine. In regard to the treatment, study on women's sexual function received less attention compared to the men's sexuality. In the past, this endeavor was relatively not well disseminated in the scientific community. Recently, there was a revolutionized surge of drug targets available to treat women with low sexual desire. It is timely to review the relevant biological approach, especially in the context of pharmacotherapy to understand this interesting clinical entity which was modulated by numerous interactive psychosocial inter-play and factors. The complex inter-play between numerous dimensional factors lends insights to understand the neural mechanism, i.e. the rewards centre pathway and its interaction with external psychosocialstimulus, e.g. relationship or other meaningful life events. The function of hormones, e.g. oxytocin or testosterone regulation was described. The role of neurotransmitters as reflected by the introduction of a molecule of flibenserin, a full agonist of the 5-HT1A and partial agonist of the D4 to treat premenopausal women with low sexual desire was deliberated. Based on this fundamental scientific core knowledge, we suggest an outline on know-how of introduction for sex therapy (i.e. "inner-self" and "outer-self") where the role of partner is narrated. Then, we also highlighted on the use of pharmacological agent as an adjunct scope of therapy, i.e. phosphodiasterase-5 (PDE-5) inhibitors and hormonal treatment in helping the patient with low sexual desire.
    Matched MeSH terms: Neurotransmitter Agents/pharmacology; Neurotransmitter Agents/therapeutic use
  18. Fulltext Embelin Protects Against Acute Pentylenetetrazole-Induced Seizures and Positively Modulates Cognitive Function in Adult Zebrafish
    Kundap UP, Choo BKM, Kumari Y, Ahmed N, Othman IB, Shaikh MF
    Front Pharmacol, 2019;10:1249.
    PMID: 31708779 DOI: 10.3389/fphar.2019.01249
    Purpose of the research: Epilepsy is a continuous process of neurodegeneration categorized by an enduring tendency to generate uncontrolled electrical firing known as seizures causing involuntary movement all over the body. Cognitive impairment and behavioral disturbances are among the more alarming co-morbidities of epilepsy. Anti-epileptic drugs (AEDs) were found to be successful in controlling epilepsy but are reported to worsen cognitive status in patients. Embelin (EMB) is a benzoquinone derived from the plant Embelia ribes and is reported to have central nervous system (CNS) activity. This study aims to evaluate the effectiveness of EMB against pentylenetetrazole (PTZ) induced acute seizures and its associated cognitive dysfunction. This was done via docking studies as well as evaluating neurotransmitter and gene expression in the zebrafish brain. The principal results: Behavioral observations showed that EMB reduced epileptic seizures and the T-maze study revealed that EMB improved the cognitive function of the fish. The docking study of EMB showed a higher affinity toward gamma-aminobutyric acid (GABAA) receptor as compared to the standard diazepam, raising the possibility of EMB working via the alpha subunit of the GABA receptor. EMB was found to modulate several genes, neurotransmitters, and also neuronal growth, all of which play an important role in improving cognitive status after epileptic seizures. Healthy zebrafish treated with EMB alone were found to have no behavioral and biochemical interference or side effects. The immunohistochemistry data suggested that EMB also promotes neuronal protection and neuronal migration in zebrafish brains. Major Conclusions: It was perceived that EMB suppresses seizure-like behavior via GABAA receptor pathway and has a positive impact on cognitive functions. The observed effect was supported by docking study, T-maze behavior, neurotransmitter and gene expression levels, and immunohistology study. The apparatus such as the T-maze and seizure scoring behavior tank were found to be a straightforward technique to score seizure and test learning ability after acute epileptic seizures. These research findings suggest that EMB could be a promising molecule for epilepsy induced learning and memory dysfunction.
    Matched MeSH terms: Neurotransmitter Agents
  19. Fulltext Review on Cross Talk between Neurotransmitters and Neuroinflammation in Striatum and Cerebellum in the Mediation of Motor Behaviour
    Abg Abd Wahab DY, Gau CH, Zakaria R, Muthu Karuppan MK, A-Rahbi BS, Abdullah Z, et al.
    Biomed Res Int, 2019;2019:1767203.
    PMID: 31815123 DOI: 10.1155/2019/1767203
    Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1β, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.
    Matched MeSH terms: Neurotransmitter Agents/pharmacology*
  20. Fulltext Heat stress modifies the lactational performances and the urinary metabolomic profile related to gastrointestinal microbiota of dairy goats
    Contreras-Jodar A, Nayan NH, Hamzaoui S, Caja G, Salama AAK
    PLoS One, 2019;14(2):e0202457.
    PMID: 30735497 DOI: 10.1371/journal.pone.0202457
    The aim of the study is to identify the candidate biomarkers of heat stress (HS) in the urine of lactating dairy goats through the application of proton Nuclear Magnetic Resonance (1H NMR)-based metabolomic analysis. Dairy does (n = 16) in mid-lactation were submitted to thermal neutral (TN; indoors; 15 to 20°C; 40 to 45% humidity) or HS (climatic chamber; 37°C day, 30°C night; 40% humidity) conditions according to a crossover design (2 periods of 21 days). Thermophysiological traits and lactational performances were recorded and milk composition analyzed during each period. Urine samples were collected at day 15 of each period for 1H NMR spectroscopy analysis. Principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) assessment with cross validation were used to identify the goat urinary metabolome from the Human Metabolome Data Base. HS increased rectal temperature (1.2°C), respiratory rate (3.5-fold) and water intake (74%), but decreased feed intake (35%) and body weight (5%) of the lactating does. No differences were detected in milk yield, but HS decreased the milk contents of fat (9%), protein (16%) and lactose (5%). Metabolomics allowed separating TN and HS urinary clusters by PLS-DA. Most discriminating metabolites were hippurate and other phenylalanine (Phe) derivative compounds, which increased in HS vs. TN does. The greater excretion of these gut-derived toxic compounds indicated that HS induced a harmful gastrointestinal microbiota overgrowth, which should have sequestered aromatic amino acids for their metabolism and decreased the synthesis of neurotransmitters and thyroid hormones, with a negative impact on milk yield and composition. In conclusion, HS markedly changed the thermophysiological traits and lactational performances of dairy goats, which were translated into their urinary metabolomic profile through the presence of gut-derived toxic compounds. Hippurate and other Phe-derivative compounds are suggested as urinary biomarkers to detect heat-stressed dairy animals in practice.
    Matched MeSH terms: Neurotransmitter Agents
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