DOPAC Research Articles

Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA‑Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA‑Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high‑performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA‑Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose‑dependent increase in extracellular levels of DA, 3‑methoxytyramine (3‑MT), and homovanillic acid (HVA), where only 0.5 mM COA‑Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA‑Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA‑Cl (0.1 mM) to test whether COA‑Cl‑induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3‑MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA‑Cl, clorgyline increased 3‑MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA‑Cl suggests that some DA was further metabolized into DOPAC, 3‑MT, and HVA. This indicates that COA‑Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA‑Cl on DA metabolism in the brain.

Loss of ON-Pathway Function in Mice Lacking Lrit3 Decreases Recovery From Lens-Induced Myopia.

To determine whether the Lrit3-/- mouse model of complete congenital stationary night blindness with an ON-pathway defect harbors myopic features and whether the genetic defect influences the recovery from lens-induced myopia. Retinal levels of dopamine (DA) and 3,4 dihydroxyphenylacetic acid (DOPAC) from adult isolated Lrit3-/- retinas were quantified using ultra performance liquid chromatography after light adaptation. Natural refractive development of Lrit3-/- mice was measured from three weeks to nine weeks of age using an infrared photorefractometer. Susceptibility to myopia induction was assessed using a lens-induced myopia protocol with -25 D lenses placed in front of the right eye of the animals for three weeks; the mean interocular shift was measured with an infrared photorefractometer after two and three weeks of goggling and after one and two weeks after removal of goggles. Compared to wild-type littermates (Lrit3+/+), both DA and DOPAC were drastically reduced in Lrit3-/- retinas. Natural refractive development was normal but Lrit3-/- mice showed a higher myopic shift and a lower ability to recover from induced myopia. Our data consolidate the link between ON pathway defect altered dopaminergic signaling and myopia. We document for the first time the role of ON pathway on the recovery from myopia induction.

Dynamic quantitative monitoring of cerebrospinal fluid monoamine neurotransmitter markers during the modeling process of chronic stress-induced depression in monkeys (Macaca mulatta).

Depression is known as the "mental cold" and is also considered a major cause of disability worldwide. It is estimated that over 300 million people worldwide suffer from severe depression, equivalent to 4.4% of the world's population. The monoamine hypothesis of depression predicts the underlying pathophysiological mechanisms of depression, but in-depth research has failed to find convincing evidence. In this study, we will dynamically and strictly quantitatively monitor the concentration changes of monoamine transmitters in the cerebrospinal fluid (CSF) of macaques, based on our previous work. In the experiment, timed and quantitative collection of CSF samples from macaques was performed and the concentration of monoamine transmitters was determined. The results showed that after 2 months of chronic stress, the concentrations of high vanillin acid (HVA) and 3,4-dihydroxy-phenylacetic acid were significantly higher in the maternal separation (MS) group, whereas there was no significant difference in dopamine and 5-hydroxyindoleacetic acid. This study is the first to observe the long-term dynamic relationship between early adversity, chronic stress, adolescent depression, and CSF monoamine concentrations. The research suggests that MS and chronic stress play an undeniable role in the pathogenesis of depression and that concentrations of HVA and dihydroxyphenylacetic acid are likely to serve as early markers of depressive-like symptoms in macaques.

The effects of Nardosinone on levodopa intervention in the treatment of Parkinson's disease

BackgroundThe roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD. Aim of the studyTo investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora. Material and methodsWe used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora. ResultsThe behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified. ConclusionOur findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD.

Response of nitrergic system in the brain of rat conditioned to intracranial self-stimulation.

The role of nitrergic system in modulating the action of psychostimulants on reward processing is well established. However, the relevant anatomical underpinnings and scope of the involved interactions with mesolimbic dopaminergic system have not been clarified. Using immunohistochemistry, we track the changes in neuronal nitric oxide synthase (nNOS) containing cell groups in the animals conditioned to intracranial self-stimulation (ICSS) via an electrode implanted in the lateral hypothalamus-medial forebrain bundle (LH-MFB) area. An increase in the nNOS immunoreactivity was noticed in the cells and fibers in the ventral tegmental area (VTA) and nucleus accumbens shell (AcbSh), the primary loci of the reward system. In addition, nNOS was up-regulated in the nucleus accumbens core (AcbC), vertical limb of diagonal band (VDB), locus coeruleus (LC), lateral hypothalamus (LH), superficial gray layer (SuG) of the superior colliculus, and periaqueductal gray (PAG). The brain tissue fragments drawn from these areas showed a change in nNOS mRNA expression, but in opposite direction. Intracerebroventricular (icv) administration of nNOS inhibitor, 7-nitroindazole (7-NI) showed decreased lever press activity in a dose-dependent manner in ICSS task. While an increase in the dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysates collected from the AcbSh of ICSS rats, pre-administration of 7-NI (icv route) attenuated the response. The study identifies nitrergic centers that probably mediate sensory, cognitive, and motor components of the goal-directed behavior.

CYP1B1 affects the integrity of the blood-brain barrier and oxidative stress in the striatum: An investigation of manganese-induced neurotoxicity.

Excessive influx of manganese (Mn) into the brain across the blood-brain barrier induces neurodegeneration. CYP1B1 is involved in the metabolism of arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate the effect of brain CYP1B1 on Mn-induced neurotoxicity. Brain Mn concentrations and α-synuclein accumulation were measured in wild-type and CYP1B1 knockout mice treated with MnCl2 (30 mg/kg) and biotin (0.2 g/kg) for 21 continuous days. Tight junctions and oxidative stress were analyzed in hCMEC/D3 and SH-SY5Y cells after the treatment with MnCl2 (200 μM) and CYP1B1-derived AA metabolites (HETEs and EETs). Mn exposure inhibited brain CYP1B1, and CYP1B1 deficiency increased brain Mn concentrations and accelerated α-synuclein deposition in the striatum. CYP1B1 deficiency disrupted the integrity of the blood-brain barrier (BBB) and increased the ratio of 3, 4-dihydroxyphenylacetic acid (DOPAC) to dopamine in the striatum. HETEs attenuated Mn-induced inhibition of tight junctions by activating PPARγ in endothelial cells. Additionally, EETs attenuated Mn-induced up-regulation of the KLF/MAO-B axis and down-regulation of NRF2 in neuronal cells. Biotin up-regulated brain CYP1B1 and reduced Mn-induced neurotoxicity in mice. Brain CYP1B1 plays a critical role in both cerebrovascular and dopamine homeostasis, which might serve as a novel therapeutic target for the prevention of Mn-induced neurotoxicity.

Biosynthesis of Cytosporones in Leotiomycetous Filamentous Fungi.

Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di- or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4-diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of "unnatural" natural products for drug discovery.

HIV-1 Tat and morphine interactions dynamically shift striatal monoamine levels and exploratory behaviors over time.

Despite the advent of combination anti-retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV-associated neurocognitive disorders (HAND). HAND can be worsened by co-morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV-1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co-exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co-exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety-like, novelty-seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase-positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context-dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty-seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time-dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV-1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.

Dysfunction of neurotransmitter metabolism is associated with the severity of depression in first-diagnosed, drug-naïve depressed patients

Background & aimsBiochemical changes of neurotransmitters underlying major depressive disorder (MDD) are unknown. This study preliminarily explored the association between neurotransmitters with MDD and the possibility of objective laboratory prediction of neurotransmitter involvement in MDD. MethodsA total of 87 first-diagnosed, drug-naïve patients with depression and 50 healthy controls (HCs) were included in the cross-sectional study. The levels and turnovers of neurotransmitters (glutamine (GLN), glutamic acid (GLU), γ-2Aminobutiric acid (GABA), kainate (KA), vanillylmandelic acid (VMA), 3-methoxy 4-hydroxyphenyl ethylene glycol (MHPG), noradrenaline (NE), homovanillic acid (HVA), dihydroxy-phenyl acetic acid (DOPAC), dopamine (DA), tryptophane (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA)) were determined and the confounding factors were adjusted. Then a correlation and a predictive analysis towards neurotransmitters for MDD were performed. ResultsAfter adjusting confounding factors, GLU (OR = 1.159), (GLU+ GABA)/GLN (OR = 1.217), DOPAC (OR = 1.106), DOPAC/DA (OR = 1.089) and (DOPAC+ HVA)/DA (OR = 1.026) enacted as risk factors of MDD, while KYN (OR = 0.992) was a protective factor. GABAergic and TRPergic pathways were associated with severity of depressive and anxiety symptoms in patients with depression. The predictive model for MDD (AUC = 0.775, 95%CI 0.683–0.860) consisted of KYN (OR = 0.990) and (GLU + GABA)/GLN (OR = 4.101). ConclusionsFirst-diagnosed, drug-naïve depression patients showed abnormal neurotransmitter composition. GLU, (GLU + GABA)/GLN, DOPAC, DOPAC/DA and (DOPAC + HVA)/DA were risk factors of MDD, while KYN was a protective factor. GABAergic and TRPergic pathways were correlated with MDD clinical characteristics. KYN and (GLU + GABA)/GLN may have a predictive value for MDD.

Olive oil tyrosols reduce α-synuclein aggregation in vitro and in vivo after ingestion in a Caenorhabditis elegans Parkinson's model.

Parkinson's disease is the neurodegenerative motor disorder with the highest incidence worldwide. Among other factors, Parkinson's disease is caused by the accumulation of α-synuclein aggregates in a patient's brain. In this work, five molecules present in the diet are proposed as possible nutraceuticals to prevent and/or reduce the formation of α-synuclein oligomers that lead to Parkinson's disease. The olive oil polyphenols tyrosol, hydroxytyrosol (HT), hydroxytyrosol acetate (HTA) and dihydroxyphenyl acetic acid (DOPAC) besides vitamin C were tested using a cellular model of α-synuclein aggregation and a Caenorhabditis elegans Parkinson's disease animal model. Levodopa was included in the assays as the main drug prescribed to treat the disease as well as dopamine, its direct metabolite. HTA and DOPAC completely hindered α-synuclein aggregation in vitro, while dopamine reduced the aggregation by 28.7%. The Parallel Artificial Membrane Permeability Assay (PAMPA) showed that HTA had the highest permeability through brain lipids among the compounds tested. Furthermore, the C. elegans Parkinson's disease model made it possible to assess the chosen compounds in vivo. The more effective substances in vivo were DOPAC and HTA which reduced the αS aggregation inside the animals by 79.2% and 76.2%, respectively. Moreover, dopamine also reduced the aggregates by 67.4% in the in vivo experiment. Thus, the results reveal the potential of olive oil tyrosols as nutraceuticals against α-synuclein aggregation.

Anti-inflammatory activity of β-glucans from different sources before and after fermentation by fecal bacteria in vitro.

β-Glucans are widely sourced and have various physiological effects, including anti-inflammatory effects. However, the strength of the anti-inflammatory activity of β-glucans from different sources remains unknown due to the lack of rapid and effective biomarkers. This study therefore aimed to screen out the β-glucans with strong anti-inflammatory activity from five different sources and to further screen out possible biomarkers in metabolites after fermenting the β-glucans with gut microorganisms. The results showed that all five β-glucans inhibited the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators and suppressed the mRNA expression level of TLR4/MyD88. Their anti-inflammatory mechanisms involved the inhibition of intracellular reactive oxygen species (ROS) production and suppression of mRNA expression of the NF-κB pathway and JNK pathway. Among them, barley β-glucan exhibited the strongest anti-inflammatory effect, followed by Ganoderma lucidum β-glucan. Enhanced anti-inflammatory activity of β-glucan was found after fermentation and may be related to the increased abundance of metabolites such as vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid. They were strongly positively correlated to the abundance of beneficial bacteria such as Blautia, suggesting that the production of those metabolites may be responsible for the flourishing of the beneficial bacteria. In conclusion, barley was a preferred raw material for the preparation of β-glucans with strong anti-inflammatory activity. Vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid were the possible biomarkers that could be utilized to evaluate the anti-inflammatory effect of β-glucans. © 2023 Society of Chemical Industry.

The Development and Full Validation of a Novel Liquid Chromatography Electrochemical Detection Method for Simultaneous Determination of Nine Catecholamines in Rat Brain.

Chemical neurotransmission, managed by neurotransmitters, has a crucial role in brain processes such as fear, memory, learning, and pain, or neuropathology such as schizophrenia, epilepsy, anxiety/depression, and Parkinson's disease. The measurement of these compounds is used to elucidate the disease mechanisms and evaluate the outcomes of therapeutic interventions. However, this can be quite difficult because of various matrix effects and the problems of chromatographic separation of analysts. In the current study; for the first time, an optimized and fully validated high-performance liquid chromatography-electrochemical detection (HPLC-EC) method according to Food and Drug Administration and European Medicines Agency Bioanalytical Validation Guidance was developed for the simultaneous analysis of nine neurotransmitter compounds, namely dopamine, homovanilic acid, vanilmandelic acid, serotonin (SER), 5-hydroxyindole-3-acetic acid, 4-hydroxy-3-methoxyphenylglycol, norepinephrine, 3,4 dihydroxyphenylacetic acid, and 3-methoxytyramine and simultaneously determined in rat brain samples. Separation was achieved with 150 mm x 4.6 mm, 2.6 μm Kinetex F5 (Phenomenex, USA) column isocratically, and analysis was carried out by HPLC equipped with a DECADE II EC detector. The method exhibited good selectivity, and the correlation coefficient values for each analyte's calibration curves were > 0.99. The detection and quantification limits ranged from 0.01 to 0.03 ng/mL and 3.04 to 9.13 ng/mL, respectively. The stability of the analyses and method robustness were also examined in detail in the study, and the obtained results are presented statistically. The developed and fully validated method has been successfully applied to actual rat brain samples, and important results have been obtained. In the rat brain sample analysis, the lowest number of SER and the highest amount of noradrenaline were found.

Neurochemical Effects of Methylphenidate and Modafinil in Ameliorating Stress-Induced Cognitive Deficits.

Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory and attention. Stimulant effects can be visualized in terms of increased cognitive abilities through enhancement of dopamine (DA) release. This study examined cognitive responses and brain DA and 5-hydroxytryptamine (5HT) levels after prolonged methylphenidate (MPH) and modafinil administration, to demonstrate their effect on stress-induced cognitive deficits in rats. Effects on cognition were evaluated by passive avoidance and water maze tests. Furthermore brain levels of DA, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5HT and 5-hydroxyindoleacetic acid (5HIAA) were analyzed by high-performance liquid chromatography coupled with electrochemical detection. We found that both MPH and modafinil improved cognition in both restrained and unrestrained rats, as examined through water maze and passive avoidance tests. Furthermore, these substance were associated with increased brain DA and 5-HT levels. Notabily, we observed decrease in DOPAC and HVA levels, while 5-HIAA levels exhibited a slight increase. The prevention of stress-induced cognitive deficits by MPH and modafinil could be elucidated through the interaction between 5HT and DA in regulating cognitive function.

Analysis of Targeted Therapy of Parkinson’s Disease with Coloaded Nanoparticles

The key to the treatment of Parkinson’s disease (PD) is delivering an effective amount of drugs into the brain to work, and supplementing the missing dopamine (Dop) in the brain is still the most effective treatment currently. In this research, borneol (Bor) was utilized to promote the drug to enter the brain through the nasal cavity, and lactoferrin (Lf) was utilized as the targeting molecule to modify the nanoparticles (NPs) so that they entered the brain and focused on the lesion site of PD to achieve targeting. They were then evaluated in vivo and in vitro, thus providing the basis for the development of the Lac-Bor/Dop NPs in PD therapy. In the experiment, the particle size of Lac-Bor/Dop NPs prepared by the optimal prescription process was 163.7±15.6 nm, the Dop drug loading was (7.86±1.68) %, and the Zeta potential was (−21.36±3.34) mV. The in vitro release confirmed that the Lac-Bor/Dop NPs had good sustained release characteristics in PBS medium. The cytotoxicity and uptake experiments confirmed that the cytotoxicity of Dop encapsulated in NPs was markedly inferior to that of free Dop (P <0.05). For SH-SY5Y cells and 16HBE cells, Bor and Lf co-modified NPs can promote cell uptake. In vivo animal imaging counts confirmed that the coloaded NPs were capable of synergistic nasal drug delivery to the brain for better brain targeting. Furthermore, a PD model induced by dopaminergic neuron injury induced by unilateral striatal injection of 6-OHDA was constructed in rats and assigned into various groups to demonstrate the therapeutic effect of NPs on PD rats. The results revealed that relative to other groups, the contralateral rotations of rats in the Lac-Bor/Dop NP group were decreased drastically after 20 days of administration (P <0.01), and the levels of Dop and dihydroxyphenylacetic acid (DOPAC) in the injured striatum were increased markedly (P <0.01), demonstrating that the delivery system could achieve excellent PD therapy effects after nasal administration.

Microbial phenolic metabolites 3-(3′,4′-dihydroxyphenyl)propanoic acid and 3′,4′-dihydroxyphenylacetic acid prevent obesity in mice fed with high-fat diet

Obesity is associated with numerous metabolic disorders, and dietary polyphenols have been confirmed to have beneficial effects on the metabolism in obesity. However, the effect of 3-(3′,4′-dihydroxyphenyl)propanoic acid (DHPA) and 3′,4′-dihydroxyphenylacetic acid (DHAA), two main metabolites of dietary polyphenols, on obesity remains poorly understood. In this study, DHPA and DHAA were found to alleviate obesity, as well as regulate insulin resistance, lipid metabolism, and oxidative stress response in high-fat diet (HFD) mice. Surprisingly, the 16S rRNA sequencing and UHPLC-Q-TOF/MS demonstrated that DHPA and DHAA only slightly disturbed the intestinal microbiome, but significantly altered the urine metabolome of HFD mice mainly by regulating pentose and glucuronate interconversion, tyrosine metabolism, pentose phosphate and tricarboxylic acid (TCA) cycle as indicated by metabolic pathway analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Correlation analysis revealed that the differential metabolites are strongly associated with body weight, blood glucose, insulin level, and superoxide dismutase (SOD) enzyme activity. Our results revealed that DHPA and DHAA exert their anti-obesity effect by regulating important metabolites in the glucose, lipid and tyrosine metabolism pathways.

Benzoic-D5 acid as D2 receptor agonist in the treatment of rotenone induced Parkinson’s disease in mice

Parkinson's disease is a progressive neurological disorder that affects movement. It is caused by the degeneration of dopamine-producing neurons in the brain. There is no cure for Parkinson's disease, but there are treatments available that can help manage the symptoms. Medications such as levodopa, dopamine agonists and Amantadine (Amd) can help to increase dopamine levels in the brain. Sodium benzoate (Benzoic-D5) is used as preservative in foods due to its antimicrobial potential. Benzoic-D5 showed a pivotal role in ameliorating the symptoms of Parkinson’s disease (PkD) in animal model. The current study is designed to probe the anti-Parkinson potential of Benzoic-D5 in the rotenone (ROT)-induced PkD mice. Behavioral studies showed improvement in sensory-motor functions, and neuromuscular strength in wire hanging test, grip strength, vertical rod test, and swim test. Evaluation of biochemical markers suggested increase in catalase (CAT) and superoxide dismutase (SOD), but decreases in the malondialdehyde (MDA) activity. Dopamine, dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) levels were improved in Benzoic-D5-treated animals. Moreover, there were down regulation of pro-inflammatory markers like TNF-α, NF-Kβ, and up regulation of anti-inflammatory IL-4 in the RT-PCR analysis. In molecular docking Benzoic-D5 showed strong binding affinity with an active site of Dopamine D2 receptor. Afterwards, ADMET analysis points to the selected drug’s acceptable properties. Conclusively, in vivo, and in silico studies propose that Benzoic-D5 possesses potentials to ameliorate symptoms of PkD. Binding energy data of Benzoic-D5 (-6.2), shows promising results compared to ROT (-6.0), and Amd (5.8).

ЭФФЕКТЫ ВОЗДЕЙСТВИЯ ХРОНИЧЕСКОЙ АЛКОГОЛИЗАЦИИ И ГИПОДИНАМИИ НА ПОКАЗАТЕЛИ ДОФАМИНЕРГИЧЕСКОЙ СИСТЕМЫ НЕКОТОРЫХ ОТДЕЛОВ ГОЛОВНОГО МОЗГА КРЫС

Purpose of work. To determine the nature of changes in the content of dopamine and its metabolites in the cerebral cortex, hypothalamus and cerebellum of rats with chronic alcohol intoxication (CAI) against the background of physical inactivity (PI). Material and methods. The experiments were carried out on outbred white male rats weighing 180-220 g. Modeling of PI was carried out by placing rats in individual cages-pencil cases, limiting their mobility, for periods of 14 and 28 days. To simulate CAI, the animals were provided with an ethanol solution as the only source of fluid for 14 and 28 days. Determination of the content of the components of the dopaminergic system (tyrosine, 3,4-dioxyphenylalanine, dopamine, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and norepinephrine) was carried out using ion-pair high-performance liquid chromatography. Results. PI for 14 days is accompanied by signs of activation of the dopaminergic system in the hypothalamus and cerebral cortex of rats. With CAI for a period of 28 days, there are signs of a decrease in the activity of the dopaminergic system in the cerebral cortex. The combined effect of PI and CAI for 14 and 28 days leads to an increase in dopamine turnover in the cerebral cortex of rats. Conclusions. With the combined effect of CAI and PI, the most pronounced changes are observed in the cerebral cortex and are accompanied on the 14th day by an increase in the levels of HVA and DOPAC, and on the 28th day by an increase in the concentration of HVA.

Effects of artificial light with different spectral composition on eye axial growth in juvenile guinea pigs.

The purpose of the study was to investigate the effect of artificial light with different spectral composition and distribution on axial growth in guinea pigs. Three-week-old guinea pigs were randomly assigned to groupsexposed to natural light, low color temperature light-emitting diode (LED) light, two full spectrum artificial lights (E light and Julia light) and blue light filtered light with the same intensity. Axial lengths of guinea pigs'eyes were measured by A-scan ultrasonography prior to the experiment and every 2 weeks during the experiment. After light exposure for 12 weeks, retinal dopamine (DA), dihydroxy-phenylacetic acid (DOPAC) levelsand DOPAC/DA ratio were analyzed by high-pressure liquid chromatography electrochemical detection and retinal histological structure was observed. Retinal melanopsin expression was detected using Western blot andimmunohistochemistry. After exposed to different kinds of light with different spectrum for 4 weeks, the axial lengths of guinea pigs' eyes in LED group and Julia light group were significantly longer than those of naturallight group. After 6 weeks, the axial lengths in LED light group were significantly longer than those of E light group and blue light filtered group. The difference between axial lengths in E light group and Julia light groupshowed statistical significance after 8 weeks (p<0.05). After 12 weeks of light exposure, the comparison of retinal DOPAC/DA ratio and melanopsin expression in each group was consistent with that of axial length. Inguinea pigs, continuous full spectrum artificial light with no peak or valley can inhibit axial elongation via retinal dopaminergic and melanopsin system.

Barbigerone Potentially Alleviates Rotenone-Activated Parkinson's Disease in a Rodent Model by Reducing Oxidative Stress and Neuroinflammatory Cytokines.

Parkinson's disease (PD) is a common age-related and slowly progressive neurodegenerative disease that affects approximately 1% of the elderly population. In recent years, phytocomponents have aroused considerable interest in the research for PD treatment as they provide a plethora of active compounds including antioxidant and anti-inflammatory compounds. Herein, we aimed to investigate the anti-Parkinson's effect of barbigerone, a natural pyranoisoflavone possessing antioxidant activity in a rotenone-induced rat model of PD. To evaluate antioxidant activity, a 0.5 mg/kg dose of rotenone was injected subcutaneously into rats. Barbigerone (10 and 20 mg/kg) was administered to rats for 28 days 1 h prior to rotenone. All behavioral parameters were assessed before sacrificing the rats. On the 29th day, all of the rats were humanely killed and assessed for biochemical changes in antioxidant enzymes (superoxide dismutase, glutathione, malondialdehyde, and catalase), neurotransmitter levels (dopamine, 5-hydroxyindoleacetic acid, serotonin, dihydroxyphenylacetic acid, and homovanillic acid levels), and neuroinflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor-α, nuclear factor kappa B, and IL-6]. The data presented in this study has shown that barbigerone attenuated rotenone-induced motor deficits including the rotarod test, catalepsy, akinesia, and open-field test. Additionally, barbigerone has shown improvements in the biochemical and neuroinflammatory parameters in the rotenone-induced rat model of PD. The results demonstrated that barbigerone exhibits antioxidant and anti-inflammatory actions via reducing oxidative stress and inflammatory cytokines. Altogether, these findings suggest that barbigerone could potentially be utilized as a therapeutic agent against PD.

Analysis of Intestinal Metabolites in SR-B1 Knockout Mice via Ultra-Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry.

Scavenger receptor class B type 1 (SR-B1), a multiligand membrane receptor, is expressed in a gradient along the gastrocolic axis. SR-B1 deficiency enhances lymphocyte proliferation and elevates inflammatory cytokine production in macrophages. However, whether SR-B1 affects intestinal metabolites is unclear. In this study, we detected metabolite changes in the intestinal tissue of SR-B1-/- mice, including amino acids and neurotransmitters, by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) and HPLC. We found that SR-B1-/- mice exhibited changes in intestinal lipid metabolites and metabolic pathways, including the glycerophospholipid, sphingolipid, linoleic acid, taurine, and hypotaurine metabolic pathways. SR-B1 deficiency influenced the contents of amino acids and neurotransmitters in all parts of the intestine; the contents of leucine (LEU), phenylalanine (PHE), tryptophan (TRP), and tyrosine (TYR) were affected in all parts of the intestine; and the contents of 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) were significantly decreased in both the colon and rectum. In summary, SR-B1 deficiency regulated intestinal lipids, amino acids, and neurotransmitter metabolism in mice.