Dopamine Metabolism Research Articles

Combating Parkinson's disease with plant-derived polyphenols: Targeting oxidative stress and neuroinflammation

Parkinson's disease (PD) is a devastating neurodegenerative disorder predominantly affecting the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra. Reactive oxygen species (ROS) generation plays a central role in the pathogenesis of PD and other neurodegenerative diseases. An imbalance between cellular antioxidant activity and ROS production leads to oxidative stress, contributing to disease progression. Dopamine metabolism, mitochondrial dysfunction, and neuroinflammation in dopaminergic neurons have been implicated in the pathogenesis of Parkinson's disease. Consequently, there is a pressing need for therapeutic interventions capable of scavenging ROS. Current pharmacological approaches, such as L-dihydroxyphenylalanine (levodopa or L-DOPA) and other drugs, provide symptomatic relief but are limited by severe side effects. Researchers worldwide have been exploring alternative compounds with less toxicity to address the multifaceted challenges associated with Parkinson's disease. In recent years, plant-derived polyphenolic compounds have gained significant attention as potential therapeutic agents. These compounds exhibit neuroprotective effects by targeting pathophysiological responses, including oxidative stress and neuroinflammation, in Parkinson's disease. The objective of this review is to summarize the current understanding of the neuroprotective effects of various polyphenols in Parkinson's disease, focusing on their antioxidant and anti-inflammatory properties, and to discuss their potential as therapeutic candidates. This review highlights the progress made in elucidating the molecular mechanisms of action of these polyphenols, identifying potential therapeutic targets, and optimizing their delivery and bioavailability. Well-designed clinical trials are necessary to establish the efficacy and safety of polyphenol-based interventions in the management of Parkinson's disease.

Caste-specific development of the dopaminergic system in bumble bees (Bombus ignitus)

The dopaminergic system is involved in caste-specific behaviors in eusocial bumble bees. However, little is known about how the caste differences in dopaminergic system are formed during pupal stages in the brains of bumble bees. Thus, we investigated the levels of dopamine-related substances and expression of genes encoding enzymes involved in dopamine synthesis and metabolism, dopamine receptors, and a dopamine transporter in the brain of female Bombus ignitus. The levels of dopamine and dopamine-related substances in the brain were significantly higher in gynes than in workers from the late pupal stage to emergence, but the dynamics were similar between the castes. The relative expression levels of genes encoding enzymes involved in dopamine synthesis (BigTh and BigDdc) and dopamine metabolism (BigNat) increased significantly from pupal stage to emergence, but there were no differences in the relative expression levels of these genes between castes. A similar pattern was seen in the relative expression levels of four dopamine receptor genes (BigDop1, BigDop2, BigDop3, and BigDopEcR) and a dopamine transporter gene (BigDat). Compared with the honey bee Apis mellifera, the caste-specific dopaminergic system in the bumble bee is less differentiated, which might reflect the degree of behavioral specialization in these two species.

Effects of unilateral cortical inactivation on monoamine metabolism in symmetrical forebrain areas of white outbred mice

BACKGROUND: Clinical observations and animal experiments have shown the lateral specificity of the action of compounds that alter monoaminergic transmission. However, the mechanism of this phenomenon has not yet been studied.AIM:To evaluate the effect of unilateral cortical spreading depression on monoamine metabolism in white outbred mice. MATERIALS AND METHODS:Eighteen sexually mature male white outbred mice were studied. Functional inactivation of the cortex of one of the cerebral hemispheres was induced using unilateral epidural application of 1 × 1 mm filter paper moistened with 25% KCl solution. Then, 15 minutes after exposure, the animals were decapitated. The norepinephrine, dopamine, serotonin, and metabolite (i.e., dioxyphenylacetic (DOPAC), homovanilinic (HVA), and 5-hydroxyindolacetic (5-HIAA) acids) content of the cerebral cortex, hippocampus, olfactory tubercle, and striatum was measured using the HPLC method with an electrochemical detector. RESULTS: The inactivation of the left hemisphere was due to a bilateral decrease in norepinephrine in the hippocampus, an ipsilateral increase in extracellular metabolism of dopamine (HVA and/or HVA/dopamine) in the olfactory tubercle and striatum, and a contralateral increase of dopamine in the cortex and hippocampus. Furthermore, the DOPAC/dopamine ratio in the right olfactory tubercle decreased with left hemisphere inactivation. Right hemisphere inactivation did not cause bilateral effects. With inactivation of the right hemisphere on the inactivation side, norepinephrine in the hippocampus decreased and HVA in the striatum increased. In the left side, with the inactivation of the right hemisphere mice, dopamine in the hippocampus increased, as well as the DOPAC level and DOPAC/dopamine ratio in the olfactory tubercle. Serotonin metabolism (5-HIAA/serotonin) in the right hippocampus and left olfactory tubercle increased only at inactivation of the right hemisphere.CONCLUSIONS:The monoaminergic effects of functional inactivation of the left and right hemisphere cortex in white outbred mice are not mirror-symmetrical.

Disulfiram Induced Psychosis in Patients Seeking Over the Counter Treatment

Disulfiram is a deterrent in the management of alcohol use associated with neuropsychiatric manifestations, of which psychosis is common. The postulated mechanism is being its metabolite diethyldithiocarbamate being an inhibitor of dopamine beta-hydroxylase (DBH), an enzyme that catalyses the metabolism of dopamine (DA) to norepinephrine (NE) which results in an increase of DA concentrations in mesolimbic system resulting in psychosis. Other mechanisms are also postulated, like direct CNS toxicity, free radical damage. Here, are the two cases that were dependent to opioid given disulfiram surreptitiously land up with psychosis. Keywords: Substance use disorders, Disulfiram, Psychosis, over the counter medicine

Citrobacter rodentium infection impairs dopamine metabolism and exacerbates the pathology of Parkinson’s disease in mice

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder with indistinct etiology and ill-defined pathophysiology. Intestinal inflammation involved in the pathogenesis of PD, but the underlying mechanism is not fully understood. Citrobacter rodentium (C.R) is a gram-negative bacterium that can be used to induce human inflammatory bowel disease in mice. Here, we investigated whether the proinflammatory effects caused by C.R infection initiate PD-like injury and/or exacerbate PD pathology and extensively studied the underlying mechanism. Mice were gavaged once with C.R and monitored for several pathological features at 9 days post infection. The results showed that C.R delivery in mice induced IBD-like symptoms, including significant weight loss, increased fecal water content, an impaired intestinal barrier, intestinal hyperpermeability and inflammation, and intestinal microbiota disturbances. Notably, C.R infection modified dopamine (DA) metabolism in the brains of both male and female mice. Subsequently, a single high dose of MPTP or normal saline was administered at 6 days post infection. At 3 days after MPTP administration, the feces were collected for 16 S rRNA analysis, and PD-like phenotypes and mechanisms were systemically analyzed. Compared with C.R or MPTP injection alone, the injection of C.R and MPTP combined worsened behavioral performance. Moreover, such combination triggered more severe dopaminergic degeneration and glial cell overactivation in the nigrostriatal pathway of mice. Mechanistically, the combination of C.R and MPTP increased the expression of TLR4 and NF-κB p65 in the colon and striatum and upregulated proinflammatory cytokine expression. Therefore, C.R infection-induced intestinal inflammation can impair dopamine metabolism and exacerbate PD pathological processes.

Approach to restless leg syndrome in hemodialysis patients

Restless legs syndrome (RLS) is an uncomfortable urge to move the legs while the person is at rest. This movement disorder is one of the problems that may develop in the follow-up of hemodialysis patients. It is important to recognize and treat these problems because they are closely related to mortality and morbidity. It is estimated that RLS symptoms occur in 3% of the adult population worldwide and in approximately 27% of hemodialysis patients. Although the pathophysiology of the disease and its relationship with its high prevalence in dialysis patients have not yet been clearly elucidated, it is predicted that pathologies such as central dopamine metabolism disorders, iron deficiency and uremia may underlie the disease. There are some pharmacological and non-pharmacological treatment methods developed based on available data. Current data in the literature regarding the effectiveness and superiority of these treatments are insufficient to clarify the treatment approach. Studies on the subject continue and the unknowns in treatment and pathophysiology are being clarified day by day.

Sleep disorders in chronic kidney disease.

Sleep disorders are highly prevalent in chronic kidney disease (CKD) but are often under-recognized. Restless legs syndrome, which is common in CKD owing to issues with dopamine metabolism and is exacerbated by iron deficiency and uraemia, can lead to poor sleep quality and increased daytime fatigue. Insomnia is also prevalent in CKD, particularly in patients requiring dialysis, with increased sleep latency and sleep fragmentation being reported. The cause of insomnia in CKD is multifactorial - poor sleep habits and frequent napping during dialysis, uraemia, medications and mood disorders have all been suggested as potential contributing factors. Sleep apnoea and CKD are also now recognized as having a bi-directional relationship. Sleep apnoea is a risk factor for accelerated progression of CKD, and fluid overload, which is associated with kidney failure, can lead to both obstructive and central sleep apnoea. The presence of obstructive sleep apnoea in CKD can exacerbate the already heightened cardiovascular morbidity and mortality in these patients, as well as leading to daytime fatigue and reduced quality of life. Increased awareness, timely diagnosis and appropriate therapeutic interventions are essential to reduce the negative impact of sleep disorders in patients with kidney disease.

Ultrastructural Changes of Neuroendocrine Pheochromocytoma Cell Line PC-12 Exposed In Vitro to Rotenone.

Rotenone is a pesticide used in research for its ability to induce changes similar, in vivo and in vitro, to those observed in Parkinson's disease (PD). This includes a selective death of dopaminergic neurons in the substantia nigra. Nonetheless, the precise mechanism through which rotenone modifies structure and function of neurons remains unclear. The PC12 cells closely resemble dopamine terminal neurons. This makes it a preferred model for studying the morphology of central dopamine neurons and predicting neurotoxicity. In this paper, we investigated the effects of 0.5 µM rotenone for 24-48 h on PC12 cell viability and ultrastructure (TEM), trying to identify primary and more evident alterations that can be related to neuronal damages similar to that seen in animal PD models. Cell viability decreased after 24 h rotenone treatment, with a further decrease after 48 h. Ultrastructural changes included vacuolar degeneration, mitochondrial mild swelling, decrease in the number of neuropeptide granules, and the loss of cell-to-cell adhesion. These findings are in agreement with previous research suggesting that rotenone, by inhibiting energy production and increasing ROS generation, is responsible for significant alterations of the ultrastructure and cell death of PC12 cells. Our data confirm the link between rotenone exposure, neuronal damage, and changes in dopamine metabolism, suggesting its role in the pathogenesis of PD.

Oxidative Stress and Neurodegeneration: Insights and Therapeutic Strategies for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative condition marked by the gradual deterioration of dopaminergic neurons in the substantia nigra. Oxidative stress has been identified as a key player in the development of PD in recent studies. In the first part, we discuss the sources of oxidative stress in PD, including mitochondrial dysfunction, dopamine metabolism, and neuroinflammation. This paper delves into the possibility of mitigating oxidative stress as a potential treatment approach for PD. In addition, we examine the hurdles and potential of antioxidant therapy, including the challenge of delivering antioxidants to the brain and the requirement for biomarkers to track oxidative stress in PD patients. However, even if antioxidant therapy holds promise, further investigation is needed to determine its efficacy and safety in PD treatment.

Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Nanoplastics aggravated TDCIPP-induced transgenerational developmental neurotoxicity in zebrafish depending on the involvement of the dopamine signaling pathway

Plastics pose a hazard to the environment. Although plastics have toxicity, microplastics (MPs) and nanoplastics (NPs) are capable of interacting with the rest pollutants in the environment, so they serve as the carriers and interact with organic pollutants to modulate their toxicity, thus resulting in unpredictable ecological risks. PS-NPs and TDCIPP were used expose from 2 h post-fertilization (hpf) to 150 days post-fertilization (dpf) to determine the bioaccumulation of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and its potential effects on neurodevelopment in F1 zebrafish (Danio rerio) offspring under the action of polystyrene nano plastics (PS-NPs). The exposure groups were assigned to TDCIPP (0, 0.4, 2 or 10 µg/L) alone group and the PS-NPs (100 µg/L) and TDCIPP co-exposed group. F1 embryos were collected and grown in clean water to 5 dpf post-fertilization. PS-NPs facilitated the bioaccumulation of TDCIPP in the gut, gill, head，gonad and liver of zebrafish in a sex-dependent manner and promoted the transfer of TDCIPP to their offspring, thus contributing to PS-NPs aggravated the inhibition of offspring development and neurobehavior of TDCIPP-induced. In comparison with TDCIPP exposure alone, the combination could notably down-regulate the levels of the dopamine neurotransmitter, whereas the levels of serotonin or acetylcholine were not notably different. This result was achieved probably because PS-NPs interfered with the TDCIPP neurotoxic response of zebrafish F1 offspring not through the serotonin or acetylcholine neurotransmitter pathway. The increased transfer of TDCIPP to the offspring under the action of PS-NPs increased TDCIPP-induced transgenerational developmental neurotoxicity, which was proven by a further up-regulation/down-regulation the key gene and protein expression related to dopamine synthesis, transport, and metabolism in F1 larvae, in contrast to TDCIPP exposure alone. The above findings suggested that dopaminergic signaling involvement could be conducive to the transgenerational neurodevelopmental toxicity of F1 larval upon parental early co-exposure to PS-NPs and TDCIPP.

Abstract LB280: Enhancing glioblastoma radiotherapy by COMT inhibition

Abstract There is an urgent unmet medical need to discover novel therapeutics to enhance the efficacy of glioma radiotherapy. Here we assessed the roles of catechol - o - methyltransferase COMT, a key enzyme in dopamine metabolism and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in glioma versus normal brain tissues. Inhibition of COMT by genetic knockout or FDA - approved COMT inhibitors significantly sensitized glioma cells to radiotherapy in vitro and murine glioma in vivo. Mechanistically, COMT inhibition in glioblastoma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral dsRNA sensing pathway and type I IFN response. Elevated type I IFNs stimulated microglial cells′ phagocytic capacity, enhancing radiotherapy efficacy. Because of the long - established safety record of the COMT inhibitors, our findings provide a solid rationale to evaluate them in combination with radiotherapy in glioma patients. Citation Format: Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-yuan Li. Enhancing glioblastoma radiotherapy by COMT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB280.

Interspecific grafting promotes poplar growth and drought resistance via regulating phytohormone signaling and secondary metabolic pathways

Populus cathayana (C) grafted onto P. deltoides (D) (C/D) can promote growth better than self-grafting (C/C and D/D). However, the mechanisms underlying growth and resistance to drought stress are not clear. In this study, we performed physiological and RNA-seq analysis on the different grafted combinations. It was found that C/D plants exhibited higher growth, net photosynthetic rate, IAA content and intrinsic water use efficiency (WUEi) than C/C and D/D plants under both well-watered and drought-stressed conditions. However, most growth, photosynthetic indices, and IAA content were decreased less in C/D, whereas ABA content, WUEi and root characteristics (e.g., root length, volume, surface area and vitality) were increased more in C/D than in other grafting combinations under drought-stressed conditions. Transcriptomic analysis revealed that the number of differentially expressed genes (DEGs) in leaves of C/D vs C/C (control, 181; drought, 121) was much lower than that in the roots of C/D vs D/D (control, 1639; drought, 1706), indicating that the rootstocks were more responsive to drought resistance. KEGG and GO functional enrichment analysis showed that the enhanced growth and drought resistance of C/D were mainly related to DEGs involved in the pathways of ABA and IAA signaling, and secondary metabolite biosynthesis, especially the pathways for lignin and dopamine synthesis and metabolism. Therefore, our results further demonstrated the dominant role of rootstock in drought resistance, and enriched our knowledge on the mechanism of how interspecific grafting enhanced the growth and drought resistance in poplar.

N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase

ABSTRACT Objectives Current treatments for Parkinson’s disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system. Methods SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson’s disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and α-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay. Results Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and α-synuclein. Conclusions Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model. Abbreviations DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson's disease in an Egyptian cohort.

Introduction: Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide. Given the complexity of PD etiology and the different metabolic derangements correlated to the disease, metabolomics profiling of patients is a helpful tool to identify patho-mechanistic pathways for the disease development. Dopamine metabolism has been the target of several previous studies, of which some have reported lower phenylalanine and tyrosine levels in PD patients compared to controls. Methods: In this study, we have collected plasma from 27 PD patients, 18 reference controls, and 8 high-risk controls to perform a metabolomic study using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results: Our findings revealed higher intensities of trans-cinnamate, a phenylalanine metabolite, in patients compared to reference controls. Thus, we hypothesize that phenylalanine metabolism has been shifted to produce trans-cinnamate via L-phenylalanine ammonia lyase (PAL), instead of producing tyrosine, a dopamine precursor, via phenylalanine hydroxylase (PAH). Discussion: Given that these metabolites are precursors to several other metabolic pathways, the intensities of many metabolites such as dopamine, norepinephrine, and 3-hydroxyanthranilic acid, which connects phenylalanine metabolism to that of tryptophan, have been altered. Consequently, and in respect to Metabolic Control Analysis (MCA) theory, the levels of tryptophan metabolites have also been altered. Some of these metabolites are tryptamine, melatonin, and nicotinamide. Thus, we assume that these alterations could contribute to the dopaminergic, adrenergic, and serotonergic neurodegeneration that happen in the disease.

Acute and Chronic Exposure to Linagliptin, a Selective Inhibitor of Dipeptidyl Peptidase-4 (DPP-4), Has an Effect on Dopamine, Serotonin and Noradrenaline Level in the Striatum and Hippocampus of Rats.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges.

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Psychic trauma causes increased impulsivity in a model of gambling addiction by altering dopamine and serotonin metabolism in the prefrontal cortex

BACKGROUND: Gambling addiction (gambling) involves frequently repeated episodes of gambling that are detrimental to social, professional, material, and family values. Gambling addiction is often combined with posttraumatic stress disorder.
 AIM: This study aimed to examine the effect of predator presentation stress on the manifestations of gambling addiction in an animal model in a test of probability and magnitude of reinforcement in the Iowa gambling task and monoamine metabolism in the prefrontal cortex of rats.
 MATERIALS AND METHODS: Rats were trained in a test of probability and magnitude of reinforcement in the Iowa gambling task in a 3-beam maze. Each run in arm 1 of the maze was reinforced with one sunflower seed, each second run in arm 2 with two seeds, and each third run in arm 3 with three seeds. Correspondingly, half of the runs in arm 2 and 2/3 of the runs in arm 3 were left unreinforced. After training, the animals were placed in a terrarium with a tiger python, one of which was victimized for its food requirements. On day 14 after predator presentation, dopamine and serotonin metabolism in the prefrontal cortex was determined using high-performance liquid chromatography with electrochemical detection.
 RESULTS: The levels of the dopamine metabolite dioxyphenylacetic acid and the ratio of dioxyphenylacetic acid to dopamine in the prefrontal cortex decreased. The levels of serotonin, its metabolite 5-hydroxyindoleacetic acid, and the ratio of 5-hydroxyindoleacetic acid to serotonin in the prefrontal cortex were also decreased in rats after exposure to a predator. Moreover, predator presentation induced significant behavioral changes in rats, increasing impulsivity in making choices in a test of probability and magnitude of reinforcement in the Iowa gambling task. The acute vital stress of predator presentation increased the number of escapes to arm 3 of the maze, suggesting that the animals exhibited more risky behavior when choosing reinforcements of different strengths and probability.
 CONCLUSIONS: The animal model showed that the depletion of the dopaminergic and serotoninergic systems of the prefrontal cortex underlies pathological gambling addiction and inadequate decision-making caused by posttraumatic stress disorder.

Integrative analysis of gene expression profiles of substantia nigra identifies potential diagnosis biomarkers in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Currently, there are no definitive diagnostic indicators for PD. In this study, we aimed to identify potential diagnostic biomarkers for PD and analyzed the impact of immune cell infiltrations on disease pathogenesis. The PD expression profile data for human SN tissue, GSE7621, GSE20141, GSE20159, GSE20163 and GSE20164 were downloaded from the Gene Expression Omnibus (GEO) database for use in the training model. After normalization and merging, we identified differentially expressed genes (DEGs) using the Robust rank aggregation (RRA) analysis. Simultaneously, DEGs after batch correction were identified. Gene interactions were determined through venn Diagram analysis. Functional analyses and protein–protein interaction (PPI) networks were used to the identify hub genes, which were visualized through Cytoscape. A Lasso Cox regression model was employed to identify the potential diagnostic genes. The GSE20292 dataset was used for validation. The proportion of infiltrating immune cells in the samples were determined via the CIBERSORT method. Sixty-two DEGs were screened in this study. They were found to be enriched in nerve conduction, dopamine (DA) metabolism, and DA biosynthesis Gene Ontology (GO) terms. The PPI network and Lasso Cox regression analysis revealed seven potential diagnostic genes, namely SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1, were subsequently validated in peripheral blood samples obtained from healthy control (HC) and PD patients, as well as in the GSE20292 dataset. The results revealed the exceptional sensitivity and specificity of these genes in PD diagnosis and monitoring. Moreover, PD patients exhibited a higher number of plasma cells, compared to HC individuals. The SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1 are potential diagnostic biomarkers for PD. Our findings also reveal the essential roles of immune cell infiltration in both disease onset and trajectory.

Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.