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Chemico-biological Interactions Sep 2023Ferroptosis, a newly identified iron-dependent form of cell death, has recently been implicated in the pathogenesis of Parkinson's disease (PD). Dl-3-n-butylphthalide...
Ferroptosis, a newly identified iron-dependent form of cell death, has recently been implicated in the pathogenesis of Parkinson's disease (PD). Dl-3-n-butylphthalide (NBP) attenuates behavioral and cognitive deficits in animal models of PD. However, the potential of NBP to prevent dopaminergic neuron death by suppressing ferroptosis has rarely been explored. In this study, we aimed to investigate the effects of NBP on ferroptosis in erastin-induced dopaminergic neurons (MES23.5 cells) and the underlying mechanisms involved in these effects. Our results demonstrated that erastin significantly decreased viability of MES23.5 dopaminergic neurons in a dose-dependent manner, which was reversible by ferroptosis inhibitors. We further verified that NBP protected erastin-treated MES23.5 cells from death by inhibiting ferroptosis. Erastin increased the mitochondrial membrane density, caused lipid peroxidation, and decreased GPX4 expression in MES23.5 cells, which could be reversed by NBP preconditioning. NBP pretreatment suppressed erastin-induced labile iron accumulation and reactive oxygen species generation. Moreover, we demonstrated that erastin significantly reduced FTH expression, and pre-administration with NBP promoted Nrf2 translocation into the nucleus and increased the protein level of FTH. Additionally, the expression of LC3B-II in MES23.5 cells pretreated with NBP before administration of erastin was lower than that in cells treated with erastin alone. NBP reduced colocalization of FTH and autophagosomes in MES23.5 cells exposed to erastin. Finally, erastin gradually inhibited NCOA4 expression in a time-dependent manner, which was reversible by NBP pretreatment. Taken together, these results indicated that NBP suppressed ferroptosis via regulating FTH expression, which was achieved by promoting Nrf2 nuclear translocation and inhibiting NCOA4-mediated ferritinophagy. As such, NBP may be a promising therapeutic agent for the treatment of neurological diseases associated with ferroptosis.
Topics: Animals; Ferroptosis; Dopaminergic Neurons; NF-E2-Related Factor 2; Iron
PubMed: 37315914
DOI: 10.1016/j.cbi.2023.110604 -
Journal of Neurochemistry Sep 2023Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to...
Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to disorders of abnormal dopamine signalling with a neurodevelopmental basis such as schizophrenia. Here we provide further evidence of vitamin D's role as a mediator of dopaminergic development by showing that it increases neurite outgrowth, neurite branching, presynaptic protein re-distribution, dopamine production and functional release in various in vitro models of developing dopaminergic cells including SH-SY5Y cells, primary mesencephalic cultures and mesencephalic/striatal explant co-cultures. This study continues to establish vitamin D as an important differentiation agent for developing dopamine neurons, and now for the first time shows chronic exposure to the active vitamin D hormone increases the capacity of developing neurons to release dopamine. This study also has implications for understanding mechanisms behind the link between DVD deficiency and schizophrenia.
Topics: Humans; Vitamin D; Dopaminergic Neurons; Dopamine; Neuroblastoma; Vitamins; Mesencephalon; Neurogenesis; Cell Differentiation
PubMed: 37084159
DOI: 10.1111/jnc.15829 -
Neuron Feb 2023In this issue of Neuron, Xie et al. record and manipulate dopaminergic activity as mice engage in parental care. Dopaminergic prediction error signals previously...
In this issue of Neuron, Xie et al. record and manipulate dopaminergic activity as mice engage in parental care. Dopaminergic prediction error signals previously implicated in food rewards were associated with retrieving isolated pups to the nest, showing that neural mechanisms long associated with reinforcement learning can be repurposed for aspects of parenting.
Topics: Mice; Animals; Reinforcement, Psychology; Learning; Reward; Dopamine; Neurons; Dopaminergic Neurons
PubMed: 36796327
DOI: 10.1016/j.neuron.2023.01.019 -
PloS One 2022Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's...
Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Locus Coeruleus; Mice; Mice, Transgenic; Norepinephrine; Parkinson Disease; Substantia Nigra; Synucleinopathies; alpha-Synuclein
PubMed: 35316276
DOI: 10.1371/journal.pone.0263074 -
Applied Radiation and Isotopes :... Dec 2014The purpose of the present study is to investigate the relationship between dopaminergic neuron destruction and 5-HT system changes in a hemiparkinsonian rat model. We...
The purpose of the present study is to investigate the relationship between dopaminergic neuron destruction and 5-HT system changes in a hemiparkinsonian rat model. We performed PET imaging studies with trans-[(18)F]Mefway in a hemiparkinsonian model of unilateral 6-hydroxydopamine (6-OHDA) rats. Region-of-interests (ROIs) were drawn in the hippocampus (HP) and cerebellum (CB). HP uptake, the ratios of specific binding to non-specific binding in the HP, and non-displaceable binding potential (BPND) in the HP were compared between 6-OHDA and control rats. As a result, unilateral 6-OHDA-lesioned rats exhibited significant bilateral reduction of HP uptake and trans-[(18)F]Mefway BPND compared to the intact control group. Therefore, the results demonstrate that destruction of the dopaminergic system causes the reduction of the serotonergic system.
Topics: Animals; Dopaminergic Neurons; Fluorine Radioisotopes; Hippocampus; Male; Metabolic Clearance Rate; Parkinsonian Disorders; Piperazines; Pyridines; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution
PubMed: 25064461
DOI: 10.1016/j.apradiso.2014.06.016 -
Developmental Neurobiology Mar 2012Dopaminergic and noradrenergic neurons constitute some of the major far projecting systems in the vertebrate brain and spinal cord that modulate the activity of circuits... (Review)
Review
Dopaminergic and noradrenergic neurons constitute some of the major far projecting systems in the vertebrate brain and spinal cord that modulate the activity of circuits controlling a broad range of behaviors. Degeneration or dysfunction of dopaminergic neurons has also been linked to a number of neurological and psychiatric disorders, including Parkinson's disease.Zebrafish (Danio rerio) have emerged over the past two decades into a major genetic vertebrate model system,and thus contributed to a better understanding of developmental mechanisms controlling dopaminergic neuron specification and axonogenesis. In this review, we want to focus on conserved and dynamic aspects of the different catecholaminergic systems, which may help to evaluate the zebrafish as a model for dopaminergic and noradrenergic cellular specification and circuit function as well as biomedical aspects of catecholamine systems.
Topics: Adrenergic Neurons; Animals; Dopaminergic Neurons; Humans; Nerve Net; Neurogenesis; Zebrafish; Zebrafish Proteins
PubMed: 21567980
DOI: 10.1002/dneu.20911 -
The European Journal of Neuroscience Mar 2024Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and loss of dopaminergic neurons of the substantia nigra pars compacta... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in dopaminergic neuron death, such as apoptosis, necrosis, pyroptosis and ferroptosis, as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying dopaminergic neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 kinase (RIP3 kinase, RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analysing biomarkers for necroptosis, such as the levels and oligomerization of phosphorylated RIPK3 (pRIPK3) and phosphorylated MLKL (pMLKL), in several PD preclinical models and in PD human tissue. Although there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD.
Topics: Humans; Dopaminergic Neurons; Parkinson Disease; Necroptosis; Cell Death; Apoptosis; Necrosis; Dopamine
PubMed: 37667848
DOI: 10.1111/ejn.16136 -
Brain Structure & Function Sep 2020Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful as an unconditioned...
Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful as an unconditioned stimulus for modelling anticipatory fear and agoraphobia in a contextual fear conditioning paradigm. In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then attempted to unravel some of the interactions with dopamine signalling using tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. We showed that acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, while chronic administrations of both drugs were effective. We found that the dlPAG stimulation induced increase number of dopaminergic neurons in the ventral tegmental area (VTA) which was reversed in both chronic buspirone and escitalopram groups. We further found a strong positive correlation between the number of dopaminergic neurons and freezing in the VTA and showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta (SNpc) in escitalopram and buspirone groups, respectively. Overall, we showed that chronic treatment with an SSRI and a 5-HT1A agonist reduced anticipatory freezing behaviour which seems to be associated, through correlative studies, with a reversal of dlPAG stimulation induced increase in number of dopaminergic neurons in the VTA and/or SNpc.
Topics: Animals; Buspirone; Citalopram; Deep Brain Stimulation; Dopaminergic Neurons; Electric Stimulation; Fear; Freezing Reaction, Cataleptic; Male; Mesencephalon; Periaqueductal Gray; Rats; Rats, Wistar; Serotonin Receptor Agonists; Selective Serotonin Reuptake Inhibitors
PubMed: 32594260
DOI: 10.1007/s00429-020-02102-w -
STAR Protocols Jun 2021Here, we describe a high-throughput 3D differentiation protocol for deriving midbrain dopaminergic neurons from human pluripotent stem cells. The use of organoids has...
Here, we describe a high-throughput 3D differentiation protocol for deriving midbrain dopaminergic neurons from human pluripotent stem cells. The use of organoids has become prevalent in disease modeling, but there is a high demand for more homogeneous cultures. Our approach is advantageous for large-scale production of uniform midbrain organoids that can be maintained in diverse formats, and our reporters allow for sorting of dopaminergic neurons. The maturing long-term organoid cultures can be used as a model for the entire midbrain. For complete details on the use and execution of this protocol, please refer to Ahfeldt et al. (2020).
Topics: Dopaminergic Neurons; Humans; Mesencephalon; Organoids; Pluripotent Stem Cells
PubMed: 33997803
DOI: 10.1016/j.xpro.2021.100463 -
Molecular Biology Reports Jul 2023Parkinson's disease (PD) is a progressive neurodegenerative disease (NDD) caused by dopaminergic neuron degeneration in the substantia nigra (SN). Orexin is a... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disease (NDD) caused by dopaminergic neuron degeneration in the substantia nigra (SN). Orexin is a neuropeptide that plays a role in the pathogenesis of PD. Orexin has neuroprotective properties in dopaminergic neurons. In PD neuropathology, there is also degeneration of orexinergic neurons in the hypothalamus, in addition to dopaminergic neurons. However, the loss of orexinergic neurons in PD began after the degeneration of dopaminergic neurons. Reduced activity of orexinergic neurons has been linked to developing and progressing motor and non-motor symptoms in PD. In addition, the dysregulation of the orexin pathway is linked to the development of sleep disorders. The hypothalamic orexin pathway regulates various aspects of PD neuropathology at the cellular, subcellular, and molecular levels. Finally, non-motor symptoms, particularly insomnia and disturbed sleep, promote neuroinflammation and the accumulation of neurotoxic proteins as a result of defects in autophagy, endoplasmic reticulum (ER) stress, and the glymphatic system. As a result, this review aimed to highlight the potential role of orexin in PD neuropathology.
Topics: Humans; Orexins; Parkinson Disease; Neurodegenerative Diseases; Neuropeptides; Dopaminergic Neurons
PubMed: 37155018
DOI: 10.1007/s11033-023-08459-5