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Journal of Immunology Research 2018Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning...
Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF-, IL-1, IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH cells, as well as apparent phagocytosis of TH cells by OX42 cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration.
Topics: Acute Disease; Animals; Astrocytes; Cell Differentiation; Cell Movement; Cells, Cultured; Cytokines; Disease Models, Animal; Dopaminergic Neurons; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Lipopolysaccharides; Male; Microglia; Neurodegenerative Diseases; Neurogenic Inflammation; Parkinson Disease; Pars Compacta; Rats; Rats, Wistar; Tyrosine 3-Monooxygenase
PubMed: 29854828
DOI: 10.1155/2018/1838921 -
Neuroscience 1989The membrane properties of pars compacta neurons in the in vitro guinea-pig substantia nigra have been studied in the presence of sodium, calcium and potassium channel...
The membrane properties of pars compacta neurons in the in vitro guinea-pig substantia nigra have been studied in the presence of sodium, calcium and potassium channel blockers. The following properties, which have already been described for dopamine-containing substantia nigra zona compacta neurons were observed: high and low threshold calcium spikes; a calcium-activated potassium-mediated transient; inward rectification. Inward rectification was sensitive to caesium ions. An additional property was seen reminiscent of an "A" current, although resistant to 4-aminopyridine. It is suggested that this outward transient is in fact a calcium activated potassium conductance. Under certain conditions calcium-mediated rhythmic depolarizations were observed. It is suggested that at least two of the properties seen (outward rectification and low threshold calcium spike) could interact to provide the basis for a pacemaker mechanism in pars compacta neurons.
Topics: Action Potentials; Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Female; Guinea Pigs; In Vitro Techniques; Membrane Potentials; Substantia Nigra
PubMed: 2552348
DOI: 10.1016/0306-4522(89)90379-5 -
The European Journal of Neuroscience May 2024Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of... (Review)
Review
Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.
Topics: Humans; Melanins; Parkinson Disease; Magnetic Resonance Imaging; Biomarkers; Locus Coeruleus; Pars Compacta
PubMed: 38441250
DOI: 10.1111/ejn.16296 -
Brain Research Bulletin Mar 1987The ascending projections of pars compacta (SNc) neurons displaced within the pars reticulata (SNr) of the substantia nigra in the rat were examined using a fluorescent...
The ascending projections of pars compacta (SNc) neurons displaced within the pars reticulata (SNr) of the substantia nigra in the rat were examined using a fluorescent retrograde tracing. Following unilateral injections of a tracer into the striatum, SNc cells within the SNr were retrogradely labeled predominantly in the caudal parts, and to a lesser extent in the rostral portions of the nucleus. These nigrostriatal projections arising from the SNc cells within the SNr were only ipsilateral. Injections of a tracer into the nucleus accumbens (Acc) did not produce any labeling of these displaced SNc cells in contrast with cells in the SNc proper. Given that the SNc neurons within the SNr project only to the striatum but not to the Acc, and that they contain dopamine but not cholecystokinin, they might be involved in the motor but not in the limbic function.
Topics: Amidines; Animals; Benzofurans; Male; Neural Pathways; Neurons; Nucleus Accumbens; Rats; Rats, Inbred Strains; Substantia Nigra
PubMed: 3580903
DOI: 10.1016/0361-9230(87)90004-9 -
Brain Research Nov 2013The aim of the present study was to examine the influence of a partial lesion of both the substantia nigra pars compacta (SNC) and retrorubral field (RRF) on the...
The aim of the present study was to examine the influence of a partial lesion of both the substantia nigra pars compacta (SNC) and retrorubral field (RRF) on the glutamatergic transmission in the cerebellum and tremor induced by harmaline in rats. 6-Hydroxydopamine (6-OHDA, 8 μg/2 μl) was injected unilaterally into the region of the posterior part of the SNC and RRF. Harmaline was administered in a dose of 30 mg/kg ip on the 8th day after the operation and the extracellular level of glutamate was measured by microdialysis in vivo in the cerebellar vermis. Harmaline induced glutamate release in the cerebellum. The lesion which encompassed 23-37% neurons in the anterior SNC, 52-54% in the posterior SNC and 47-55% in the RRF did not influence the basal extracellular glutamate level but decreased the harmaline-induced release of this neurotransmitter. Tremor evoked by harmaline was also visibly inhibited by the above lesion. The results of the present study seem to indicate that midbrain dopaminergic neurons influence glutamatergic transmission in the cerebellum which may be important for generation of the tremor induced by harmaline.
Topics: Animals; Cerebellum; Dopamine; Dopaminergic Neurons; Glutamic Acid; Harmaline; Male; Rats; Rats, Wistar; Substantia Nigra; Tremor
PubMed: 24012623
DOI: 10.1016/j.brainres.2013.08.059 -
Pharmacology, Biochemistry, and Behavior Jan 2021Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying... (Review)
Review
Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying opioid abuse and addiction are still not fully understood. This review discusses recent progress in basic research dissecting receptor mechanisms and circuitries underlying opioid reward and addiction. We first review the canonical GABA-dopamine neuron hypothesis that was upheld for half a century, followed by major findings challenging this hypothesis. We then focus on recent progress in research evaluating the role of the mesolimbic and nigrostriatal dopamine circuitries in opioid reward and relapse. Based on recent findings that activation of dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is equally rewarding and that GABA neurons in the rostromedial tegmental nucleus (RMTg) and the substantia nigra pars reticula (SNr) are rich in mu opioid receptors and directly synapse onto midbrain DA neurons, we proposed that the RTMg→VTA → ventrostriatal and SNr → SNc → dorsostriatal pathways may act as the two major neural substrates underlying opioid reward and abuse. Lastly, we discuss possible integrations of these two pathways during initial opioid use, development of opioid abuse and maintenance of compulsive opioid seeking.
Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Dopamine; Dopaminergic Neurons; Humans; Mesencephalon; Neural Pathways; Opioid-Related Disorders; Pars Compacta; Pars Reticulata; Receptors, Opioid, mu; Reward; Synapses; Ventral Tegmental Area; gamma-Aminobutyric Acid
PubMed: 33227308
DOI: 10.1016/j.pbb.2020.173072 -
Journal of Proteomics Dec 2013This article gives a detailed description of a protocol using density gradient centrifugation for the enrichment of neuromelanin granules and synaptosomes from low... (Clinical Trial)
Clinical Trial
UNLABELLED
This article gives a detailed description of a protocol using density gradient centrifugation for the enrichment of neuromelanin granules and synaptosomes from low amounts (≥0.15g) of human substantia nigra pars compacta tissue. This has a great advantage compared to already existing methods as it allows for the first time (i) a combined enrichment of neuromelanin granules and synaptosomes and (ii) just minimal amounts of tissue necessary to enable donor specific analysis. Individual specimens were classified as control or diseased according to clinical evaluation and neuropathological examination. For the enrichment of synaptosomes and neuromelanin granules from the same tissue sample density gradient centrifugations using Percoll® and Iodixanol were performed. The purity of resulting fractions was checked by transmission electron microscopy. We were able to establish a reproducible and easy to handle protocol combining two different density gradient centrifugations: using an Iodixanol gradient neuromelanin granules were enriched and in parallel, from the same sample, a fraction of synaptosomes with high purity using a Percoll® gradient was obtained. Our subfractionation strategy will enable a subsequent in depth proteomic characterization of neurodegenerative processes in the substantia nigra pars compacta in patients with Parkinson's disease and dementia with Lewy bodies compared to appropriate controls.
BIOLOGICAL SIGNIFICANCE
Key features of Parkinson's disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta, an associated loss of the brain pigment neuromelanin and a resulting impairment of the neuronal network. The accumulation of iron binding neuromelanin granules is age- and disease-dependent and disease specific alterations could affect the neuronal iron homeostasis leading to oxidative stress induced cell death. The focus of the described method is the analysis of neuromelanin granules as well as axonal cell-endings of nerve cells (synaptosomes) of individual donors (control and diseased). It is the basis for the identification of disease-relevant changes in the iron homeostasis and the generation of new insight into altered protein compositions or regulations which might lead to disturbed communications between nerve cells resulting in pathogenic processes.
Topics: Centrifugation, Density Gradient; Cytoplasmic Granules; Female; Humans; Male; Melanins; Neurodegenerative Diseases; Proteomics; Substantia Nigra; Synaptosomes
PubMed: 23917253
DOI: 10.1016/j.jprot.2013.07.015 -
Mechanisms of Ageing and Development Jan 2017Parkinson's and Alzheimer's diseases (PD and AD, respectively) are considered to be diseases of advanced brain ageing, which seems to involve high levels of reactive... (Review)
Review
Parkinson's and Alzheimer's diseases (PD and AD, respectively) are considered to be diseases of advanced brain ageing, which seems to involve high levels of reactive oxygen species (ROS). AD neurodegeneration is initially apparent in the hippocampus; as AD progresses, many more brain regions are affected. PD-associated neurodegeneration is relatively limited to dopaminergic neurons of the substantia nigra pars compacta (SNpc), especially in cases in which patients inherit particular disease-causing mutations. Thus, the task of elucidating mechanisms by which loss of function of one particular protein triggers death of a subset of neurons may be more approachable. Understanding the mechanisms of neurodegeneration in these forms of PD may not only shed light on avenues leading toward therapeutic strategies in PD and other neurodegenerative diseases, but also on those leading toward understanding natural ageing. Neurodegeneration in PD patients harboring homozygous loss-of-function mutations in the PARK2 gene may result from unbalanced levels of ROS, which are mostly produced in mitochondria and can irreparably damage macromolecules and trigger apoptosis. This review discusses mitochondrial sources of ROS, how ROS can trigger apoptosis, mechanisms by which Parkin loss-of-function may cause neurodegeneration by increasing ROS levels, and concludes with hypotheses regarding selective SNpc dopaminergic neuron vulnerability.
Topics: Alzheimer Disease; Animals; Apoptosis; Cellular Senescence; Dopaminergic Neurons; Humans; Parkinson Disease; Pars Compacta; Reactive Oxygen Species; Ubiquitin-Protein Ligases
PubMed: 27374431
DOI: 10.1016/j.mad.2016.06.008 -
Neurobiology of Aging Dec 2015Age being a risk factor for Parkinson's disease, assessment of age-related changes in the human substantia nigra may elucidate its pathogenesis. Increase in Marinesco...
Age being a risk factor for Parkinson's disease, assessment of age-related changes in the human substantia nigra may elucidate its pathogenesis. Increase in Marinesco bodies, α-synuclein, free radicals and so forth in the aging nigral neurons are clear indicators of neurodegeneration. Here, we report the glial responses in aging human nigra. The glial numbers were determined on Nissl-stained sections. The expression of glial fibrillary acidic protein, S100β, 2', 3'-cyclic nucleotide 3' phosphodiesterase, and Iba1 was assessed on cryosections of autopsied midbrains by immunohistochemistry and densitometry. The glial counts showed a biphasic increase, of which, the first prominent phase from fetal age to birth could be physiological gliogenesis whereas the second one after middle age may reflect mild age-related gliosis. Astrocytic morphology was altered, but glial fibrillary acidic protein expression increased only mildly. Presence of type-4 microglia suggests possibility of neuroinflammation. Mild reduction in 2', 3'-cyclic nucleotide 3' phosphodiesterase-labeled area denotes subtle demyelination. Stable age-related S100β expression indicates absence of calcium overload. Against the expected prominent gliosis, subtle age-related morphological alterations in human nigral glia attribute them a participatory role in aging.
Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Astrocytes; Calcium; Child; Child, Preschool; Female; Glial Fibrillary Acidic Protein; Humans; Infant; Male; Microglia; Middle Aged; Nerve Degeneration; Neurogenic Inflammation; Parkinson Disease; Pars Compacta; Risk Factors; S100 Calcium Binding Protein beta Subunit; Young Adult
PubMed: 26433682
DOI: 10.1016/j.neurobiolaging.2015.08.024 -
Journal of Neuroscience Research Aug 2014Dopaminergic neurons of the substantia nigra pars compacta (SNc) are involved in the control of movement, sleep, reward, learning, and nervous system disorders and...
Dopaminergic neurons of the substantia nigra pars compacta (SNc) are involved in the control of movement, sleep, reward, learning, and nervous system disorders and disease. To date, a thorough characterization of the ion channel phenotype of this important neuronal population is lacking. Using immunohistochemistry, we analyzed the somatodendritic expression of voltage-gated ion channel subunits that are involved in pacemaking activity in SNc dopaminergic neurons in 6-, 21-, and 40-day-old rats. Our results demonstrate that the same complement of somatodendritic ion channels is present in SNc dopaminergic neurons from P6 to P40. The major developmental changes were an increase in the dendritic range of the immunolabeling for the HCN, T-type calcium, Kv4.3, delayed rectifier, and SK channels. Our study sheds light on the ion channel subunits that contribute to the somatodendritic delayed rectifier (Kv1.3, Kv2.1, Kv3.2, Kv3.3), A-type (Kv4.3) and calcium-activated SK (SK1, SK2, SK3) potassium currents, IH (mainly HCN2, HCN4), and the L- (Cav1.2, Cav1.3) and T-type (mainly Cav3.1, Cav3.3) calcium currents in SNc dopaminergic neurons. Finally, no robust differences in voltage-gated ion channel immunolabeling were observed across the population of SNc dopaminergic neurons for each age examined, suggesting that differing levels of individual ion channels are unlikely to distinguish between specific subpopulations of SNc dopaminergic neurons. This is significant in light of previous studies suggesting that age- or region-associated variations in the expression profile of voltage-gated ion channels in SNc dopaminergic neurons may underlie their vulnerability to dysfunction and disease.
Topics: Animals; Calcium Channels; Dendrites; Dopaminergic Neurons; Pars Compacta; Potassium Channels; Rats; Rats, Wistar
PubMed: 24723263
DOI: 10.1002/jnr.23382