Aftereffects of microinjections of neurotensin into the substantia nigra of the brain on conditioned motor responses in rats with lesions to serotoninergic neurons

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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Effect of Subarachnoid Bupivacaine Block on Anesthetic Requirements for Thiopental in Rats

Anesthesiology ◽

10.1097/00000542-199804000-00024 ◽

1998 ◽

Vol 88 (4) ◽

pp. 1036-1042 ◽

Cited By ~ 33

Author(s):

Sunil Eappen ◽

Igor Kissin

Keyword(s):

Local Anesthetic ◽

Direct Action ◽

Afferent Input ◽

Crossover Design ◽

Hemodynamic Parameters ◽

Motor Responses ◽

Withdrawal Reflex ◽

Corneal Reflex ◽

To Receive ◽

The Brain

Background Subarachnoid bupivacaine blockade has been reported to reduce thiopental and midazolam hypnotic requirements in patients. The purpose of this study was to examine if local anesthetically induced lumbar intrathecal blockade would reduce thiopental requirements for blockade of motor responses to noxious and nonnoxious stimuli in rats. Methods After intrathecal and external jugular catheter placement, rats were assigned randomly to two groups in a crossover design study, with each rat to receive either 10 microl of 0.75% bupivacaine or 10 microl of normal saline intrathecally. The doses of intravenously administered thiopental required to ablate the eyelid reflex, to block the withdrawal reflex of a front limb digit, and to block the corneal reflex were compared. In two separate groups of animals, hemodynamic parameters and concentrations of thiopental in the brain were compared between intrathecally administered bupivacaine and saline. Results The thiopental dose required to block the described responses was decreased with intrathecally administered bupivacaine versus intrathecally administered saline from (mean +/- SD) 40 +/- 5 to 24 +/- 4 mg/kg (P < 0.001) for the eyelid reflex, from 51 +/- 6 to 29 +/- 6 mg/kg (P < 0.005) for front limb withdrawal, and from 67 +/- 8 to 46 +/- 8 mg/kg (P < 0.01) for the corneal reflex. The concentration of thiopental in the brain at the time of corneal reflex blockade for the group given bupivacaine was significantly lower than in the group given saline (24.1 vs. 35.8 microg/g, P = 0.02). Conclusion This study demonstrates that lumbar intrathecally administered local anesthetic blockade decreases anesthetic requirements for thiopental for a spectrum of end points tested. This effect is due neither to altered pharmacokinetics nor to a direct action of the local anesthetic on the brain; rather, it is most likely due to decreased afferent input.

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Parkinson's Disease

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch012 ◽

2019 ◽

pp. 252-273 ◽

Cited By ~ 1

Author(s):

Vaibhav Walia ◽

Ashish Gakkhar ◽

Munish Garg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Older Patients ◽

Neurodegenerative Disorder ◽

Progressive Loss ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Biomolecules ◽

10.3390/biom10030391 ◽

2020 ◽

Vol 10 (3) ◽

pp. 391 ◽

Cited By ~ 6

Author(s):

Margaux Teil ◽

Marie-Laure Arotcarena ◽

Emilie Faggiani ◽

Florent Laferriere ◽

Erwan Bezard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Clinical Trials ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Curative Treatment ◽

Preclinical Studies ◽

Cytoplasmic Inclusions ◽

The Many ◽

The Brain

Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Lipopolysaccharide Induces a Significant Increase in Expression of Iron Regulatory Hormone Hepcidin in the Cortex and Substantia Nigra in Rat Brain

Endocrinology ◽

10.1210/en.2007-1626 ◽

2008 ◽

Vol 149 (8) ◽

pp. 3920-3925 ◽

Cited By ~ 70

Author(s):

Qin Wang ◽

Fang Du ◽

Zhong-Ming Qian ◽

Xiao Hu Ge ◽

Li Zhu ◽

...

Keyword(s):

Substantia Nigra ◽

Iron Homeostasis ◽

Brain Regions ◽

Iron Regulation ◽

Rt Pcr ◽

Immunofluorescence Analysis ◽

Specific Regulation ◽

First Time ◽

The Brain ◽

Hepcidin Mrna

Hepcidin plays an essential role in maintaining normal iron homeostasis outside the brain. This recently discovered iron regulation hormone is predominantly expressed in the liver, and regulated by iron and hypoxia. As an antimicrobial peptide, this hormone is also elevated during infections and inflammation. In this study we investigated the expression of hepcidin mRNA and protein in different brain regions, including the cortex, hippocampus, striatum, and substantia nigra, and the effects of lipopolysaccharide (LPS) on the expression of hepcidin using quantitative real-time RT-PCR and immunofluorescence analysis. Our data provided further evidence for the existence of hepcidin in all the regions we examined. We also demonstrated for the first time that LPS administration by iv injection can regulate the expression of hepcidin mRNA and protein not only in peripheral organs such as the liver, but also in the brain. LPS induced a significant increase in the expression of hepcidin mRNA and protein in the cortex and substantia nigra, but not in the hippocampus and striatum, indicating a regionally specific regulation of LPS on hepcidin in the brain. The relevant mechanisms and the functions of hepcidin in the brain remain to be elucidated.

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Combined use of silver staining of the retrograde tracer WGAapoHRP-Au and pre-embedding immunocytochemistry for electron microscopy: demonstration of dopaminergic terminals in synaptic contact with striatal neurons projecting to the substantia nigra in the rat.

Journal of Histochemistry & Cytochemistry ◽

10.1177/40.6.1588034 ◽

1992 ◽

Vol 40 (6) ◽

pp. 889-892 ◽

Cited By ~ 6

Author(s):

R Arai ◽

Y Kojima ◽

M Geffard ◽

K Kitahama ◽

T Maeda

Keyword(s):

Electron Microscopy ◽

Substantia Nigra ◽

Silver Staining ◽

Synaptic Contact ◽

Immunoperoxidase Staining ◽

Immunoperoxidase Technique ◽

Striatal Neurons ◽

Combined Use ◽

Cryostat Sections ◽

The Brain

We investigated the applicability of the pre-embedding immunoperoxidase technique to WGAapoHRP-Au retrograde tracing. After injection of the tracer into the substantia nigra of rat, the brain was fixed and cryostat sections were immunostained for dopamine. The sections were osmicated and silver-stained to amplify the colloidal gold particles. Products of both the immunoperoxidase staining and the silver staining could be detected and distinguished by electron microscopy at low magnification. The ultrastructure was so well preserved that synaptic characteristics could be investigated. Dopaminergic terminals were demonstrated to synapse with striatal neurons projecting to the substantia nigra.

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Internal Models of Target Motion: Expected Dynamics Overrides Measured Kinematics in Timing Manual Interceptions

Journal of Neurophysiology ◽

10.1152/jn.00862.2003 ◽

2004 ◽

Vol 91 (4) ◽

pp. 1620-1634 ◽

Cited By ~ 116

Author(s):

Myrka Zago ◽

Gianfranco Bosco ◽

Vincenzo Maffei ◽

Marco Iosa ◽

Yuri P. Ivanenko ◽

...

Keyword(s):

Visual Target ◽

A Priori ◽

Target Motion ◽

Uniform Motion ◽

Time To Contact ◽

Motor Responses ◽

Visual Inputs ◽

Gravity Effects ◽

Series Of Experiments ◽

The Brain

Prevailing views on how we time the interception of a moving object assume that the visual inputs are informationally sufficient to estimate the time-to-contact from the object's kinematics. Here we present evidence in favor of a different view: the brain makes the best estimate about target motion based on measured kinematics and an a priori guess about the causes of motion. According to this theory, a predictive model is used to extrapolate time-to-contact from expected dynamics (kinetics). We projected a virtual target moving vertically downward on a wide screen with different randomized laws of motion. In the first series of experiments, subjects were asked to intercept this target by punching a real ball that fell hidden behind the screen and arrived in synchrony with the visual target. Subjects systematically timed their motor responses consistent with the assumption of gravity effects on an object's mass, even when the visual target did not accelerate. With training, the gravity model was not switched off but adapted to nonaccelerating targets by shifting the time of motor activation. In the second series of experiments, there was no real ball falling behind the screen. Instead the subjects were required to intercept the visual target by clicking a mousebutton. In this case, subjects timed their responses consistent with the assumption of uniform motion in the absence of forces, even when the target actually accelerated. Overall, the results are in accord with the theory that motor responses evoked by visual kinematics are modulated by a prior of the target dynamics. The prior appears surprisingly resistant to modifications based on performance errors.

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Changes in neurotransmitter levels associated with the deficiency of some essential amino acids in the diet

British Journal Of Nutrition ◽

10.1079/bjn19920098 ◽

1992 ◽

Vol 68 (2) ◽

pp. 409-420 ◽

Cited By ~ 18

Author(s):

José L. Venero ◽

Antonio J. Herrera ◽

Alberto Machado ◽

Josefina Cano

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Substantia Nigra ◽

Corpus Striatum ◽

Essential Amino Acids ◽

Serotoninergic System ◽

Main Metabolite ◽

Isoleucine Leucine ◽

Low Protein ◽

The Brain

The contents of dopamine (DA) and serotonin (5-HT) and their metabolites were measured in rat substantia nigra and corpus striatum following dietary changes, including restriction of protein content (low-protein diet; LPD) and the contents of several large neutral amino acids (isoleucine, leucine, methionine, phenylalanine, tryptophan and valine) for 25 d. The LPD produced an increase in the concentration of tyrosine (TYR) in the two regions of the brain studied. This effect was also observed with all amino acid deficiencies studied except for valine in the substantia nigra, tryptophan in the striatum and phenylalanine in both regions. Likewise, the concentration of 5-hydroxyindolacetic acid (5-HIAA), the main metabolite of 5-HT, increased in the substantia nigra but not in the striatum after LPD, as well as with all the amino acid deficiencies studied, with the exception of tryptophan deficiency. In this case there was a dramatic effect on all components of the serotoninergic system, with decreases in the concentration of tryptophan (TRP; precursor), 5-HT and 5-HIAA. This behaviour clearly shows an interrelationship between precursor (TRP) availability and 5-HT synthesis and metabolism. With valine deficiency, dopaminergic and serotoninergic systems demonstrated opposite effects in the substantia nigra and the corpus striatum, and the behaviour of the two monoamines was also opposite within each structure. The significance of these changes is discussed.

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Automatic substantia nigra segmentation in neuromelanin-sensitive MRI by deep neural network in patients with prodromal and manifest synucleinopathy

Physiological Research ◽

10.33549/physiolres.934380 ◽

2019 ◽

pp. S453-S458

Author(s):

R. Krupička ◽

S. Mareček ◽

C. Malá ◽

M. Lang ◽

O. Klempíř ◽

...

Keyword(s):

Neural Network ◽

Substantia Nigra ◽

Signal Intensity ◽

Substantia Nigra Pars Compacta ◽

The Neural Network ◽

Intensity Information ◽

Ideal Tool ◽

Magnetic Resonance Imaging Mri ◽

The Brain

Neuromelanin (NM) is a black pigment located in the brain in substantia nigra pars compacta (SN) and locus coeruleus. Its loss is directly connected to the loss of nerve cells in this part of the brain, which plays a role in Parkinson’s Disease. Magnetic resonance imaging (MRI) is an ideal tool to monitor the amount of NM in the brain in vivo. The aim of the study was the development of tools and methodology for the quantification of NM in a special neuromelanin-sensitive MRI images. The first approach was done by creating regions of interest, corresponding to the anatomical position of SN based on an anatomical atlas and determining signal intensity threshold. By linking the anatomical and signal intensity information, we were able to segment the SN. As a second approach, the neural network U-Net was used for the segmentation of SN. Subsequently, the volume characterizing the amount of NM in the SN region was calculated. To verify the method and the assumptions, data available from various patient groups were correlated. The main benefit of this approach is the observer-independency of quantification and facilitation of the image processing process and subsequent quantification compared to the manual approach. It is ideal for automatic processing many image sets in one batch.

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