No changes in behaviour, nigro-striatal system neurochemistry or neuronal cell death following toxic multiple oral paraquat administration to rats

1996 ◽  
Vol 15 (7) ◽  
pp. 583-591 ◽  
Author(s):  
PS Widdowson ◽  
MJ Farnworth ◽  
R. Upton ◽  
MG Simpson
Keyword(s):  
Cerebral Cortex ◽  
Locomotor Activity ◽  
Rat Brain ◽  
Grip Strength ◽  
Cell Damage ◽  
Benzodiazepine Receptors ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Brain Regions ◽  
Nigrostriatal System

We have examined whether the widely used herbicide, paraquat (1,1'-dimethyl-4,4'dipyridylium) may accumu late in rat brain following multiple oral dosing (5 mg paraquat ion/kg/day) for 14 days and whether this dosing regime may produce signs of neurotoxicity. This dosing regime may determine whether low dose exposure to mammals may be neurotoxic. Using [14C]paraquat to measure tissue and plasma paraquat concentrations, we observed significantly higher plasma and tissue paraquat concentrations in brain, liver, lungs and kidneys of rats which received multiple doses for 14 days, as compared to paraquat concentrations in tissues of rats which received only a single paraquat dose. Brain paraquat concentrations measured 24 h after dosing were tenfold higher in rats receiving 14 daily oral doses of paraquat, as compared to concentrations follow ing a single oral dose. A neuropathological study of the rat brain yielded no evidence that multiple paraquat dosing resulted in neuronal cell damage. Particular attention was paid to the nigrostriatal system. The paraquat treated rats gained approximately 10% less body weight over the 15 day experimental period as compared with controls demon strating that the dose of paraquat was toxic to the animals. Measurements of locomotor activity using open field tests or activity monitors did not reveal any statistically significant differences between control animals and those receiving paraquat. Fore- and hind-limb grip strength were not significantly different between the paraquat treated and control rats at any time point during the dosing regime, nor was there any evidence for locomotor co ordination deficits in any of the animals receiving paraquat. Densities of dopamine D1 and D2, NMDA, muscarinic and benzodiazepine receptors in the cerebral cortex and striatum were not significantly different between controls and rats which had received multiple paraquat doses. Concentrations of catecholamine neurotransmitters in the striatum, hypothalamus and frontal cerebral cortex were also measured to examine whether there was evidence for catecholamine depletion in these brain regions. We did not observe any significant reductions in dopamine, noradrenaline or DOPAC concentrations in any brain region of paraquat treated rats as compared with controls. On the contrary, dopamine concentrations in the striatim were significantly elevated in paraquat treated animals following a 15 day paraquat dosing regime. We attribute these changes in catecholamine concentrations to the general toxicity of paraquat which produces a stress response. In conclusion, we could not find any evidence that multiple paraquat dosing can lead to changes in locomotor activity or grip strength. In addition, the absence of neuropathology or changes in neurochemistry in the nigrostriatal tract demonstrates that paraquat does not behave like MPP+(N-methyl-4-phenylpyridinium), the neurotoxic metabolite of MPTP

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

2021 ◽  
pp. 019262332110077
Author(s):  
Catherine A. Picut ◽  
Odete R. Mendes ◽  
David S. Weil ◽  
Sarah Davis ◽  
Cynthia Swanson
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nmda Receptor Antagonists ◽  
Neonatal Rats ◽  
Receptor Antagonists ◽  
Fluoro Jade B ◽  
Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

scholarly journals Birth delivery mode alters perinatal cell death in the mouse brain

2018 ◽  
Vol 115 (46) ◽  
pp. 11826-11831 ◽  
Author(s):  
Alexandra Castillo-Ruiz ◽  
Morgan Mosley ◽  
Andrew J. Jacobs ◽  
Yarely C. Hoffiz ◽  
Nancy G. Forger
Keyword(s):  
Cell Death ◽  
Brain Development ◽  
Vaginal Delivery ◽  
Maternal Separation ◽  
Developmental Process ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Brain Regions ◽  
Delivery Mode ◽  
Gestation Length

Labor and a vaginal delivery trigger changes in peripheral organs that prepare the mammalian fetus to survive ex utero. Surprisingly little attention has been given to whether birth also influences the brain, and to how alterations in birth mode affect neonatal brain development. These are important questions, given the high rates of cesarean section (C-section) delivery worldwide, many of which are elective. We examined the effect of birth mode on neuronal cell death, a widespread developmental process that occurs primarily during the first postnatal week in mice. Timed-pregnant dams were randomly assigned to C-section deliveries that were yoked to vaginal births to carefully match gestation length and circadian time of parturition. Compared with rates of cell death just before birth, vaginally-born offspring had an abrupt, transient decrease in cell death in many brain regions, suggesting that a vaginal delivery is neuroprotective. In contrast, cell death was either unchanged or increased in C-section–born mice. Effects of delivery mode on cell death were greatest for the paraventricular nucleus of the hypothalamus (PVN), which is central to the stress response and brain–immune interactions. The greater cell death in the PVN of C-section–delivered newborns was associated with a reduction in the number of PVN neurons expressing vasopressin at weaning. C-section–delivered mice also showed altered vocalizations in a maternal separation test and greater body mass at weaning. Our results suggest that vaginal birth acutely impacts brain development, and that alterations in birth mode may have lasting consequences.

scholarly journals Identification of proteins differentially expressed by glutamate treatment in cerebral cortex of neonatal rats

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Ju-Bin Kang ◽  
Dong-Ju Park ◽  
Phil-Ok Koh
Keyword(s):  
Cerebral Cortex ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Differentially Expressed ◽  
Heat Shock Protein 60 ◽  
Sprague Dawley ◽  
Two Dimensional Gel Electrophoresis ◽  
Specific Proteins

AbstractGlutamate leads to neuronal cell damage by generating neurotoxicity during brain development. The objective of this study is to identify proteins that differently expressed by glutamate treatment in neonatal cerebral cortex. Sprague-Dawley rat pups (post-natal day 7) were intraperitoneally injected with vehicle or glutamate (10 mg/kg). Brain tissues were isolated 4 h after drug treatment and fixed for morphological study. Moreover, cerebral cortices were collected for protein study. Two-dimensional gel electrophoresis and mass spectrometry were carried out to identify specific proteins. We observed severe histopathological changes in glutamate-exposed cerebral cortex. We identified various proteins that differentially expressed by glutamate exposure. Identified proteins were thioredoxin, peroxiredoxin 5, ubiquitin carboxy-terminal hydrolase L1, proteasome subunit alpha proteins, isocitrate dehydrogenase, and heat shock protein 60. Heat shock protein 60 was increased in glutamate exposed condition. However, other proteins were decreased in glutamate-treated animals. These proteins are related to anti-oxidant, protein degradation, metabolism, signal transduction, and anti-apoptotic function. Thus, our findings can suggest that glutamate leads to neonatal cerebral cortex damage by regulation of specific proteins that mediated with various functions.

Neuronal cell death due to glutamate excitotocity is mediated by P38 activation in the rat cerebral cortex

2006 ◽  
Vol 403 (3) ◽  
pp. 233-238 ◽  
Author(s):  
J.E. Segura Torres ◽  
V. Chaparro-Huerta ◽  
M.C. Rivera Cervantres ◽  
R. Montes-González ◽  
M.E. Flores Soto ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Cortex ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rat Cerebral Cortex

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2021 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Young Min Oh ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

Abstract W P385: Hypertension-Induced Hypoxia Leads to Neurodegeneration in a Novel Model of Accelerated Cerebrovascular Disease

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Limor Raz ◽  
Kiran Bhaskar ◽  
Gary A Rosenberg
Keyword(s):  
White Matter ◽  
Carotid Artery ◽  
Time Course ◽  
Small Vessel Disease ◽  
Cell Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Normal Diet ◽  
Cresyl Violet ◽  
Chronic Hypertension

Hypertension is a major risk factor contributing to cerebrovascular diseases such as stroke and vascular cognitive impairment (VCI). Elevated blood pressure leads to cerebral small vessel disease, resulting neuronal cell death and cognitive dysfunction. We developed a unique animal model of clinical VCI in the spontaneously hypertensive stroke prone (SHR-SP) rat, characterized by significant white matter disease, neuroinflammation and behavioral deficits induced by a Japanese Permissive Diet (JPD) and unilateral carotid artery occlusion (UCAO). We hypothesized that the SHR-SP rat has neuropathological changes in the cortex and hippocampus due to effects of hypertension on neurodegeneration. To test the hypothesis, we performed permanent right side UCAO (hypoxia) at 12 weeks (12W) of age in male SHR-SP rats (n=5). Following surgery, rats were placed on a JPD and received 1% NaCl in drinking water (hypertension). Control rats were fed a normal diet and underwent right carotid artery isolation (n=4). A preliminary time course of NeuN and Cresyl Violet staining, from hypoxia onset (12W) to sacrifice (16W), showed decreased neuronal survival and elevated neuroinflammatory response (astro- and micro-gliosis by GFAP and Iba1 staining, respectively) in the experimental group as compared to controls. Microbleeds and endothelial cell damage were observed by Hematoxylin and Eosin histology. Immunohistochemistry showed an up-regulation of hypoxia inducible factor-1α (HIF-1α), implicating a hypoxia-mediated mechanism in neurodegeneration. We observed disruption of the blood brain barrier beginning at 13W, with progressive changes by 16W. MRI-T2 imaging showed significantly larger infarct sizes on the left as compared to the right side hippocampus of experimental rats versus controls (1409656.67±262032 and 1174952.89±145886 (mean±SE), respectively; p<0.009). Our results indicate that chronic hypertension may effect neurodegenerative changes, not only in the white matter, but also in the cortex and hippocampus. Supported by NIH/NINDS RO1 NS045847-07A1.

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