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.

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.

scholarly journals MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

2015 ◽  
Vol 35 (12) ◽  
pp. 1903-1909 ◽  
Author(s):  
Vincent Prinz ◽  
Anna-Maria Hetzer ◽  
Susanne Müller ◽  
Mustafa Balkaya ◽  
Christoph Leithner ◽  
...  
Keyword(s):  
Time Course ◽  
Time Window ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Ischemic Lesion ◽  
Mk 801 ◽  
Delayed Treatment ◽  
Secondary Time

Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies.

Changes in retinal ganglion cell axons after optic nerve crush: neurofilament expression is not the sole determinant of calibre

1995 ◽  
Vol 73 (9-10) ◽  
pp. 599-604 ◽  
Author(s):  
Michael Minzenberg ◽  
Michelle Berkelaar ◽  
Garth Bray ◽  
Lisa Mckerracher
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Time Course ◽  
Intact Cell ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Axonal Loss ◽  
Retinal Ganglion ◽  
Nerve Crush

After injury in the central nervous system of adult mammals, many of the axons that remain attached to their intact cell bodies degenerate and decrease in calibre. To understand this process better, we have investigated the relationship between axonal loss, cell loss, and the time course of changes in axonal calibre. Optic nerves (ONs) were crushed and the numbers and sizes of axons remaining close to the cell bodies (2 mm from the eye) and near the site of the lesion (6 mm from the eye) were determined for nerves examined between 1 week and 3 months after injury. Comparison with the retinal ganglion cell (RGC) counts from the same animals revealed that axonal loss was concomitant with cell body loss for at least the first 2 weeks after injury. However, there was no significant change in the calibre of the surviving neurons until 1 month after injury. Thereafter, the axonal calibre was decreased equally along the ON. No progressive somatofugal atrophy was observed. These decreases in axonal calibre occur much later than the immediate drop in neurofilament (NF) expression that also follows injury. The late effect of injury on axonal calibre suggests that NF expression is not the sole determinant of axon size of the RGC fibers in the ON. Other factors are likely additional contributing factors, such as the decreased rate of axonal transport that would help maintain the axonal neurofilament content.Key words: axonal calibre, axotomy, neuronal cell death, neurofilaments, retinal ganglion cell, optic nerve.

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

scholarly journals Optimized-SopungSunkiwon, a Herbal Formula, Attenuates AβOligomer-Induced Neurotoxicity in Alzheimer’s Disease Models

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jin Gyu Choi ◽  
Sun Yeou Kim ◽  
Jong Woo Kim ◽  
Myung Sook Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Medicinal Herbs ◽  
Glutathione Depletion ◽  
Age Related

Alzheimer’s disease (AD), the most common form of dementia, is an age-related neurodegenerative disease that is characterized by memory dysfunction, neuronal cell damage, and neuroinflammation. It is believed that AD-related pathology is mostly due to the overproduction of Aβ, especially the oligomeric form (AβO), in the brain. Evidence of the effects of multifunctional medicinal herbs in the treatment of AD has been steadily increasing. Optimized-SopungSunkiwon (OSS), a multiherbal formulation that is composed of six medicinal herbs derived from SopungSunkiwon, is a traditional medicine that is prescribed for neurodegenerative disorders in elderly patients. We previously reported that OSS showed an antiamnesic and memory enhancing effect in mice, but it is unknown whether OSS has a protective effect against AβO neurotoxicity. In this study, we investigated the effects of OSS in AD models induced by AβOin vitroandin vivo. We found that OSS protected neuronal cells and inhibited the generation of nitric oxide and reactive oxygen species against AβO toxicityin vitro. These results were confirmed byin vivodata that oral administration of OSS for 14 days attenuated memory impairments and neuronal cell death by modulating gliosis, glutathione depletion, and synaptic damage in the mouse hippocampus induced by AβO.

Polygalae Radix Extract Protects Cultured Rat Granule Cells Against Damage Induced by NMDA

2004 ◽  
Vol 32 (04) ◽  
pp. 599-610 ◽  
Author(s):  
Hyun Joo Lee ◽  
Ju Yeon Ban ◽  
Sang Bum Koh ◽  
Nak Sul Seong ◽  
Kyung Sik Song ◽  
...  
Keyword(s):  
Cell Death ◽  
Granule Cells ◽  
Cell Damage ◽  
Glutamate Release ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Inhibitory Effect ◽  
Trypan Blue Exclusion ◽  
Trypan Blue Exclusion Test

Polygalae Radix (PR) from Polygala tenuifolia (Polygalaceae) is traditionally used in China and Korea, as this herb has a sedative, anti-inflammatory and antibacterial agent. To extend our understanding of the pharmacological actions of PR in the CNS on the basis of its CNS inhibitory effect, the present study examined whether PR has the neuroprotective action against N-methyl-D-aspartate (NMDA)-induced cell death in primarily cultured rat cerebellar granule neurons. PR, over a concentration range of 0.05 to 5 μg/ml, inhibited NMDA (1 mM)-induced neuronal cell death, which was measured by a trypan blue exclusion test and a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. PR (0.5 μg/ml) inhibited glutamate release into medium induced by NMDA (1 mM), which was measured by HPLC. Pre-treatment of PR (0.5 μg/ml) inhibited NMDA (1 mM)-induced elevation of intracellular Ca 2+ concentration ([ Ca 2+] i ), which was measured by a fluorescent dye, Fura 2-AM, and generation of reactive oxygen species (ROS). These results suggest that PR prevents NMDA-induced neuronal cell damage in vitro.

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 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 this study, we investigated the effects of baicalein on the development of prion diseases. 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.

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