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.

scholarly journals Lovastatin reduces neuronal cell death in hippocampal CA1 subfield after pilocarpine-induced status epilepticus: preliminary results

2005 ◽  
Vol 63 (4) ◽  
pp. 972-976 ◽  
Author(s):  
Pauline Rangel ◽  
Roberta Monterazzo Cysneiros ◽  
Ricardo Mario Arida ◽  
Marly de Albuquerque ◽  
Diego Basile Colugnati ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Seizure Activity ◽  
Hippocampal Formation ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Cell Loss ◽  
Cell Number ◽  
Control Group ◽  
Cell Counts

OBJECTIVE: To further characterize the capacity of lovastatin to prevent hippocampal neuronal loss after pilocarpine-induced status epilepticus (SE) METHOD: Adult male Wistar rats were divided into four groups: (A) control rats, received neither pilocarpine nor lovastatin (n=5); (B) control rats, received just lovastatin (n=5); (C) rats that received just pilocarpine (n=5); (D) rats that received pilocarpine and lovastatin (n=5). After pilocarpine injection (350mg/kg, i.p.), only rats that displayed continuous, convulsive seizure activity were included in our study. Seizure activity was monitored behaviorally and terminated with an injection of diazepam (10 mg/kg, i.p.) after 4 h of convulsive SE. The rats treated with lovastatin received two doses of 20mg/kg via an oesophagic probe immediately and 24 hours after SE induction. Seven days after pilocarpine-induced SE, all the animals were perfused and their brains were processed for histological analysis through Nissl method. RESULTS: The cell counts in the Nissl-stained sections performed within the hippocampal formation showed a significant cell loss in rats that received pilocarpine and presented SE (CA1= 26.8 ± 13.67; CA3= 38.1 ± 7.2; hilus= 43.8 ± 3.95) when compared with control group animals (Group A: CA1= 53.2 ± 9.63; CA3= 63.5 ± 13.35; hilus= 59.08 ± 10.24; Group B: CA1= 74.3 ± 8.16; CA3= 70.1 ± 3.83; hilus= 70.6 ± 5.10). The average neuronal cell number of CA1 subfield of rats that present SE and received lovastatin (44.4 ± 17.88) was statically significant increased when compared with animals that just presented SE. CONCLUSION: Lovastatin exert a neuroprotective role in the attenuation of brain damage after SE.

scholarly journals Mutant A53T α-Synuclein Induces Neuronal Death by Increasing Mitochondrial Autophagy

2011 ◽  
Vol 286 (12) ◽  
pp. 10814-10824 ◽  
Author(s):  
Vinay Choubey ◽  
Dzhamilja Safiulina ◽  
Annika Vaarmann ◽  
Michal Cagalinec ◽  
Przemyslaw Wareski ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Mitochondrial Dysfunction ◽  
Cortical Neurons ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Dominant Negative ◽  
Contributing Factors ◽  
Mitofusin 2

Parkinson disease is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. α-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of α-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T α-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T α-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models.

scholarly journals Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

2003 ◽  
Vol 23 (10) ◽  
pp. 1117-1128 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Protein Modification ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Animals ◽  
Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

scholarly journals Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Kazuyuki Miyamoto ◽  
Hirokazu Ohtaki ◽  
Kenji Dohi ◽  
Tomomi Tsumuraya ◽  
Dandan Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Time Window ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

scholarly journals Mud sticks after all: Chronically implanted microelectrodes but not electrical stimulation cause c-fos expression along their trajectory

2017 ◽  
Author(s):  
Patrick Pflüger ◽  
Richard C. Pinnell ◽  
Nadja Martini ◽  
Ulrich G. Hofmann
Keyword(s):  
Brain Tissue ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Glial Scar ◽  
Tissue Response ◽  
High Frequency Stimulation ◽  
Dorsolateral Striatum ◽  
Frequency Stimulation ◽  
The Brain

ABSTRACTThe goal of CNS implanted devices is to build a stable brain-machine-interface. The brain tissue response to the foreign body limits the functionality and viability of this brain-machine connection. Notably the astrocytic glial scar formation and inflammation with resulting neuronal cell loss is considered to be responsible for the signal deterioration over time. We chronically implanted a polyimide microelectrode in the dorsolateral striatum of rats. First, we analyzed the c-fos immunoreactivity following high frequency stimulation (HFS) of the dorsolateral striatum and second, using GFAP and ED1 immunocytochemistry, the brain tissue response. Acute as well as chronic HFS showed no significant change of neuronal c-fos expression in the dorsolateral striatum and corresponding cortical areas. We found that the sole chronic implantation of a polyimide microelectrode leads to a reaction of the surrounding neurons, i.e. c-fos expression, along the implantation trajectory. We also observed the formation of a glial scar around the microelectrode with a low number of inflammation cells. Histological and statistical analysis of NeuN positive cells showed no ‘kill zone’, which accompanied neuronal cell death around the implantation site.

scholarly journals Neuroinflammatory Cytokine Response, Neuronal Death and Microglial Proliferation in the Hippocampus of Rats During the Early Period After Lateral Fluid-Percussion-Induced Traumatic Injury of the Neocortex

2021 ◽  
Author(s):  
Ilia G. Komoltsev ◽  
Liya V. Tretyakova ◽  
Stepan O. Frankevich ◽  
Natalia I. Shirobokova ◽  
Aleksandra A. Volkova ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Time Course ◽  
Traumatic Injury ◽  
Early Period ◽  
Neuronal Cell ◽  
Corticosterone Level ◽  
Cell Loss ◽  
Hippocampal Damage ◽  
Fluid Percussion ◽  
Lateral Fluid Percussion

Abstract Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid-percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response.

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.

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.

scholarly journals Novel Neuroprotective Agents to Treat Neonatal Hypoxic-Ischemic Encephalopathy: Inter-Alpha Inhibitor Proteins

2020 ◽  
Vol 21 (23) ◽  
pp. 9193
Author(s):  
Liam M. Koehn ◽  
Xiaodi Chen ◽  
Aric F. Logsdon ◽  
Yow-Pin Lim ◽  
Barbara S. Stonestreet
Keyword(s):  
Brain Injury ◽  
Premature Infants ◽  
Time Window ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neonatal Rat ◽  
Hypoxic Ischemic Encephalopathy ◽  
Limited Effectiveness ◽  
Ischemic Encephalopathy

Perinatal hypoxia-ischemia (HI) is a major cause of brain injury and mortality in neonates. Hypoxic-ischemic encephalopathy (HIE) predisposes infants to long-term cognitive deficits that influence their quality of life and place a large burden on society. The only approved treatment to protect the brain after HI is therapeutic hypothermia, which has limited effectiveness, a narrow therapeutic time window, and is not considered safe for treatment of premature infants. Alternative or adjunctive therapies are needed to improve outcomes of full-term and premature infants after exposure to HI. Inter-alpha inhibitor proteins (IAIPs) are immunomodulatory molecules that are proposed to limit the progression of neonatal inflammatory conditions, such as sepsis. Inflammation exacerbates neonatal HIE and suggests that IAIPs could attenuate HI-related brain injury and improve cognitive outcomes associated with HIE. Recent studies have shown that intraperitoneal treatment with IAIPs can decrease neuronal and non-neuronal cell death, attenuate glial responses and leukocyte invasion, and provide long-term behavioral benefits in neonatal rat models of HI-related brain injury. The present review summarizes these findings and outlines the remaining experimental analyses necessary to determine the clinical applicability of this promising neuroprotective treatment for neonatal HI-related brain injury.

scholarly journals Diabetes Accelerates Retinal neuronal cell Death in A Mouse Model of endogenous Hyperhomocysteinemia

2009 ◽  
Vol 1 ◽  
pp. OED.S2855 ◽  
Author(s):  
Preethi S. Ganapathy ◽  
Penny Roon ◽  
Tracy K.V.E. Moister ◽  
Barbara Mysona ◽  
Sylvia B. Smith
Keyword(s):  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Plasma Homocysteine ◽  
Retinal Ganglion ◽  
Neuronal Cell Loss ◽  
Onset Of Diabetes ◽  
Plexiform Layers ◽  
Post Onset

Hyperhomocysteinemia has been implicated in visual dysfunction. We reported recently that mice with endogenous hyperhomocysteinemia, due to mutation of the cystathionine-β-synthase ( cbs) gene, demonstrate loss of neurons in the retinal ganglion cell (RGC) layer and other retinal layers as homocysteine levels increase. Some clinical studies implicate hyperhomocysteinemia in the pathogenesis of diabetic retinopathy, which is also characterized by RGC loss. The present study used cbs+/– mice to determine whether modest elevation of plasma homocysteine, in the presence of diabetes, accelerates neuronal cell loss. Diabetes (DB) was induced in 3 wk old cbs+/– and wildtype mice using streptozotocin; four groups of mice were studied: DB cbs+/– non-DB cbs+/– DB cbs+/+; non-DB cbs+/+. One group of diabetic cbs+/– mice was maintained on a high methionine diet (HMD, 0.5% methionine drinking water) to increase plasma homocysteine slightly. Eyes were harvested at 5, 10 and 15 weeks post-onset of diabetes; retinal cryosections were examined by light microscopy and subjected to systematic morphometric analysis. Diabetic cbs+/– had significantly fewer RGCs at 5 weeks compared to age-matched, non-diabetic cbs+/– and wildtype controls (10.0 ± 0.5 versus 14.9 ± 0.5 and 15.8 ± 0.6 cells/100 μm retina length, respectively). Significant differences in retinas of DB/high homocysteine versus controls were obtained 15 wks post-onset of diabetes including fewer RGCS and decreased thickness of inner nuclear and plexiform layers. Moderate increases in plasma homocysteine coupled with diabetes cause a more dramatic alteration of retinal phenotype than elevated homocysteine or diabetes alone and suggest that diabetes accelerates the retinal neuronal death in hyperhomocysteinemic mice.

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