Emergence of spontaneous seizures during the year following lithium/pilocarpine-induced epilepsy and neuronal loss within the right temporal cortices

OBJECTIVES/SPECIFIC AIMS: We previously developed a translationally relevant model of temporal lobe epilepsy (TLE) in which glutamine synthetase is irreversibility inhibited by methionine sulfoximine (MSO), resulting in spontaneous seizures and dentate hilar neuron loss. The objective of this study was to determine the effects of chronic BCAA ingestion on neuronal viability in the dentate hilus in the MSO model of TLE. METHODS/STUDY POPULATION: Sixteen rats were randomly divided into 2 groups: 8 rats drank a 4% aqueous solution of all 3 BCAAs (BCAA group) ad libitum for 31 days, and the other 8 rats drank regular water (control group) for the same period. After 10 days of drinking, a microinfusion cannula (Alzet osmotic pump, model 2004) was surgically implanted in the right dentate gyrus to continuously infuse MSO at a rate of 0.625 g/hour for 28 days. After 31 days of drinking, rats were perfused transcardially with 0.9% NaCl followed by 4% paraformaldehyde in phosphate buffer. The brains were removed and fixed, sectioned on a Vibratome at 50-μm thickness, and were mounted on a gelatin-coated slides and stained with NeuN. Neuron counts in the hilar region were performed ipsilateral and contralateral to the infusion site using a stereological technique. RESULTS/ANTICIPATED RESULTS: Rats in the BCAA group had 37% fewer neurons in the ipsilateral dentate hilus than the control group (5.8×10−4±6.8×10−5 vs. 8.9×10−4±5.6×10−5 cells, respectively, p<0.01). Similarly, rats in the BCAA group had 39% fewer neurons in the contralateral dentate hilus than the control group (5.0×10−4±5.8×10−5 vs. 7.0×10−4±3.4×10−5 cells, respectively, p=0.01). DISCUSSION/SIGNIFICANCE OF IMPACT: This study demonstrates that chronic ingestion of BCAAs aggravates hilar neuronal loss in a translationally relevant rodent model of MTLE. This study gives important insight into how BCAAs may affect neuronal viability. Although the role of BCAAs on seizure activity is poorly understood, these results suggest that BCAAs may play an important role in neurochemical modulation and neurotoxicity.

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An autopsy-proven case of Corticobasal degeneration heralded by Pontine infarction

BMC Neurology ◽

10.1186/s12883-021-02178-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dallah Yoo ◽

Sung-Hye Park ◽

Sungwook Yu ◽

Tae-Beom Ahn

Keyword(s):

Neurodegenerative Disorders ◽

Clinical Manifestations ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Executive Dysfunction ◽

Lacunar Infarction ◽

Cortical Atrophy ◽

Dystonic Posturing ◽

Proven Case ◽

The Right

Abstract Background Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction. Case presentation A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration. Conclusions The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.

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Locally Applied Valproate Enhances Survival in Rats after Neocortical Treatment with Tetanus Toxin and Cobalt Chloride

BioMed Research International ◽

10.1155/2013/497485 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Dirk-Matthias Altenmüller ◽

Jonas M. Hebel ◽

Michael P. Rassner ◽

Silvanie Volz ◽

Thomas M. Freiman ◽

...

Keyword(s):

Tetanus Toxin ◽

Cobalt Chloride ◽

Local Application ◽

Controlled Study ◽

Epileptic Focus ◽

Depth Electrodes ◽

Spontaneous Seizures ◽

Neocortical Epilepsy ◽

The Right ◽

Therapy Strategies

Purpose. In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2).Methods. In rats, VPA (n=5) or sodium chloride (NaCl) (n=5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes.Results. All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P<0.01). In both groups, witnessed deaths occurred in the context of seizures. At least3/4of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures.Conclusions. The novel TeT/CoCl2approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.

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Investigation of the Neuronal Aggregate Generating Seizures in the Rat Tetanus Toxin Model of Epilepsy

Journal of Neurophysiology ◽

10.1152/jn.00211.2002 ◽

2002 ◽

Vol 88 (6) ◽

pp. 2919-2927 ◽

Cited By ~ 26

Author(s):

G. T. Finnerty ◽

J.G.R. Jefferys

Keyword(s):

Phase Difference ◽

Tetanus Toxin ◽

Neuronal Networks ◽

Dorsal Hippocampus ◽

Interictal Spikes ◽

Population Spikes ◽

Spontaneous Seizures ◽

Spatially Distributed ◽

The Right

A key question in epilepsy is the organization and size of the neuronal networks necessary for generating seizures. Hypotheses include: a single focal neuronal network drives seizure discharges across the brain, which may or may not be identical with the circuits that generate interictal spikes; or multiple neuronal networks link together in re-entrant loops or other long-range networks. It remains unclear whether any of these hypotheses apply to spontaneous seizures in freely moving animals. We used the tetanus toxin chronic model of epilepsy to test the different predictions made by each hypothesis about the propagation and interaction of epileptic discharges during seizures. Seizures could start in either the injected or noninjected dorsal hippocampus, suggesting that seizures have multifocal onsets in the tetanus toxin model. During seizures, individual bursts propagated in either direction, both between the right and left dorsal hippocampi, and between CA3 and the dentate gyrus in the same hippocampus. These findings argue against one site “driving” seizures or seizures propagating around a limbic loop. Specifically, the side leading each burst switched a median of three times during the first 20 s of a seizure. Analysis of bursts during seizures suggested that the network at each recording site acted like a neuronal oscillator. Coupling of population spikes in right and left CA3 increased during the early part of seizures, but the cross-correlation of their whole-discharge waveforms changed little over the same period. Furthermore, the polarity of the phase difference between population spikes did not follow the phase difference for complete discharges. We concluded that the neuronal aggregate necessary for seizures in our animals comprises multiple spatially distributed neuronal networks and that the increased synchrony of the output (population spike firing) of these networks during the early part of seizures may contribute to seizure generation.

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Deficits in motor and cognitive functions in an adult mouse model of hypoxia-ischemia induced stroke

Scientific Reports ◽

10.1038/s41598-020-77678-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Li Feng ◽

Chun-Xia Han ◽

Shu-Yu Cao ◽

He-Ming Zhang ◽

Gang-Yi Wu

Keyword(s):

Cognitive Deficits ◽

Neuronal Loss ◽

Behavioral Changes ◽

Morris Water Maze Test ◽

Functional Deficits ◽

Stroke Research ◽

Ipsilateral Striatum ◽

Histological Data ◽

The Right

AbstractIschemic strokes cause devastating brain damage and functional deficits with few treatments available. Previous studies have shown that the ischemia-hypoxia rapidly induces clinically similar thrombosis and neuronal loss, but any resulting behavioral changes are largely unknown. The goal of this study was to evaluate motor and cognitive deficits in adult HI mice. Following a previously established procedure, HI mouse models were induced by first ligating the right common carotid artery and followed by hypoxia. Histological data showed significant long-term neuronal losses and reactive glial cells in the ipsilateral striatum and hippocampus of the HI mice. Whereas the open field test and the rotarod test could not reliably distinguish between the sham and HI mice, in the tapered beam and wire-hanging tests, the HI mice showed short-term and long-term deficits, as evidenced by the increased number of foot faults and decreased hanging time respectively. In cognitive tests, the HI mice swam longer distances and needed more time to find the platform in the Morris water maze test and showed shorter freezing time in fear contextual tests after fear training. In conclusion, this study demonstrates that adult HI mice have motor and cognitive deficits and could be useful models for preclinical stroke research.

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[D-Ala2, D-Leu5]-Enkephalin (Dadle) Reduces Inflammation Responses after Transient Global Ischemia

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.345.343 ◽

2011 ◽

Vol 345 ◽

pp. 343-348

Author(s):

Shu Yan Wang ◽

Ya Le Duan ◽

Qing Wen Zeng ◽

Zheng Zhao ◽

Xiang Rui Wang

Keyword(s):

Neuronal Loss ◽

Brain Regions ◽

Global Ischemia ◽

Single Infusion ◽

Vessel Occlusion ◽

Ischemic Brain ◽

Transient Global Ischemia ◽

Δ Opioid Receptor ◽

The Right ◽

Inflammation Responses

[D-Ala2, D-Leu5]-Enkephalin (DADLE) is a δ-opioid receptor antagonist and has been shown to reduce neuronal loss in the selectively vulnerable brain regions after transient global ischemia. Here, we investigate whether this protection is mediated by the DADLE's modulation of the postischemia inflammation responses. After implanted with cannula at the right lateral ventricle, rats underwent 10 minutes of transient global ischemia by four vessel occlusion. Rats received a single infusion of DADLE (12.5 nmol) via the intracerebral cannula at the onset of reperfusion. At the time of 72 h after ischemia, we investigated GFAP expression via immunohistochemistry. we also tested the level of MDA and the activities of SOD and CAT. The results show that DADLE can reduce reactive astrocytosis and increase SOD activities. The study reveals the neuroprotection mechanism of DADLE in the ischemic brain is related to reduce inflammation responses.

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Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms21082820 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2820 ◽

Cited By ~ 1

Author(s):

Na Kyung Lee ◽

Hunnyun Kim ◽

Jehoon Yang ◽

Jeyun Kim ◽

Jeong Pyo Son ◽

...

Keyword(s):

Cognitive Impairment ◽

Disease Progression ◽

Treatment Options ◽

Neuronal Loss ◽

Vascular Cognitive Impairment ◽

Wild Type ◽

Heterogeneous Nature ◽

Vascular Compromise ◽

5Xfad Mice ◽

The Right

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer’s disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.

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An Autopsy Case of Preclinical/Early Clinical Pick Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz077 ◽

2019 ◽

Vol 78 (10) ◽

pp. 971-974

Author(s):

Keitaro Okada ◽

Yukiko Hata ◽

Yoichiro Takayanagi ◽

Tsutomu Takahashi ◽

Isao Takayanagi ◽

...

Keyword(s):

Granular Layer ◽

Neuronal Loss ◽

Anterior Cingulate ◽

Cingulate Gyrus ◽

Anterior Cingulate Gyrus ◽

Pick Bodies ◽

Temporal Lobes ◽

History Of ◽

The Right ◽

Pick Disease

Abstract Here, we report a 74-year-old woman with a long history of schizophrenia but no clinical manifestation of dementia. Cause of death after autopsy was atherosclerotic heart disease. Although neuropathological investigation showed no significant brain atrophy, superficial microvacuolation with neuronal loss was restrictedly detected in the right anterior cingulate gyrus by microscopic examination. Pick bodies (PBs) positive for Bodian and Bielshowsky staining and 3-repeat-tau were detected in frontal and temporal lobes and limbic regions. Prevalence of PBs was most frequent in the right anterior cingulate gyrus and lateral base, followed by other neocortical regions of the frontal lobe, amygdala, and granular layer of the hippocampus. Although the number of glial inclusions was low, ramified astrocytes and various forms of astrocytes with AT8-positive inclusions were also found. Thus, the case may reflect preclinical or very early clinical Pick disease. Distribution of PBs does not necessarily have to be consistent with previously reported preclinical/early clinical Pick disease. These results show that tau pathology in the earlier stage of Pick disease may be heterogeneous, and the anterior cingulate gyrus may be initially affected in Pick disease. Neuropathological examination, including immunohistochemistry without case selection, is useful in identifying clinical and pathological manifestations of Pick disease.

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The Effects of IGF-1 Treatment after Hypoxic-Ischemic Brain Injury in Adult Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.79 ◽

1993 ◽

Vol 13 (4) ◽

pp. 609-616 ◽

Cited By ~ 148

Author(s):

Jian Guan ◽

Chris Williams ◽

Mark Gunning ◽

Carina Mallard ◽

Peter Gluckman

Keyword(s):

Neuronal Loss ◽

Ischemic Injury ◽

Insulin Receptors ◽

Intraventricular Injection ◽

Dependent Manner ◽

Protective Effects ◽

Adult Rats ◽

Cortical Temperature ◽

The Right ◽

Hypoxic Ischemic Injury

Intraventricular injection of insulin-like growth factor 1 (IGF-1) 2 h after hypoxic–ischemic injury reduces neuronal loss. To clarify the mode of action, we compared histological outcome between treatment groups in the following three studies: 0, 0.5, 5, and 50 μg IGF-1 given 2 h after injury; 0 and 20 μg IGF-1 given 1 h before; and 20 μg IGF-1 and insulin or vehicle alone given 2 h after. Unilateral hypoxic-ischemic injury was induced in adult rats by ligation of the right carotid and exposure to 6% O2 for 10 min. Histological outcome was evaluated in the cortex, striatum, and hippocampus 5 days later. Five to 50 μg IGF-1 reduced the incidence of infarction and neuronal loss in a dose-dependent manner in all regions (p < 0.05), and 50 μg reduced the infarction rate from 87 to 26% (p < 0.01). Pretreatment did not alter outcome. IGF-1 improved outcome compared with equimolar doses of insulin (p < 0.05) and did not affect systemic glucose concentrations or cortical temperature. The results indicate that the neuronal protective effects of IGF-1 are specific and are not mediated via insulin receptors, hypothermia, or hypoglycemic mechanisms. Centrally administered IGF-1 appears to provide worthwhile trophic support to cells within most cerebral structures after transient hypoxic-ischemic injury.

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Unilateral Creutzfeldt-Jakob Disease Presenting as Rapidly Progressive Aphasia

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100040944 ◽

1994 ◽

Vol 21 (4) ◽

pp. 350-352 ◽

Cited By ~ 17

Author(s):

Andrew Kirk ◽

L.C. Ang

Keyword(s):

Left Hemisphere ◽

Right Hemisphere ◽

Molecular Layer ◽

Neuronal Loss ◽

Occipital Cortex ◽

Spongiform Change ◽

History Of ◽

Jakob Disease ◽

The Right ◽

Ct And Mri

Abstract:A 64-year-old man presented with a three day history of progressive Broca’s aphasia, followed within 3 weeks by exclusively right-sided myoclonus, rigidity, and dystonia. Within 4 weeks he was globally aphasie. He died within 7 weeks of onset. In the final week, rigidity and myoclonus became bilateral. CT and MRI were normal. SPECT showed diminished perfusion of the left hemisphere. EEG showed periodic discharges on the left. At autopsy, there were marked cortical spongiform change, neuronal loss, and gliosis throughout the left hemisphere and in the right occipital cortex. Elsewhere in the right hemisphere, spongiform change was non-existent to minimal. There was moderate spongiform change in the molecular layer of the cerebellar cortex, much more marked on the left. Clinical and pathological unilateral cerebral predominance extended to the ipsilateral cerebellum. Creutzfeldt-Jakob disease is an important consideration in patients with rapidly progressive unilateral cerebral signs associated with a movement disorder.

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