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PubMed1996

Thromboxane synthetase inhibitor ameliorates delayed neuronal death in the CA1 subfield of the hippocampus after transient global ischemia in gerbils.

Thromboxane A2 accumulates in the hippocampus after global ischemia and may play a key role in postischemic hypoperfusion. Thromboxane synthetase inhibitor (OKY-046) inhibits the accumulation of thromboxane A2 and promotes prostacycline production. Therefore, we set out to determine whether the inhibition of thromboxane synthesis would ameriolate postischemic neuronal death. Three groups of six Mongolian gerbils were subjected to different treatments: untreated control, untreated ischemia, and treated ischemia. Immediately after forebrain ischemia, OKY-046 (10 mg/kg) was injected intraperitoneally into the treated group. After 7 days of survival, the histopathology of the brain was examined. Pyramidal cell density in the CA1 sector in the treated group was 147 +/- 70 nuclei/mm (mean +/- SD), which was significantly (p < 0.05) higher than than in the untreated group (33 +/- 10 (nuclei/mm). The findings were 231 +/- 7 nuclei/mm for the control group. No significant difference was seen in the profile of temporal muscle temperature before and after ischemia between the groups. Ultrastructurally, the vessels in the CAI sector showed lumen patency in the treated group, whereas occluded vessels with an extended perivascular space were observed in the untreated group. Thromboxane synthetase inhibitor thus partly ameliorates the selective vulnerability of the hippocampus after forebrain ischemia, suggesting that thromboxane A2 is involved in the development of delayed neuronal death, independently of any thermal effect.

Animals↗

PubMed1998

Advances in Huntington's disease: implications for experimental therapeutics.

The gene mutation causing Huntington's disease was identified in 1993 as an expanded trinucleotide repeat within the coding region for a 348-kd protein called huntingtin. The mechanism by which this cytosine-adenosine-guanosine repeat produces the progressive signs and symptoms of Huntington's disease remains uncertain, but recent advances have begun to provide insights into this process. Promising developments include transgenic mouse models of Huntington's disease with neuronal intranuclear inclusions, the identification of differential neuronal features which might account for the selective vulnerability of neurons seen in Huntington's disease and further evidence for the role of excitotoxicity and impaired mitochondrial energy production. These observations have suggested new therapeutic strategies, and have lent further support for experimental therapeutics aimed at improving mitochondrial function and reducing excitotoxic injury.

Age of Onset↗

PubMed2000

Internuclear ophthalmoplegia after coronary artery catheterization and percutaneous transluminal coronary balloon angioplasty.

A retrospective chart review was performed for identification of patients with isolated internuclear ophthalmoplegia (INO) postcardiac catheterization from two neuro-ophthalmology units. Of the 110 patients with a diagnosis of INO who were evaluated during the observation period, five patients (4.5%) demonstrated relatively isolated INO occurring in the perioperative period of a cardiac endovascular procedure. These five patients underwent diagnostic catheterization alone (three patients), balloon angioplasty (one patient), or stent placement (one patient). All patients improved, with resolution of diplopia in primary position after a mean period of 82 days. The occurrence of INO in the postcardiac catheterization setting is not uncommon, and it appears to be related to dorsal pontine ischemia. The pontomesencephalic medial longitudinal fasciculus is supplied by small-caliber perforating end-arteries from the basilar trunk, which increases selective vulnerability of this area. Cardiac catheterization may precipitate microemboli involving these vessels, leading to internuclear ophthalmoplegia.

Aged↗

PubMed2001

Delirium.

BACKGROUND: Delirium is a serious and often undetected neuropsychiatric syndrome. Failure to recognize and manage delirium can lead to longer hospital stays and increased morbidity and mortality, especially among the elderly. REVIEW SUMMARY: This article reviews definitions and diagnosis. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the International Statistical Classification of Diseases and Related Health Problems, 10th edition, criteria are quite similar in their diagnostic criteria. Risk factors include advanced age, preexisting brain disease or cognitive impairment, multiple medications, and severe medical problems. Delirium in the elderly can be more subtle and recovery more prolonged. Diagnosis is more complex if there is already an underlying dementia. An organized approach should be used to discover etiology and in ordering appropriate laboratory studies. At the cellular level, delirium is considered to be a reversible disregulation of neuronal membrane function. This involves a selective vulnerability of certain populations of neurons and neurotransmitter dysfunction. Practical treatment issues are reviewed. CONCLUSIONS: Despite advances, delirium is usually still diagnosed at the bedside. Having an organized approach to diagnosis and understanding the underlying pathophysiology should help with overall evaluation and treatment.

Journal Article↗

PubMed2005

Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in Pick disease.

Group I metabotropic glutamate receptors (mGluR1) regulate synaptic transmission through the stimulation of phospholipase Cbeta1 (PLCbeta1) and then by the activation of protein kinase C (PKC). Considering these properties, it is conceivable that major cortical functional deficits may be attributed to abnormal mGluR processing and signaling. The present work examines mGluRI expression and signaling in the frontal cortex (area 8) of 3 cases with Pick disease (PiD), a neurodegenerative disease with abnormal phospho-tau accumulation, in comparison with 3 age-matched controls by means of glutamate binding assays, enzymatic activity, gel electrophoresis and Western blotting, solubility and immunoprecipitation assays, and confocal microscopy. Reduced expression levels of PLCbeta1 and reduced PLCbeta1 activity have been found in PiD. The expression levels of the nonrelated phospholipase PLCgamma, a substrate of tyrosine kinase, are also reduced in PiD. This is accompanied by a marked decrease in the expression of cPKCalpha and increased expression of the inner band (76 kDa) of the nPKCdelta doublet at the expense of a decrease of the phosphorylated (active) form (78 kDa). In contrast, L-[3H]glutamate-specific binding to mGluRs is augmented in PiD cases, mainly because of the higher mGluR1 and mGluRs expression levels detected. No modifications in PLCbeta1 solubility have been observed in PiD and no interactions between PLCbeta1 and tau have been demonstrated in diseased and control cases. Moreover, double-labeling immunofluorescence and confocal microscopy have shown no colocalization of phospho-tau (AT8 antibody) and PLCbeta1 in phospho-tau inclusions, including Pick bodies. These results demontrate for the first time abnormal mGluR signaling in the cerebral cortex in PiD and selective vulnerability of phospholipases and PKC to PiD.

Aged↗

PubMed2005

Brain damage after heat stroke.

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammon's horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

Aged↗

PubMed2005

The jaundiced gunn rat model of auditory neuropathy/dyssynchrony.

OBJECTIVE: High levels of bilirubin are neurotoxic and may result in deafness or auditory neuropathy/auditory dyssynchrony (AN/AD). The jaundiced (jj) Gunn rat animal model of kernicterus has electrophysiologic and neuroanatomic abnormalities of brainstem auditory nuclei with normal cochlear microphonic recordings. We examined morphologic changes in the cochlea, spiral ganglion, and auditory nerve and relate these findings to current understanding of AN/AD. METHODS: At 15 days of age, jj and nonjaundiced (Nj) littermates were injected with sulfadimethoxine (sulfa) and killed 3 days later by transcardial perfusion. Sections were cut through decalcified temporal bones, cochlear nerves, and auditory brainstem and processed for light and electron microscopy and immunohistochemical localization of calbindin-D and parvalbumin. RESULTS: Spiral ganglion neurons were severely degenerated with a paucity of myelinated axons in jj animals. Electron microscopy of the intramodilar auditory nerve revealed a lack of large caliber axons in jj-sulfa versus Nj-sulfa controls. Large diameter degenerating axons were characterized by an electron-dense atrophied axis cylinder resembling an axonopathy. CONCLUSIONS: Our findings of abnormal spiral ganglion cells and selective loss of large, myelinated auditory nerve fibers with no abnormalities in cochlear hair cells, support the sulfa-treated jj Gunn rat as a model for bilirubin induced AN/AD. The paucity of large caliber neurons undermines temporal coding of auditory information and neural synchrony and demonstrates that in addition to brainstem auditory nuclei, spiral ganglion neurons are selectively vulnerable to bilirubin toxicity.

Animals↗

PubMed2003

Diffusion magnetic resonance imaging study of a rat hippocampal slice model for acute brain injury.

Diffusion magnetic resonance imaging (MRI) provides a surrogate marker of acute brain pathology, yet few studies have resolved the evolution of water diffusion changes during the first 8 hours after acute injury, a critical period for therapeutic intervention. To characterize this early period, this study used a 17.6-T wide-bore magnet to measure multicomponent water diffusion at high b-values (7 to 8,080 s/mm(2)) for rat hippocampal slices at baseline and serially for 8 hours after treatment with the calcium ionophore A23187. The mean fast diffusing water fraction (Ffast) progressively decreased for slices treated with 10-microM/L A23187 (-20.9 +/- 6.3% at 8 hours). Slices treated with 50-micromol/L A23187 had significantly reduced Ffast 80 minutes earlier than slices treated with 10-microM/L A23187 (P < 0.05), but otherwise, the two doses had equivalent effects on the diffusion properties of tissue water. Correlative histologic analysis showed dose-related selective vulnerability of hippocampal pyramidal neurons (CA1 > CA3) to pathologic swelling induced by A23187, confirming that particular intravoxel cell populations may contribute disproportionately to water diffusion changes observed by MRI after acute brain injury. These data suggest diffusion-weighted images at high b-values and the diffusion parameter Ffast may be highly sensitive correlates of cell swelling in nervous issue after acute injury.

Acute Disease↗

PubMedDate not supplied

Bilirubin encephalopathy.

In babies of low birth weight dying in the first week of life, bilirubin encephalopathy involving the thalamus only or the thalamus and one or two other areas occurred in nineteen of 376 cases examined over a 10 year period. Although coexistent germinal layer haemorrhage was present in sixteen, this was not thought to be an aetiological factor. Bile stained hyaline membranes in nine of the nineteen were considered to indicate the possibility of protein-bound bilirubin traversing a vascular barrier in these cases. This pattern of predominant lateral thalamic involvement may indicate selective vulnerability of this area in this group. It contrasts sharply with the localization in classical kernicterus (three cases) and in a disparate group where yellow discolouration of future white matter areas was observed (thirteen cases).

Bilirubin↗

PubMedDate not supplied

Excitotoxic mechanisms in hypoglycaemic hippocampal injury.

Light and electron microscopy were used to study the effect of hypoglycaemia on selectively vulnerable neurons of rat hippocampus with and without pharmacologic blockade of the N-methyl-D-aspartate (NMDA)-preferring receptor with 2-amino-7-phosphonoheptanoic acid (AP-7). In control hypoglycaemic hippocampi, dark cell change occurs predominantly in dentate granule cells. The topography and ultrastructural appearance of these changes is distinct from that produced by ischaemia or status epilepticus. In hypoglycaemia, mitochondrial calcium accumulation characteristic of ischaemia or status epilepticus is not seen. NMDA receptor blockade markedly attenuates the hypoglycaemic cell injury. Similar attenuation of ischaemic and epileptic brain damage by NMDA receptor blockade suggest that excessive neuronal excitation is a common mechanism of injury in each of the three conditions.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Neuronal alterations in hippocampus following severe hypoglycaemia: a light microscopic and ultrastructural study in the rat.

Because they induce similar neuropathological changes (ischaemic cell change with microvacuolization), it has been suggested that ischaemia, status epilepticus and hypoglycaemia produce cell death by similar mechanisms, especially those resulting from intracellular calcium accumulation. We have recently demonstrated microvacuolation of neurons, mitochondrial swelling (the electron microscopic correlate of microvacuolization) and massive mitochondrial calcium sequestration (using the pyroantimonate technique) following ischaemia or status epilepticus. We therefore studied the selectively vulnerable neurons of rat hippocampus by light and electron microscopy (including the pyroantimonate technique) following 30 and 60 min of EEG isoelectricity resulting from insulin hypoglycaemia. The neuropathology at the light and EM level is unique and different from that following status epilepticus or ischaemia. The most constant finding is dark cell change of the granule cells at the tip of the dentate gyrus. In contrast to status epilepticus and ischaemia, hippocampal pyramidal neurons are far less frequently involved. Microvacuoles are rarely seen and, when present, their ultrastructural correlate is swollen Golgi apparatus, not dilated mitochondria. No intracellular calcium accumulation is demonstrable with pyroantimonate technique. Thus the cellular alterations produced by hypoglycaemia differ in character and distribution from those produced by anoxia-ischaemia. Mitochondrial calcium accumulation is not prominent in cell death from hypoglycaemia. Whether calcium toxicity plays another, subtler role in hypoglycaemic brain injury is unknown.

Animals↗

PubMed2004

Up-regulation of a growth arrest and DNA damage protein (GADD34) in the ischaemic human brain: implications for protein synthesis regulation and DNA repair.

GADD34 is a growth arrest and DNA damage inducible gene up-regulated in response to DNA damage, cell cycle arrest and apoptosis. It is thought that GADD34 may play a crucial role in cell survival in ischaemia. GADD34 expression was assessed immunohistochemically in post-mortem human hippocampal tissue obtained from patients surviving for defined periods (0-24 h; 24 h-7 days) after a cardiac arrest and in age-matched control subjects. In control brain, cytoplasm staining in GADD34 immunopositive cells was faint but present throughout the hippocampus and cortex. There was minimal change in GADD34 expression in the group surviving 0-24 h after cardiac arrest. However GADD34 immunostaining was markedly increased in selectively vulnerable regions in the 24 h-7 day survival group. Increased GADD34 staining was present in ischaemic neurones and in some morphologically normal neurones after cardiac arrest. Extensive ischaemic damage was found to correlate with elevated GADD34 immunostaining in the CA1 layer of the hippocampus (**P < 0.0016). In addition, GADD34 was found to colocalize with proliferating cell nuclear antigen in some neurones. The up-regulation of GADD34 in response to global ischaemia in the human brain plus its influence on protein synthesis and DNA repair suggests that this protein may have the potential to influence cell survival.

Adolescent↗

PubMed1994

Neuropathology of cerebral ischemia and hypoxia: recent advances in experimental studies on its pathogenesis.

Cerebral hypoxia and ischemia are two of the most common disorders of the central nervous system. The pathomechanism has been a focus of interest in neuroscience for many years not only because of the clinical significance but also because of the peculiar distribution of the lesion (selective vulnerability) depending on the type of injury. This article reviews recent advances in the study of hypoxia-induced tissue injury of the central nervous system.

Anemia↗

PubMed2003

Structural and functional dichotomy of human midcingulate cortex.

Anterior cingulate cortex is comprised of perigenual and midcingulate regions based on cytology, imaging and connections. Its anterior (aMCC) and posterior (pMCC) parts and transition to posterior area 23 were evaluated in six human cingulate gyri with Nissl staining and immunoreactions for neuron-specific nuclear binding protein and intermediate neurofilament proteins (NFP), and their pain and emotion functions evaluated in standard coordinates. Morphological differences included a poorly differentiated layer III with few NFP-expressing neurons in aMCC and a very dense layer Va with small and large pyramids intermingled in pMCC. The density of NFP-positive, layer Vb neurons was higher in pMCC than in aMCC. The junction of pMCC with area 23 had a dysgranular area 23d with clumps of layer IV neurons and a very dense layer Va. Each case was co-registered to standard coordinates and the regional borders identified and measured. Although both regions had overall equivalent activations during noxious cutaneous thermal stimulation, the posterior two-thirds of pMCC was relatively inactive. About 60% of fear-induced activity was in aMCC, sadness and happiness activated perigenual cortex, and neither were activated with non-emotion tasks. Thus, pain activity is coupled to fear in aMCC, while other MCC processing is not related to affect. Beyond midcingulate duality, this is the first report of a very dense layer Va for areas p24' and 23 and the features of transitional area 23d. The MCC dichotomy suggests that two circuits differentially regulate the two cingulate motor areas, and involvement of aMCC in pain and fear make it selectively vulnerable to chronic pain and stress syndromes.

Adult↗

PubMed2006

Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain.

Deficits of neurotrophic support caused by reduced levels of brain-derived neurotrophic factor (BDNF) have been implicated in the selective vulnerability of striatal neurones in Huntington's disease (HD). Therapeutic strategies based on BDNF administration have been proposed to slow or prevent the disease progression. However, the effectiveness of BDNF may depend on the proper expression of its receptor TrkB. In this study, we analysed the expression of TrkB in several HD models and in postmortem HD brains. We found a specific reduction of TrkB receptors in transgenic exon-1 and full-length knock-in HD mouse models and also in the motor cortex and caudate nucleus of HD brains. Our findings also demonstrated that continuous expression of mutant huntingtin is required to down-regulate TrkB levels. This was shown by findings in an inducible HD mouse model showing rescue of TrkB by turning off mutant huntingtin expression. Interestingly, the length of the polyglutamine tract in huntingtin appears to modulate the reduction of TrkB. Finally, to analyse the effect of BDNF in TrkB we compared TrkB expression in mutant huntingtin R6/1 and double mutant (R6/1 : BDNF+/-) mice. Similar TrkB expression was found in both transgenic mice suggesting that reduced TrkB is not a direct consequence of decreased BDNF. Therefore, taken together our findings identify TrkB as an additional component that potentially might contribute to the altered neurotrophic support in HD.

Adult↗

PubMed2006

Diacylglycerol kinase zeta is involved in the process of cerebral infarction.

Diacylglycerol kinase (DGK) is an enzyme that phosphorylates a second messenger diacylglycerol (DG) and is involved in a variety of pathophysiological cellular responses. We have previously reported that DGKzeta may be involved in the selective vulnerability of hippocampal CA1 neurons in transient forebrain ischemia. In this study we aimed to further elucidate functional implications of DGK isozymes in the cerebral cortex suffering from infarction using a focal ischemic model. In the early phase of 90 min of middle cerebral artery occlusion, DGKzeta-immunoreactivity is reduced rapidly in the nucleus of cortical neurons in the ischemic core, while DGKiota and other neuronal proteins such as MAP-2 and NeuN remain intact. This suggests that rapid disappearance of DGKzeta in ischemic neurons is a quite early event precedent to neuronal degeneration in response to ischemia. Furthermore, in the late inflammatory phase of infarction DGKzeta-immunoreactivity is detected in non-neuronal cells including factor VIII-positive endothelial cells and ED-1-positive phagocytic cells. The present study suggests that DGKzeta may play roles in various processes of ischemic brain damage including neuronal death and non-neuronal inflammatory response.

Animals↗

PubMed1999

Calcium dynamics and buffering in motoneurones of the mouse spinal cord.

1. A quantitative analysis of endogenous calcium homeostasis was performed on 65 motoneurones in slices of the lumbar spinal cord from 2- to 8-day-old mice by simultaneous patch-clamp and microfluorometric calcium measurements. 2. Somatic calcium concentrations were monitored with a temporal resolution in the millisecond time domain. Measurements were performed by using a monochromator for excitation and a photomultiplier detection system. 3. Somatic calcium signalling was investigated during defined voltage-clamp protocols. Calcium responses were observed for membrane depolarizations positive to -50 mV. A linear relation between depolarization time and free calcium concentrations ([Ca2+]i) indicated that voltage-dependent calcium influx dominated the response. 4. Endogenous calcium homeostasis was quantified by using the 'added buffer' approach. In the presence of fura-2 and mag-fura-5, calcium transients decayed according to a monoexponential function. Decay-time constants showed a linear dependence on dye concentration and the extrapolated constant in the absence of indicator dye was 371 +/- 120 ms (n = 13 cells, 21 C). 5. For moderate elevations (< 1 microM), recovery kinetics of depolarization-induced calcium transients were characterized by a calcium-independent, 'effective' extrusion rate gamma = 140 +/- 47 s-1 (n = 13 cells, 21 C). 6. The endogenous calcium binding ratio for fixed buffers in spinal motoneurones was kappaB' = 50 +/- 17 (n = 13 cells), indicating that less than 2 % of cytosolic calcium ions contributed to [Ca2+]i. 7. Endogenous binding ratios in spinal motoneurones were small compared to those found in hippocampal or cerebellar Purkinje neurones. From a functional perspective, they provided motoneurones with rapid dynamics of cytosolic [Ca2+]i for a given set of influx, extrusion and uptake mechanisms. 8. With respect to pathophysiological conditions, our measurements are in agreement with a model where the selective vulnerability of spinal motoneurones during excitotoxic conditions and motoneurone disease partially results from low endogenous calcium buffering.

Animals↗

PubMed1983

Effects of anoxia on the stimulated release of amino acid neurotransmitters in the cerebellum in vitro.

The effect of anoxia and ischemia on the release of amino acid transmitters from cerebellar slices induced by veratridine or high [K+] was studied. Synaptic specificity was tested by examining the tetradotoxin (TTX)-sensitive and the Ca2+-dependent components of stimulated release. Evoked release of endogenous amino acids was investigated in addition to more detailed studies on the stimulated efflux of preloaded [14C]GABA and D-[3H]aspartate (a metabolically more stable anologue of acidic amino acids). [14C]GABA release evoked by either method of stimulation was unaffected by periods of up to 35 min of anoxia and declined moderately by 45 min. In contrast, induced release of D-[3H]Asp increased markedly during anoxia to a peak at about 25 min, followed by a decline when anoxia was prolonged to 45 min. Evidence was obtained that the increased evoked efflux of D'[3H]Asp from anoxic slices was not due to impaired reuptake of the released amino acid and that it was completely reversible by reoxygenation of the slices. Results of experiments examining the evoked release of endogenous amino acids in anoxia were consistent with those obtained with the exogenous amino acids. Only 4 of the 10 endogenous amino acids studied exhibited TTX-sensitive veratridine-induced release under aerobic conditions (glutamate, aspartate, GABA, and glycine). Anoxia for 25 min did not affect the stimulated efflux of these amino acids with the exception of glutamate, which showed a significant increase. Compared with anoxia, effects of ischemia on synaptic function appeared to be more severe. Veratridine-evoked release of [14C]GABA was already depressed by 10 min and that of D-[3H[Asp showed a modest elevation only a 5 min. Stimulated release of D-Asp and labelled GABA declined progressively after 5 min. These findings were compared with changes in tissue ATP concentrations and histology. The latter studies indicated that in anoxia the earliest alterations are detectable in glia and that nerve terminals were the structures by far the most resistant to anoxic damage. The results thus indicated that evoked release of amino acid transmitters in the cerebellum is compromised only by prolonged anoxia in vitro. In addition, it would appear that the stimulated release of glutamate is selectively accentuated during anoxia. This effect may have a bearing on some hypoxic behavioral changes and, perhaps, also on the well-known selective vulnerability of certain neurons during hypoxia.

Amino Acids↗