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PubMed1984

Effects of ethanol on cultured glial cells: proliferation and glutamine synthetase activity.

The development of glial-enriched cultures prepared from 15-day-old embryonic chick cerebral hemispheres was examined after exposure to ethanol. Between culture days 6 and 10, ethanol was added to the medium at 4 concentrations: 0.1%, 0.5%, 1.0% and 2.0% (w/v). During the drug exposure interval, morphologic maturation of the cultures was surveyed with phase microscopy; cell proliferation was assessed by cell counts and DNA content. Exposure to ethanol concentrations of 0.1% and 0.5% resulted in only minimal changes in the parameters investigated, whereas biosynthetic and enzymatic activities were altered at a threshold dose of 1.0% ethanol. A small number of cells resembling reactive astrocytes were encountered in cultures exposed to 1.0% and 2.0% ethanol. In these cultures the number of cells and DNA content were lower than in control cultures. Additionally, [14C]leucine incorporation into protein and glutamine synthetase activity were markedly diminished in cultures treated with 1.0% and 2.0% ethanol. The ethanol-related reduction in glutamine synthetase activity was not accompanied by an equivalent decrease in protein content, suggesting that glutamine synthetase or cells rich in this enzyme are selectively vulnerable to ethanol. Impairment in glutamate/glutamine metabolism may be a potential consequence of ethanol-induced changes in glutamine synthetase activity.

Animals↗

PubMed1992

Ultrastructure of spared dopamine terminals in caudate-putamen nuclei of adult rats neonatally treated with intranigral 6-hydroxydopamine.

Residual dopamine terminals in the dorsal striatum, caudate-putamen nuclei (CPN), of adult rats neonatally lesioned with 6-hydroxydopamine (6-OHDA) sustain a relatively high level of dopamine release. We examined whether there were morphological differences in the spared dopamine terminals that might correlate with this increased efficacy. Postnatal male rat pups from 50 litters were pretreated with desmethylimipramine (DMI) to protect from non-specific monoamine damage, then given unilateral intranigral injections of 6-OHDA or vehicle. Coronal sections through the CPN and substantia nigra of the surviving adult animals from each litter were co-processed for immunoautoradiographic or immunoperoxidase localization of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). Quantitative ultrastructural analysis established that in animals showing maximal (greater than 90%) depletions in immunoautoradiographic labeling for TH, the number of TH-labeled axons in the CPN ipsilateral to the 6-OHDA injections was reduced to one third of the number seen in the contralateral, unlesioned hemisphere, or the CPN from vehicle-injected animals. The ultrastructural features of residual terminals ipsilateral to 6-OHDA lesions were morphologically similar to those of the contralateral side or in vehicle-injected animals. However, in comparison with controls, these TH-labeled terminals had significantly larger mean cross-sectional diameters. When subdivided into groups according to size, there were significantly fewer small (0.0-0.1 micron 2) and more large (0.41-0.50 micron 2) TH-immunoreactive profiles in lesioned versus unlesioned CPN. The remaining TH-labeled terminals ipsilateral to the 6-OHDA lesions also appeared to be more often in direct contact with unlabeled soma and proximal dendrites as opposed to dendritic spines in the unlesioned CPN. These results suggest that the enhanced activity of dopamine neurons innervating the CPN after nigral 6-OHDA lesions may contribute to changes in size and target of their terminals. Alternatively, the observed large size of remaining dopamine terminals may reflect selective vulnerability of smaller axons to 6-OHDA toxicity.

Aging↗

PubMed1993

Increases in sulphated glycoprotein-2 mRNA levels in the rat brain after transient forebrain ischemia or partial mesodiencephalic hemitransection.

Sulphated glycoprotein-2, thought to be involved in programmed cell death in peripheral organs, has been detected at increased levels in brain degenerative states. In this paper we have investigated the regional and cellular expression of this protein during development of brain lesion. With this aim sulphated glycoprotein-2 mRNA levels were studied in models of ischemic (transient forebrain ischemia) or mechanical (partial mesodiencephalic hemitransection) brain injuries using in situ hybridization histochemistry. Marked increases in sulphated glycoprotein-2 mRNA were observed in lesioned brains in both models. In addition, we report a shift in the regional distribution of positive cells in both lesion models 1-7 days post-lesion. After transient forebrain ischemia, sulphated glycoprotein-2 mRNA increases were always localized in selectively vulnerable regions (caudate-putamen, hippocampal formation), showing a temporal change in the pattern of intraregional distribution from less to more lesioned parts. In the case of mechanical lesion at 1 day, increased labelling had a widespread distribution on the lesioned side and was also observed on the intact side near the midline. In contrast, at 7 days increased labelling was restricted to regions directly lesioned (either areas whose input and/or output connections were severed by the transection or areas which were directly affected by the mechanical lesion). Analysis at the cellular level revealed that at both time intervals and in both lesion models most cell bodies overlain by dense clusters of specific grains were non-neuronal cells. The distribution patterns and their change over time suggest that at least some of these cells are inflammatory and phagocytic cells. The majority of degenerating neuronal cells after ischemia did not show increased levels of sulphated glycoprotein-2 mRNA. However, seven days after hemitransection and at all time intervals after transient ischemia, some cells clearly identifiable as neurons exhibited increased sulphated glycoprotein-2 mRNA levels.

Animals↗

PubMed1995

The dual specificity phosphatase PAC-1 is transcriptionally induced in the rat brain following transient forebrain ischemia.

PAC-1 mRNA has previously been found only in activated T-cells in vitro and in vivo. The gene encodes a dual specificity protein phosphatase that regulates MAP kinase activity. Here, I describe that PAC-1 mRNA is induced also in neurons in the rat brain following 30 min of forebrain ischemia. At 6, 12 and 24 h after ischemia, PAC-1 mRNA was found most prominently in hippocampal cells which are resistant to 30 min of forebrain ischemia, but not in the selectively vulnerable CA1 sector. At later time points and in control animals no PAC-1 mRNA could be detected in any brain region. The protein-tyrosine/threonine phosphatase PAC-1, therefore, may be involved in adaptational responses of hippocampal cells resistant to ischemic injury.

Animals↗

PubMed1995

Differential expression of heme oxygenase-1 in cultured cortical neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress.

Heme oxygenase exists as two isoenzymes designated heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). HO-2 is made constitutively in many cell types whereas HO-1 is a stress protein inducible by heat, heavy metals, ultraviolet irradiation, and oxidative stress. Recombinant rat HO-1 was expressed in bacteria and antiserum designated HO-1713 was raised against the purified protein. HO-1713 detected recombinant rat HO-1 and recombinant rat HO-2. In rat tissues it detected HO-1 and a second, unidentified band designated HO-L (heme oxygenase-like immunoreactivity) which was not HO-2. Cultured rat cortical neurons and forebrain astrocytes were exposed to hydrogen peroxide (0.14-0.7 micromolar for 30 or 60 min). Neurons which contained little detectable HO-1 and which were sensitive to hydrogen peroxide at the high end of the dose curve failed to induce HO-1 by Western blot analysis. In contrast, cultured rat forebrain astrocytes which contained HO-1 under normal culture conditions and which were resistant to injury by hydrogen peroxide, increased their content of immunoreactive HO-1 by 7-fold within 3 h after exposure. Our results support a protective role for HO-1 in oxidative injury and suggest that the relative inability of neurons to increase HO-1 after oxidative stress may contribute to their selective vulnerability vis-a-vis astrocytes. They also suggest that differential expression of heme oxygenase in studies utilizing CNS cultures may alter normal cell physiology and cell survival.

Antibodies↗

PubMed1994

Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor.

To study the roles of bFGF and its receptor in the process of neuronal cell death and the wound repair response, we induced 10 min of transient global cerebral ischemia in rats and measured changes in expression of both bFGF and the FGF receptor, flg. CA1 pyramidal cells are selectively vulnerable to ischemia and die one to 3 days after 10 min of ischemia. In these cells, bFGF mRNA was induced by 6 hours, reached a maximal level by 24 h after ischemia, and subsequently decreased. Message for the FGF receptor, flg, was present in the pyramidal cells layer, and vanished almost completely in parallel with neuronal death. In the granule cell layer of dentate gyrus, the expression of bFGF mRNA increased more rapidly. It was maximal by 6 h and returned to the basal level by 3 days. In the hilus of the dentate gyrus, bFGF expression was maximal at 24 h and returned to control levels by 3 days. Despite the rapid changes in expression of bFGF mRNA, there was no significant change of bFGF immunoreactivity in either the CA1 pyramidal cell layer or in the granule cell layer of dentate gyrus within 3 days after ischemia. The apparent failure of the message to be efficiently translated supports the idea that translation is impaired under conditions where ischemia leads to delayed neuronal cell death. Expression of bFGF mRNA, FGFR mRNA and bFGF immunoreactivity increased dramatically in a broad area of CA1 subfield from 7 days until 30 days after ischemia because of increased expression by reactive glial cells. We suggest that these rapid and complex changes in the expression of bFGF mRNA and bFGF protein may be part of a coordinated response to ischemic injury that is designed to minimize the severity of neuron death.

Animals↗

PubMed1996

Spermidine/spermine N1-acetyltransferase mRNA levels show marked and region-specific changes in the early phase after transient forebrain ischemia.

Considerable evidence points to an involvement of natural polyamines (putrescine, spermidine and spermine) in trophic regulation of brain tissue. Spermidine/spermine N1-acetyltransferase is the key enzyme in the interconversion pathway which leads to the formation of spermidine and putrescine from spermine and spermidine, respectively. In the present paper we have studied using in situ hybridization histochemistry the levels of spermidine/spermine N1-acetyltransferase mRNA in the rat central nervous system after transient forebrain ischemia. In the first hours after the insult, a modest increase in spermidine/spermine N1-acetyltransferase mRNA levels was observed in ependymal cells and other non-neuronal cells of all telencephalic and diencephalic regions. In addition, major increases in spermidine/spermine N1-acetyltransferase mRNA levels were observed in regions selectively vulnerable to the ischemic insult, such as striatum, hippocampus and cerebral cortex, during the first day post-reperfusion. The time course and extent of labelling increase were subregion- and cell-specific. At the cellular level, the labelling appeared markedly increased in neurons (8-10 fold in ventromedial striatum and CA1 region) and, to a lesser extent, in non-neuronal cells. The increase in SSAT mRNA levels was not directly related to cell degeneration, as it was detected in both some vulnerable and some resistant cell populations. However, the peak increase of SSAT labelling was precocious in resistant neurons (such as those of ventromedial striatum and dentate gyrus granular layer) and delayed or very limited in vulnerable neurons (such as those of CA1 pyramidal layer and dorsolateral striatum). The increase in spermidine/spermine N1-acetyltransferase may contribute to the increase in putrescine and decrease in spermidine levels observed after ischemia and gives further support to the notion that polyamine metabolism in the early phase after lesion is oriented towards putrescine production. This phenomenon could be relevant in determining the prevalence of neurotrophic vs. neurotoxic effects of polyamines.

Acetyltransferases↗

PubMedDate not supplied

Comparative experimental viral labyrinthitis.

Because of difficulties in studying acute deafness and vertigo in humans, animal models of viral labyrinthitis have played an important role in increasing our understanding of how viruses damage the inner ear. Investigators have been able to correlate viral labyrinthine infection to histopathologic changes and electrophysiologic consequences in experimental animals. Experimental viral labyrinthitis studies have convincingly demonstrated the selective vulnerability of inner ear cell types to different viruses. These findings are relatively consistent across animal species for many viruses. By understanding the pathogenesis of viral labyrinthitis in an animal model, we may learn how better to prevent or treat virus-induced deafness and vertigo in humans.

Animals↗

PubMed1994

Long-term treatment with ammonia affects the content and release of taurine in cultured cerebellar astrocytes and granule neurons.

High (50 mM) K+ stimulated the release of preloaded [3H]taurine from cultured cerebellar astrocytes and granule neurons with a delayed onset and only when the stimulus was applied in isoosmotic, but not in hypertonic (50 mM sucrose) medium. The process thus exhibited characteristics typical for the osmosensory or osmoregulatory response noted in a variety of nerve cell cultures. Addition of 1 mM NH4Cl to the astrocytic culture for 24 h increased the unstimulated release of [3H]taurine. However, this increase was not suppressed in a hypertonic medium, thus differing from the response accompanying regulatory volume decrease in astrocytes exposed to hypoosmolar or high potassium media. In accordance with the enhanced unstimulated release of [3H]taurine, addition of 1 mM NH4Cl decreased by 15% the taurine content in these cells. However, the addition abolished the stimulatory effect of 50 mM K+ on [3H]taurine release, indicating a loss of the osmosensory response of the cells. By contrast, treatment of granule neurons with 1 mM NH4Cl for 24 h remained without effect on any of the components of [3H]taurine release. However, the treatment increased the taurine content in granule neurons by 43%. This increase resembles the response usually noted in astrocytes adapted to hyperosmotic medium and may at least in part, reflect adaptation of the neurons to the slight increase in medium osmolarity due to the addition of ammonium chloride. The results are consistent with the selective vulnerability of astrocytes to hyperammonemic conditions, adding credence to earlier morphological observations.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗

PubMedDate not supplied

Selectivity of excitotoxic mechanisms in Alzheimer's disease.

Dysfunction of glutamatergic neurons in Alzheimer's disease may actually participate in some of the neurodegenerative processes via potential excitotoxic mechanisms. Two hypotheses are advanced which describe how a generalized excitotoxic mechanism could interact with unique metabolic properties of specific cell types leading to their selective vulnerability in Alzheimer's disease.

Alzheimer Disease↗

PubMedDate not supplied

The indusium griseum: is it involved in Alzheimer's disease?

The histopathology of the indusium griseum (IG), a displaced hippocampal anlage, was studied in five patients with Alzheimer's disease (AD) and five controls. In the AD group, the IG had occasional neurons with granulovacuolar change (GVD) and rare Hirano bodies (HB), but no senile plaques (SP), neurofibrillary tangles (NFT), or neurons staining for phosphorylated neurofilament antigen. There was a slight but not statistically significant diminution of neurons within the IG. In all AD cases, the hippocampus showed abundant AD-associated histopathology. In the control cases, only rare neurons with GVD were present in the IG. These findings indicate that although single neurons within the IG may show some of the cytologic changes seen in the hippocampal neurons in normal aging and AD, IG neurons do not express the full range and severity of histopathologic abnormalities characteristic of AD. This suggests that factors other than selective vulnerability of neurons of hippocampal origin might be operating to induce the neuropathologic picture of AD.

Aged↗

PubMedDate not supplied

Age-related changes in excitatory amino acid receptors in two mouse strains.

The present study examined the binding of [3H]-L-glutamate to NMDA receptors, [3H]-kainate to kainate receptors, and [3H]-AMPA to AMPA/quisqualate receptors in the brains of C57Bl and BALB/c mice as a function of increasing age. Significant decreases in binding to NMDA receptors occurred with increasing age (3 to 30 months) in a majority of cortical and hippocampal brain regions from the C57Bl and BALB/c strains of mice. Significant decreases in binding to kainate and AMPA receptors were found in the inner frontal and parietal cortices and stratum lacunosum/moleculare of CA1 in both strains. These regions also exhibited the greatest percent decline in NMDA binding sites with aging. The loss of NMDA receptors in the stratum lacunosum/moleculare of CA1 was greater in the BALB/c mice than the C57Bl strain. These results demonstrate that a few brain regions have age-associated reductions in all three ionotropic EAA receptors; however, the NMDA receptor appears to be selectively vulnerable to the aging process throughout much of the cerebral cortex and hippocampus.

Aging↗

PubMed1984

Choline production from choline-containing phospholipids: a hypothetical role in Alzheimer's disease and aging.

Deficits in certain long-axon cholinergic brain neurons have been demonstrated both in senile dementia of the Alzheimer type (SDAT) and, to a lesser degree, in association with the cognitive and memory impairments sometimes seen with normal aging. Our studies support a hypothesis concerning the selective vulnerability of these neurons. In our superfused brain slice system, acetylcholine (ACh) release was dependent on the concentration of exogenous choline, at rest and during electrical stimulation. Decreases in intracellular levels of ACh and choline accounted for only a small fraction of the quantities of these compounds released into the superfusates, suggesting that some tissue pool of bound choline, such as the phospholipids (PL), might have liberated choline. In choline-free medium, the release and tissue content of ACh were sustained; thus, choline released from the putative endogenous pool can be utilized for ACh synthesis. We hypothesize that the use, by cholinergic neurons, of choline originating from the breakdown of membrane PL, may result in an impoverishment in certain PL. Since only cholinergic neurons use their membrane PL as a reservoir for their neurotransmitter's precursor, this relationship might explain the major deficits in long-axon cholinergic nerve terminals seen in SDAT and other age-related memory disorders.

Acetylcholine↗

PubMed1995

Heavy metals and the etiology of Parkinson's disease and other movement disorders.

Heavy metals, such as iron and manganese, are involved in neurologic disease. Most often these diseases are associated with abnormal environmental exposures or abnormal accumulations of heavy metals in the body. There is increasing recognition that heavy metals normally present in the body also may play a role in disease pathogenesis through free radical formation. When a part of the brain known as the basal ganglia is affected, movements become disordered. Parkinson's disease is one of the most common movement disorders and is related to destruction of neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. The combination of high concentration of iron and the neurotransmitter, dopamine, may contribute to the selective vulnerability of the SNpc. Dopamine can auto-oxidize to produce free radicals particularly in the presence of iron and other heavy metals.

Animals↗

PubMed1988

The effect of transient ischemia on 2-[14C]deoxyglucose metabolism in the rat hippocampus pretreated with kainic acid.

CA1 pyramidal neurons are selectively vulnerable to ischemia. 2-[14C]Deoxyglucose (2-DG) autoradiography was employed to measure local glucose utilization in the rat hippocampus after transient ischemia, under the condition of unilateral prevention of ischemic CA1 pyramidal cell necrosis by unilateral lesioning of Schaffer collaterals (left side). Columnar 2-DG uptake patterns in the CA1 region with intact Schaffer collaterals (right side) was observed 19-22 h after recirculation, though no laterality was noted 3 and 8 h after recirculation. In the right subiculum, higher 2-DG uptake was observed 19-22 h after recirculation in 5 out of 8 animals. These results suggest that Schaffer collaterals play a role in modulating glucose metabolism in the CA1 and subiculum during recirculation.

Animals↗

PubMed1993

Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes.

Detailed analyses of the neuropathologic changes in the cerebral cortex of elderly individuals and Alzheimer's disease patients have demonstrated that certain components of the neocortical and hippocampal circuits are likely to be selectively vulnerable. In order to investigate the distribution of lesions associated with aging as well as with the earliest symptoms of Alzheimer's disease, we performed a quantitative neuropathological evaluation of sixty-one non-demented patients from a geriatric hospital. All of the cases had neurofibrillary tangles in layer II of the entorhinal cortex, and many cases had an involvement of the CA1 field of the hippocampus and the inferior temporal cortex. In all of the cases, amyloid deposition was not correlated with age or with the number of neurofibrillary tangles. In addition, eight cases showed much higher neurofibrillary tangle counts than the remainder of the cases. It is proposed that these cases may represent the neuropathological correlate of the earliest stage of Alzheimer's disease that could antedate the appearance of clinical signs of cognitive decline and memory impairment.

Aged↗

PubMed1993

Delayed histologic damage and neuron death in the substantia nigra reticulata following transient forebrain ischemia depends on the extent of initial striatal injury.

Transient forebrain ischemia in normoglycemic, normotensive rodents reproducibly causes selectively vulnerable neurons in the striatum to degenerate within 24 h. Neurons in the substantia nigra reticulata (SNR) are resistant to this acute process. Histologic evidence demonstrates that the combination of acute ischemic injury to the caudate nucleus and globus pallidus is associated with delayed neuron degeneration in the SNR that matures at 3 weeks after reperfusion. Ischemia, like certain ablative neurotoxin lesions, may provoke degenerative, perhaps transneuronal events that continue to evolve long after the initial insult.

Animals↗

PubMed1994

Prolonged production of hydroxyl radical in rat hippocampus after brain ischemia-reperfusion is decreased by 21-aminosteroids.

Transient global ischemia may lead to persistent production of reactive oxygen species in selected brain regions thereby contributing to selective vulnerability to ischemia. Using cerebral microdialysis, we assessed the production of the highly reactive hydroxyl radical (OH.) in rat hippocampus during global ischemia and reperfusion (IR). During IR, perfusate containing salicylic acid was collected and analyzed for non-enzymatic hydroxylation of salicylate to 2,3-DHBA. Since 21-aminosteroids can attenuate excitatory amino acid-mediated OH. production in the brain, we repeated the experiments after administration of the 21-aminosteroid, U-74389G. The data indicate that 2,3-DHBA level increased progressively between 15 and 60 min after reperfusion, reaching values nearly three times the baseline value at 60 min. U-74389G, given 30 min before ischemia, greatly attenuated the increase in 2,3-DHBA during reperfusion. This is the first evidence for prolonged OH. production in the hippocampus after reperfusion in vivo which can be prevented by 21-aminosteroids.

Animals↗