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H Hörtnagl

Publications and source records attributed to H Hörtnagl.

At least 19 recordsLinked to original sources
PubMed2005

Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development.

Serotonergic neurones are among the first to develop in the central nervous system. Their survival and maturation is promoted by a variety of factors, including serotonin itself, brain-derived neurotrophic factor (BDNF) and S100beta, an astrocyte-specific Ca(2+) binding protein. Here, we used BDNF-deficient mice and cell cultures of embryonic raphe neurones to determine whether or not BDNF effects on developing serotonergic raphe neurones are influenced by its action on glial cells. In BDNF-/- mice, the number of serotonin-immunoreactive neuronal somata, the amount of the serotonin transporter, the serotonin content in the striatum and the hippocampus, and the content of 5-hydroxyindoleacetic acid in all brain regions analysed were increased. By contrast, reduced immunoreactivity was found for myelin basic protein (MBP) in all brain areas including the raphe and its target region, the hippocampus. Exogenously applied BDNF increased the number of MBP-immunopositive cells in the respective culture systems. The raphe area displayed selectively reduced immunoreactivity for S100beta. Accordingly, S100beta was increased in primary cultures of pure astrocytes by exogenous BDNF. In glia-free neuronal cultures prepared from the embryonic mouse raphe, addition of BDNF supported the survival of serotonergic neurones and increased the number of axon collaterals and primary dendrites. The latter effect was inhibited by the simultaneous addition of S100beta. These results suggest that the presence of BDNF is not a requirement for the survival and maturation of serotonergic neurones in vivo. BDNF is, however, required for the local expression of S100beta and production of MBP. Therefore BDNF might indirectly influence the development of the serotonergic system by stimulating the expression of S100beta in astrocytes and the production MBP in oligodendrocytes.

Animals↗
PubMed2003

Time gated fluorescence spectroscopy in Barrett's oesophagus.

BACKGROUND AND AIMS: Specialised intestinal metaplasia and its dysplastic transformation, which precedes cancer in Barrett's oesophagus cannot be differentiated in standard gastroscopy. The aim of this study was to investigate whether laser induced protoporphyrin IX fluorescence permits the detection of specialised intestinal metaplasia and dysplasia during endoscopy and to take biopsy specimens in a guided rather than random manner. METHODS: In 53 patients with Barrett's oesophagus 5-aminolaevulinic acid was sprayed on the mucosa. Approximately 60 to 120 minutes later, biopsy specimens were taken based on point-like measurements of delayed fluorescence intensity ratios of protoporphyrin IX in vivo. Two independent pathologists examined the 596 biopsy specimens taken, 168 of which were selected to be investigated by a third pathologist. Among these specimens only those (n=141) with a consensus diagnosis by at least two pathologists and p53 expression as additional marker were included in the analysis. RESULTS: The median of normalised fluorescence intensity (ratio of delayed PpIX fluorescence intensity to immediate autofluorescence intensity) in non-dysplastic specialised intestinal metaplasia (0.51, 68% CI 0.09 to 1.92) and low grade dysplasia (1.89, 68% CI 0.55 to 3.92) differed significantly (p<0.005). Dysplasia was detected at a rate 2.8-fold higher compared with screening endoscopy despite taking fewer specimens. In addition, three early cancers were detected for the first time. Moreover, this method permitted differentiation of specialised intestinal metaplasia from junctional or gastric-fundic type epithelium (p<0.013). CONCLUSIONS: For the first time it was possible to differentiate low grade dysplasia from non-dysplastic Barrett's mucosa during endoscopy based on delayed laser induced fluorescence endoscopy of PpIX. Furthermore, the method helps to detect specialised intestinal metaplasia in short Barrett's oesophagus.

Adenocarcinoma↗
PubMed2002

Role of 5-HT1A receptors in the control of food intake in obese Zucker rats of different ages.

The present study describes the role of 5-HT1A receptors in the serotonergic control of food intake in obese Zucker rats of different ages. In addition, serotonin (5-HT) and cholecystokinin (CCK) content and 5-HT turnover were determined in various brain regions. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 100 microg/kg) stimulated food intake in 3-month-old lean control rats but inhibited feeding in obese Zucker rats (300 microg/kg). This pattern remained the same in 6-month-old rats. At 10 months of age, 8-OH-DPAT lost its inhibitory activity in the obese rats but still stimulated feeding in lean controls (300 microg/kg). 5-HT levels were higher in the hypothalamus and in the frontal and parietal cortices of 3-month-old obese Zucker rats and were associated with a lower cortical turnover. In the parietal cortex and the hypothalamus of 6-month-old rats, 5-HT levels were still higher, linked with a lower hypothalamic turnover. No differences were observed in 10-month-old rats. CCK content was not different between obese Zucker rats and lean rats. The persistently different feeding responses to 8-OH-DPAT in obese Zucker rats and lean controls may be related to changes in brain 5-HT metabolism in the obese Zucker rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Serotonergic lesion of median raphe nucleus alters nerve growth factor content and vulnerability of cholinergic septohippocampal neurons in rat.

About 45% of the serotonergic raphe neurons are reported to express nerve growth factor (NGF) receptors. We therefore investigated whether selective serotonergic lesions of the median or dorsal raphe nuclei are associated with changes in NGF protein levels of the brain and whether the loss of serotonergic function alters the vulnerability of cholinergic septohippocampal neurons. In adult rats the hippocampal NGF content changed in a biphasic way after lesion of the median raphe nucleus by 5,7-dihydroxytryptamine (5,7-DHT), with a significant increase after 2-3 weeks of up to 35%, followed by a significant reduction of 22% below control levels after 7 weeks, and a return to control levels within the following 4 weeks. By contrast, the decrease in hippocampal serotonin and 5-hydroxyindoleacetic acid remained throughout the observation period of 11 weeks, being still reduced to 15 and 30% of the control levels, respectively. In the frontal cortex the partial loss of the serotonergic innervation projecting from the median raphe was associated 5 weeks after 5,7-DHT injection with an increase in NGF protein of 39.7+/-9.6% (P<0.05), which remained elevated up to 11 weeks. At 9 weeks after 5,7-DHT, the lesion of the septohippocampal cholinergic neurons induced by the cholinotoxin ethylcholine aziridinium (AF64A) was exaggerated (P<0.05) as compared to AF64A-treated rats with intact serotonergic innervation. The present data indicate that a serotonergic lesion of the median raphe nucleus results in biphasic changes of NGF protein content and in a delayed increase in the vulnerability of septohippocampal cholinergic neurons.

5,7-Dihydroxytryptamine↗
PubMed2001

Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration.

The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen-glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 beta-estradiol in the dose range of 0.5-1.0 microm significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-alpha and the modulation of Bcl proteins by 17 beta-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.

Animals↗
PubMed2000

Clonidine modulates BAY K 8644-induced rat behavior and neurotransmitter changes in the brain.

BAY K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4[2-trifluoromethyl-phenyl]-pyridine-5-carboxylate), an activator of dihydropyridine-sensitive Ca(2+) channels, injected in rats [2 mg/kg intraperitoneally (i.p.)], induces behavioral changes including ataxia, increased sensitivity to auditory stimulation, stiff tail, arched back, limb tonus and clonus, and rolling over. Neurochemical changes in the brain 45 min after application of 2 mg/kg were characterized by a significant decrease of noradrenaline in the amygdala (-27.8%, P<0.02) and piriform cortex (-16.3%, P<0.02). No significant changes of catecholamines were found in the hippocampal subregions CA1, CA3 and dentate gyrus or in the septum as compared to controls. The dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the amygdala were elevated by 60% (P<0.02) and 66.7% (P<0.02), respectively. In the septum, a 52.6% (P<0.02) increase of HVA was observed. Analysis of amino acids revealed a marked increase of gamma-aminobutyric acid (GABA) content (+50.4%, P<0.001) in the septum. Pretreatment of the rats with the alpha(2)-adrenoceptor agonist, clonidine (0.1 mg/kg i.p.), 30 min before BAY K 8644 (2 mg/kg i.p.) injection completely abolished the behavioral and neurochemical changes. The data suggest that the Ca(2+)-dependent neurotransmitter release provoked by BAY K 8644 can be modulated by stimulation of presynaptic alpha(2)-adrenoceptors. The effect of clonidine on the GABAergic system may represent an important mechanism involved in the prevention of BAY K 8644-induced behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

The neuronal monoamine transporter VMAT2 is regulated by the trimeric GTPase Go(2).

Monoamines such as noradrenaline and serotonin are stored in secretory vesicles and released by exocytosis. Two related monoamine transporters, VMAT1 and VMAT2, mediate vesicular transmitter uptake. Previously we have reported that in the rat pheochromocytoma cell line PC 12 VMAT1, localized to peptide-containing secretory granules, is controlled by the heterotrimeric G-protein Go(2). We now show that in BON cells, a human serotonergic neuroendocrine cell line derived from a pancreatic tumor expressing both transporters on large, dense-core vesicles, VMAT2 is even more sensitive to G-protein regulation than VMAT1. The activity of both transporters is only downregulated by Galphao(2), whereas comparable concentrations of Galphao(1) are without effect. In serotonergic raphe neurons in primary culture VMAT2 is also downregulated by pertussis toxin-sensitive Go(2). By electron microscopic analysis from prefrontal cortex we show that VMAT2 and Galphao(2) associate preferentially to locally recycling small synaptic vesicles in serotonergic terminals. In addition, Go(2)-dependent modulation of VMAT2 also works when using a crude synaptic vesicle preparation from this brain area. We conclude that regulation of monoamine uptake by the heterotrimeric G proteins is a general feature of monoaminergic neurons that controls the content of both large, dense-core and small synaptic vesicles.

Animals↗
PubMed2000

Serotonin uptake and release mechanisms in developing cultures of rat embryonic raphe neurons: age- and region-specific differences.

The development of serotonergic neurons of the rat raphe was followed in primary neuronal cell cultures taken at embryonic days embryonic day 13 and embryonic day 14 from three different raphe sub-groups, topographically defined with respect to their position to the isthmus as rostral (R1), intermediate (R2) and caudal (R3). In neurons cultivated from embryonic day 13 raphe serotonin, immunoreactivity was detected after only two days in vitro in the rostral R1 and the intermediate R2 sub-groups. Within two weeks of cultivation the number of serotonergic neurons as well as the dendritic branching continuously increased in all three sub-groups. In cultures obtained from embryonic day 13 raphe a specific uptake of [3H]serotonin could not be detected during the first days in vitro. Specific uptake as well as regulated serotonin release, however, was clearly discernible in these cultures after nine days in vitro, indicating developmental differentiation of the initially immature serotonergic neurons in culture. In contrast, serotonergic neurons obtained from the three raphe sub-groups at embryonic day 14 took up and released [3H]serotonin, as early as after two days in culture. Basal as well as stimulated serotonin release was diminished when preincubating the cells with tetanus toxin, which cleaves synaptobrevin thereby blocking exocytosis. Our data indicate that the differential development of serotonergic neurons in the various raphe sub-groups in vivo is also sustained in culture. The differences observed when comparing neurons from embryonic days 13 and 14 suggest that a short time-period of about 24h appears to be crucial for the developmental upregulation of serotonin uptake, storage and release.

Animals↗
PubMed2000

Role of nitric oxide in the ethylcholine aziridinium model of delayed apoptotic neurodegeneration in vivo and in vitro.

The involvement of nitric oxide in neurodegenerative processes still remains incompletely characterized. Although nitric oxide has been reported to be an important mediator in neuronal degeneration in different models of cell death involving NMDA-receptor activation, increasing evidence for protective mechanisms has been obtained. In this study the role of nitric oxide was investigated in a model of NMDA-independent, delayed apoptotic cell death, induced by the neurotoxin ethylcholine aziridinium ethylcholine aziridinium both in vivo and in vitro. For the in vivo evaluation rats received bilateral intracerebroventricular injections of ethylcholine aziridinium (2nmol/ventricle) or vehicle. In the hippocampus a transient decrease in nitric oxide synthase activity occurred, reaching its lowest levels three days after ethylcholine aziridinium treatment (51.7+/-9.8% of controls). The decrease coincided with the maximal reduction in choline acetyltransferase activity as marker for the extent of cholinergic lesion. The effect of pharmacological inhibition of nitric oxide synthase was tested by application of various nitric oxide synthase inhibitors with different selectivity for the nitric oxide synthase-isoforms. Unspecific nitric oxide synthase inhibition resulted in a significant potentiation of the loss of choline acetyltransferase activity in the hippocampus measured seven days after ethylcholine aziridinium application, whereas the specific inhibition of neuronal or inducible nitric oxide synthase was ineffective. These pharmacological data are suggestive for a neuroprotective role of nitric oxide generated by endothelial nitric oxide synthase. In vitro experiments were performed using serum-free primary neuronal cell cultures from hippocampus, cortex and septum of E15-17 Wistar rat embryos. Ethylcholine aziridinium-application in a range of 5-80microM resulted in delayed apoptotic neurodegeneration with a maximum after three days as confirmed by morphological criteria, life-death assays and DNA laddering. Nitric oxide synthase activity in harvested cells decreased in a dose- and time-dependent manner. Nitric oxide production as determined by measurement of the accumulated metabolite nitrite in the medium was equally low in controls and in ethylcholine aziridinium treated cells (range 0.77-1.86microM nitrite). An expression of inducible nitric oxide synthase messenger RNA could not be detected by semiquantitative RT-PCR 13h after ethylcholine aziridinium application. The present data indicate that in a model of delayed apoptotic neurodegeneration as induced by ethylcholine aziridinium neuronal cell death in vitro and in vivo is independent of the cytotoxic potential of nitric oxide. This is confirmed by a decrease in nitric oxide synthase activity, absence of nitric oxide production and absence of inducible nitric oxide synthase expression. In contrast, evidence for a neuroprotective role of nitric oxide was obtained in vivo as indicated by the exaggeration of the cholinergic lesion after unspecific nitric oxide synthase inhibition by N-nitro-L-arginine methylester.

Animals↗
PubMed2000

Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures.

To assess the neuroprotective potential of melatonin in apoptotic neuronal cell death, we investigated the efficacy of melatonin in serum-free primary neuronal cultures of rat cortex by using three different models of caspase-dependent apoptotic, excitotoxin-independent neurodegeneration and compared it to that in necrotic neuronal damage. Neuronal apoptosis was induced by either staurosporine or the neurotoxin ethylcholine aziridinium (AF64A) with a delayed occurrence of apoptotic cell death (within 72 h). The apoptotic component of oxygen-glucose deprivation (OGD) unmasked by glutamate antagonists served as a third model. As a model for necrotic cell death, OGD was applied. Neuronal injury was quantified by LDH release and loss of metabolic activity. Although melatonin (0.5 mM) partly protected cortical neurons from OGD-induced necrosis, as measured by a significant reduction in LDH release, it was not effective in all three models of apoptotic cell death. In contrast, exaggeration of neuronal damage by melatonin was observed in native cultures as well as after induction of apoptosis. The present data suggest that the neuroprotectiveness of melatonin strongly depends on the model of neuronal cell death applied. As demonstrated in three different models of neuronal apoptosis, the progression of the apoptotic type of neuronal cell death cannot be withhold or is even exaggerated by melatonin, in contrast to its beneficial effect in the necrotic type of cell death.

Animals↗
PubMed1998

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy.

The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.

Amino Acids↗
PubMed1998

Photodynamic therapy of nonresectable cholangiocarcinoma.

BACKGROUND & AIMS: Successful treatment in nonresectable Bismuth type III and IV cholangiocarcinoma is seldom achieved. The aim of this study was to evaluate the effect of photodynamic therapy on cholestasis, quality of life, and survival in these patients. METHODS: Nine patients with advanced nonresectable cholangiocarcinomas Bismuth type III and IV, who showed no sufficient drainage (bilirubin decrease <50%) after endoscopic stent insertion, underwent photodynamic therapy. Two days after intravenous application of a hematoporphyrin derivate, intraluminal photoactivation was performed cholangioscopically. Serum bilirubin, quality of life, and survival time were assessed in two monthly intervals after photodynamic therapy. RESULTS: After photodynamic therapy, bilirubin serum levels declined from 318 +/- 72 to 103 +/- 35 micromol/L (P = 0.0039) with no significant increase during the two monthly follow-ups. Quality of life indices improved dramatically and remained stable (e.g., Karnofsky index from 32.2% +/- 8.13% to 68.9% +/- 6.1%; P = 0.0078). Thirty-day mortality was 0%, and median survival time was 439 days. CONCLUSIONS: This study provides clear evidence that photodynamic therapy is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas Bismuth type III and IV. Compared with published data, survival time seems to be prolonged.

Bile Duct Neoplasms↗
PubMed1997

Catecholamine detection using enzymatic amplification.

Different amplification sensors based on the substrate recycling principle were investigated with respect to their applicability to catecholamine detection. In the bioelectrocatalytic approach, glassy carbon electrodes were modified by laccase or a PQQ-dependent glucose dehydrogenase. Substrate recycling occurs and the detection limit is in the lower nanomolar concentration range (e.g. 10 nM dopamine and 1 nM noradrenaline for the laccase- and glucose dehydrogenase-modified electrodes, respectively). Combinations of glucose dehydrogenase with laccase or tyrosinase were investigated as bienzymatic probes. Among the systems we studied, the laccase/glucose dehydrogenase sensor is the most sensitive (detection limit: 0.5 nM adrenaline). The selectivities of the different sensor systems are discussed. Application of the laccase/glucose dehydrogenase electrode in different media (i.e. brain homogenate, heart effluate) was successfully shown. For samples with high concentrations of interfering substances (uric and ascorbic acid), the interferences can be effectively removed using enzymatic methods.

Biosensing Techniques↗
PubMed1997

Pathophysiological aspects of human neurodegenerative diseases.

This review summarizes the most intriguing topical pathophysiological theories that contribute to current molecular understanding of the most important adult-onset human neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The pathophysiological aspects discussed include genetic linkages, involvement of cytokines and excitotoxic amino acids, contribution of oxidative stress, roles of neurotrophic factors and beta-amyloid deposition, the significance of apoptotic cell death and possible risk factors. An attempt is made to point out common characteristics of these neurodegenerative diseases. Present knowledge of the pathophysiological background of these diseases may provide an encouraging basis for the development of new therapeutic strategies which actually interact with the cascade of neurodegeneration and go beyond the mere pharmacological substitution of neurotransmitter deficits.

Amyloid beta-Peptides↗
PubMed1997

Moderate lesion of the rat cholinergic septohippocampal pathway increases hippocampal nerve growth factor synthesis: evidence for long-term compensatory changes?

Moderate lesions of the septohippocampal pathway by intraventricular infusions of ethylcholine aziridinium (AF64A) induced a dose-dependent decrease of hippocampal choline acetyltransferase (ChAT) activity, which partially recovered between 1 and 5 weeks after treatment. The cholinergic deficit was associated with an increase in nerve growth factor (NGF) mRNA only within the hippocampal dentate gyrus and hilus by maximally 51% and 111% 3 and 7 weeks after AF64A treatment, respectively, whereas no changes in brain-derived neurotrophic factor- and neurotrophin-3 mRNA were observed. The content of NGF protein transiently increased in the ventral part of the hippocampus 3 weeks after AF64A infusion but returned to control levels at 5 weeks. At that time, however, NGF content as well as ChAT activity were significantly increased in the septum, suggesting an increased utilization of NGF by the remaining cholinergic neurons. Thus, the present data provide correlative evidence for a critical role of endogenous NGF in neuroregeneration and plasticity of the cholinergic basal forebrain in case of incipient damage.

Animals↗
PubMed1997

Active compression-decompression cardiopulmonary resuscitation in standing position over the patient: pros and cons of a new method.

Active compression-decompression cardiopulmonary resuscitation (ACD-CPR) has been introduced to improve outcome of CPR after cardiac arrest. Usually, ACD-CPR is performed with the rescuer kneeling beside the patient (ACD-B), but ACD-CPR with the rescuer in standing position (ACD-S) has been taught and applied in some centres in addition to conventional ACD-CPR (ACD-B). The aim of this randomised and cross-over study was to evaluate the new technique of ACD-S and to compare it with conventional ACD-B. Twelve professional rescuers (aged 30.8 +/- 7.9 years) applied both methods of ACD-CPR on a manikin. We obtained the following results. (1) Duration of CPR performance was comparable for ACD-S (13.2 +/- 7.1 min) and ACD-B (15.5 +/- 10.2 min, P = 0.48). (2) Pain in the upper extremity and pain in the vertebral column were the main reasons for break-off by the rescuers. Exhaustion was judged to be similar during ACD-S (5.3 +/- 2.3) and ACD-B (6.2 +/- 2.1; on a rating scale with 1 = no and 9 = complete exhaustion). (3) Oxygen consumption was significantly higher during ACD-S (P < 0.005), whereas heart rate and lactate levels did not differ. (4) Decompression forces were lower than compression forces. The averaged decompression forces in both methods were similar during the first 2 min and the last min. Compression forces decreased in ACD-S from 55.1 to 48.9 kp (P = 0.002) and in ACD-B from 52.8 to 47.0 kp (P = 0.069). We conclude that ACD-CPR in standing position can be considered equal to ACD-B in view of maximal duration of CPR, exhaustion of the rescuers and decompression forces. The decrease of compression forces in ACD-S and ACD-B as well as the difference between compression forces in ACD-S and ACD-B seem to be of no clinical relevance, and exhaustion was judged to be similar despite oxygen consumption being higher in ACD-S than in ACD-B.

Adult↗
PubMed1997

Induction of apoptosis in vitro and in vivo by the cholinergic neurotoxin ethylcholine aziridinium.

The patterns of cell death induced by the cholinergic neurotoxin ethylcholine aziridinium have been investigated in vitro and in vivo. In vitro, the drug induced apoptosis both in neuronal SK-N-MC cells (human neuroblastoma cells) and in non-neuronal 293 cells (a human embryonic kidney cell line). Apoptosis was developed maximally between 15 and 24 h of exposure to ethylcholine aziridinium (100 microM). At the ultrastructural level apoptotic cells were characterized by condensation and margination of nuclear chromatin, fragmentation of nuclei and the formation of apoptotic bodies. Inhibition of endonuclease by zinc almost completely prevented the occurrence of apoptosis. The free radical scavenger Tempol effectively inhibited ethylcholine aziridinium-induced apoptosis by 78.6 +/- 10.3% (n=4), whereas cycloheximide and actinomycin D were only partially effective. In vivo, following injection of ethylcholine aziridinium (2 nmol) into the lateral ventricle of rat brain a high incidence of apoptotic cells as verified by in situ tailing was visible in the periventricular tissue. Neurons as well as glia were affected by the neurotoxin. The number of apoptotic cells peaked two to three days after injection of ethylcholine aziridinium and declined thereafter. Up to one week after ethylcholine aziridinium no signs for the induction of apoptosis in the medial septal nucleus were found. This study provides clear evidence that a neurotoxic compound that induces programmed cell death in vitro is likely to have the same capacity in vivo. Yet, in the case of ethylcholine aziridinium, both the in vitro and the in vivo induction of programmed cell death appears to be an additional feature of ethylcholine aziridinium, which may be independent of the well-established degenerative effect of ethylcholine aziridinium on the cholinergic septohippocampal pathway. The present data indicate that ethylcholine aziridinium provides a useful tool to study molecular mechanisms of neuronal apoptosis.

Animals↗