Publications by authors named "Joachim Hartmann"

18 Publications

  • Page 1 of 1

Gestational Age and Neonatal Electrocardiograms.

Pediatrics 2021 Nov 24. Epub 2021 Nov 24.

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Interpretation of the neonatal electrocardiogram (ECG) is challenging due to the profound changes of the cardiovascular system in this period. We aimed to investigate the impact of gestational age (GA) on the neonatal ECG and create GA-specific reference values.

Methods: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation of neonates. ECGs and echocardiograms were obtained and systematically analyzed. GA, weight, height, and other baseline variables were registered.

Results: We included 16 462 neonates (52% boys) with normal echocardiograms. The median postnatal age was 11 days (range 0 to 30), and the median GA was 281 days (range 238 to 301). Analyzing the ECG parameters as a function of GA, we found an effect of GA on almost all investigated ECG parameters. The largest percentual effect of GA was on heart rate (HR; 147 vs 139 beats per minute), the QRS axis (103° vs 116°), and maximum R-wave amplitude in V1 (R-V1; 0.97 vs 1.19 mV) for GA ≤35 vs ≥42 weeks, respectively. Boys had longer PR and QRS intervals and a more right-shifted QRS axis within multiple GA intervals (all P < .01). The effect of GA generally persisted after multifactorial adjustment.

Conclusions: GA was associated with significant differences in multiple neonatal ECG parameters. The association generally persisted after multifactorial adjustment, indicating a direct effect of GA on the developing neonatal cardiac conduction system. For HR, the QRS axis, and R-V1, the use of GA-specific reference values may optimize clinical handling of neonates.
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http://dx.doi.org/10.1542/peds.2021-050942DOI Listing
November 2021

Modified Marshall Score Predicts Mortality in Patients With Walled-off Pancreatic Necrosis Treated in an Intensive Care Unit.

Pancreas 2019 10;48(9):e68-e70

Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Copenhagen, Denmark Intensive Care Unit, Hvidovre Hospital, Copenhagen, Denmark Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Copenhagen, Denmark

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http://dx.doi.org/10.1097/MPA.0000000000001409DOI Listing
October 2019

[Waiting Times For Admission Into A Psychotherapeutic Inpatient Treatment - Results of A Prospective Study In South-Württemberg].

Psychother Psychosom Med Psychol 2019 Aug 16;69(8):323-331. Epub 2019 Jan 16.

Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Ulm.

Introduction: Waiting times for the admission into a so called psychosomatic hospital in Germany prevent the necessary immediate treatment. They lead to further incapacity for work and chronic manifestation of the disease. It is reported that most psychosomatic hospitals have waiting times, but there are no studies on data on that. Therefore, it was the aim of this study to access prospectively in a defined region, how long it takes for the patients to get an outpatient preliminary talk and thereafter, how long they have to wait for their admission.

Methods: 7 hospitals out of the region of South-Württemberg took part on this study, 2 of them had bigger day hospitals. Data were assessed prospectively in 2015 over 9 months, in total 916 admissions were assessed.

Results: The waiting time until a preliminary talk, in which the indication for inpatient treatment was secured, was in the mean 25 days (SD=31). The waiting time after this talk until admission was 56 days (SD=47). Patients who waited for a day treatment had to wait even longer. An urgency remark, given by the therapist of the preliminary talk, as well as a private illness insurance led to shorter waiting times. The diagnosis had no influence on the waiting time.

Conclusions: The waiting times are substantial and imply a burden for the patient and also for the health care system. It is recommended to assess and publish these waiting times on a regularly basis. Politics, but also the actors in the health care system should discuss if and how this deficit can be changed.
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http://dx.doi.org/10.1055/a-0813-1123DOI Listing
August 2019

Neuroprotective effects of bilobalide are accompanied by a reduction of ischemia-induced glutamate release in vivo.

Brain Res 2011 Nov 6;1425:155-63. Epub 2011 Oct 6.

Department of Pharmacology, College of Pharmacy, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.

Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40-50% when given at 10mg/kg 1h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the striatum which returned to baseline levels after reperfusion. Extracellular levels of glutamate were increased by more than ten-fold in striatal tissue, and by four- to fivefold in hippocampal tissue (penumbra). Bilobalide did not affect glucose levels but strongly attenuated glutamate release in both core and penumbra regions. Bilobalide was equally active when given locally via the microdialysis probe and also reduced ischemia-induced glutamate release in vitro in brain slices. We conclude that bilobalide is a strong neuroprotectant in vivo at doses that can be used therapeutically in humans. The mechanism of action evidently involves reduction of glutamate release, thereby reducing excitotoxicity.
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http://dx.doi.org/10.1016/j.brainres.2011.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217178PMC
November 2011

Metabolic and transmitter changes in core and penumbra after middle cerebral artery occlusion in mice.

Brain Res 2010 Feb 2;1312:101-7. Epub 2009 Dec 2.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.

Middle cerebral artery occlusion (MCAO) is a popular model in experimental stroke research and causes prominent ischemic damage in the forebrain. To characterize metabolic changes induced by MCAO, we have induced permanent MCAO in mice that were implanted with a microdialysis probe in either striatum or hippocampus. Immediately after the onset of ischemia, glucose levels dropped to <10% of basal values in the striatum while they dropped to 50%, and recovered thereafter, in hippocampus. Extracellular levels of glutamate rose 80-fold in the striatum but only 10-fold, and in a transient fashion, in hippocampus. In striatum, release of acetylcholine briefly increased, then dropped to very low values. Both glycerol and choline levels increased strongly during ischemia in the striatum reflecting membrane breakdown. In hippocampus, glycerol increased transiently while the increase of choline levels was moderate. Taken together, these observations delineate metabolic changes in ischemic mouse brain with the striatum representing the core area of ischemia. In comparison, the dorsal hippocampus was identified as a brain area suitable for monitoring metabolic responses in the penumbra region.
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http://dx.doi.org/10.1016/j.brainres.2009.11.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812654PMC
February 2010

Neurotransmitters and energy metabolites in amyloid-bearing APP(SWE)xPSEN1dE9 Mouse Brain.

J Pharmacol Exp Ther 2010 Feb 21;332(2):364-70. Epub 2009 Oct 21.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas, USA.

Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, synaptic loss and central cholinergic dysfunction, dysfunction of energy metabolism, and dementia; however, the interactions between these hallmarks remain poorly defined. We studied a well characterized mouse model of amyloid deposition, the doubly transgenic APP(SWE)xPSEN1dE9 mouse. At 10 to 14 months of age, these mice had high levels of amyloid peptides (6.6 microg/g wet weight) and widespread amyloid plaques. Extracellular levels of acetylcholine (ACh) were determined by microdialysis in the hippocampus and were comparable with nontransgenic mice from the same colony. In the open field, both mouse strains responded with a 3-fold increase of hippocampal ACh release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5- to 6-fold increases of ACh levels in both mouse strains. High-affinity choline uptake and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice, whereas lactate levels were slightly (p = 0.06) and glutamate levels significantly (p = 0.02) lower in transgenic mice. Exploration caused increases of glucose and lactate, whereas infusion of scopolamine (1 microM) increased glucose but not lactate. Glutamate levels were increased by scopolamine, whereas glycerol remained constant under all the conditions. We conclude that amyloid peptide production and plaque deposition causes minor changes in cholinergic function and energy metabolites in transgenic mice in vivo. Amyloid peptide formation and/or deposition may not be sufficient for long-term cholinergic or metabolic dysfunction.
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http://dx.doi.org/10.1124/jpet.109.161091DOI Listing
February 2010

Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice.

J Pharm Pharm Sci 2009 ;12(1):79-85

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.

Purpose: Alzheimer s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE.

Methods: We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice.

Results: Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 microM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 microM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice.

Conclusions: In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer s disease.
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http://dx.doi.org/10.18433/j3mk59DOI Listing
September 2009

Role of glycine receptors and glycine release for the neuroprotective activity of bilobalide.

Brain Res 2008 Mar 31;1201:143-50. Epub 2008 Jan 31.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.

Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to interact with neuronal transmission mediated by glutamate, gamma-aminobutyric acid (GABA) and glycine. The goal of this study was to test the interaction of bilobalide with glycine in assays of neuroprotection. In rat hippocampal slices exposed to N-methyl-D-aspartate (NMDA), release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 microM). Glycine (10-100 microM) antagonized the inhibitory action of bilobalide in this assay. In a second assay of excitotoxicity, we measured tissue water content as an indicator of cytotoxic edema formation in hippocampal slices which were exposed to NMDA. In this assay, edema formation was suppressed by bilobalide but bilobalide's action was attenuated in the presence of glycine and of D-serine (100 microM each). To investigate bilobalide's interaction with glycine receptors directly, we determined 36chloride flux in rat cortico-hippocampal synaptoneurosomes. Glycine (100 microM) was inactive in this assay indicating an absence of functional glycine-A receptors in this preparation. [3H]Glycine was used to assess binding at the glycine binding site of the NMDA receptor but bilobalide was found to be inactive in this assay. Finally, [3H]glycine release was monitored in hippocampal slices exposed to oxygen-glucose deprivation. In this model, glycine release was induced by ischemia, an effect that was strongly reduced by bilobalide. We conclude that bilobalide does not interact with glycine receptors in neurochemical assays but it significantly reduces the release of glycine under ischemic conditions. This effect likely contributes to bilobalide's neuroprotective effects in assays of excitotoxicity and ischemia.
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http://dx.doi.org/10.1016/j.brainres.2008.01.052DOI Listing
March 2008

Choline availability and acetylcholine synthesis in the hippocampus of acetylcholinesterase-deficient mice.

Neurochem Int 2008 May 16;52(6):972-8. Epub 2007 Oct 16.

Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, TX, USA.

Mice deficient for acetylcholinesterase (AChE) have strongly increased extracellular levels of acetylcholine (ACh) in the dorsal hippocampus [Hartmann, J., Kiewert, C., Duysen, E.G., Lockridge, O., Greig, N.H., Klein, J., 2007. Excessive hippocampal acetylcholine levels in acetylcholinesterase-deficient mice are moderated by butyrylcholinesterase activity. J. Neurochem. 100, 1421-1429]. Using microdialysis, we found that increased ACh levels are accompanied by decreased levels of extracellular choline which were 1.60 microM in AChE-deficient mice and 4.36 microM in wild-type mice. Addition of choline (10 microM) to the perfusion fluid, while ineffective in wild-type animals, more than doubled extracellular ACh levels in AChE-deficient mice. High-affinity choline uptake (HACU), as measured ex vivo in corticohippocampal synaptosomes, was more than doubled in AChE-deficient mice. Inhibition of HACU by hemicholinium-3 (HC-3) in vivo reduced extracellular levels of ACh by 60% in wild-type mice but by more than 90% in AChE-deficient mice. Decreased ACh levels caused by infusion of HC-3 or tetrodotoxin (TTX) were accompanied by increased levels of free choline. Infusion of scopolamine (1 microM) caused a fivefold increase of ACh levels in wild-type animals but only a 50% increase in AChE-deficient mice. In conclusion, absence of AChE causes dynamic changes in the ratio of choline to ACh. High levels of extracellular ACh are accompanied by reduced levels of extracellular choline, and ACh release becomes strongly dependent on choline availability. Similar changes may take place in patients chronically exposed to AChE inhibitors.
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http://dx.doi.org/10.1016/j.neuint.2007.10.008DOI Listing
May 2008

Excessive hippocampal acetylcholine levels in acetylcholinesterase-deficient mice are moderated by butyrylcholinesterase activity.

J Neurochem 2007 Mar 22;100(5):1421-9. Epub 2006 Dec 22.

Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106, USA.

Central cholinergic systems are involved in a plethora of brain functions and are severely and selectively damaged in neurodegenerative diseases such as Alzheimer's disease and dementia with Lewy bodies. Cholinergic dysfunction is treated with inhibitors of acetylcholinesterase (AChE) while the role of butyrylcholinesterase (BChE) for brain cholinergic function is unclear. We have used in vivo microdialysis to investigate the regulation of hippocampal acetylcholine (ACh) levels in mice that are devoid of AChE (AChE-/- mice). Extracellular ACh levels in the hippocampus were 60-fold elevated in AChE-/- mice compared with wild-type (AChE+/+) animals. In AChE-/- mice, calcium-free conditions reduced hippocampal ACh levels by 50%, and infusion of tetrodotoxin by more than 90%, indicating continuous ACh release. Infusion of a selective AChE inhibitor (BW284c51) caused a dose-dependent, up to 16-fold increase of extracellular ACh levels in AChE+/+ mice but did not change ACh levels in AChE-/- mice. In contrast, infusion of a selective inhibitor of BChE (bambuterol) caused up to fivefold elevation of ACh levels in AChE-/- mice, but was without effect in AChE+/+ animals. These results were corroborated with two other specific inhibitors of AChE and BChE, tolserine and bis-norcymserine, respectively. We conclude that lack of AChE causes dramatically increased levels of extracellular ACh in the brain. Importantly, in the absence of AChE, the levels of extracellular ACh in the brain are controlled by the activity of BChE. These results point to a potential usefulness of BChE inhibitors in the treatment of central cholinergic dysfunction in which brain AChE activity is typically reduced.
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http://dx.doi.org/10.1111/j.1471-4159.2006.04347.xDOI Listing
March 2007

Observation of long-lived muonic hydrogen in the 2S state.

Phys Rev Lett 2006 Nov 9;97(19):193402. Epub 2006 Nov 9.

Institut für Teilchenphysik, ETH Zürich, 8093 Zürich, Switzerland.

The kinetic energy distribution of ground state muonic hydrogen atoms mup(1S) is determined from time-of-flight spectra measured at 4, 16, and 64 hPa H2 room-temperature gas. A 0.9 keV component is discovered and attributed to radiationless deexcitation of long-lived mu p(2S) atoms in collisions with H2 molecules. The analysis reveals a relative population of about 1%, and a pressure-dependent lifetime (e.g., 30.4 +21.4/-9.7 ns at 64 hPa) of the long-lived mu p(2S) population, equivalent to a 2S quench rate in mu p(2S)+H2 collisions of 4.4 +2.1/-1.8 x 10(11) s(-1) at liquid-hydrogen density.
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http://dx.doi.org/10.1103/PhysRevLett.97.193402DOI Listing
November 2006

Role of GABAergic antagonism in the neuroprotective effects of bilobalide.

Brain Res 2007 Jan 28;1128(1):70-8. Epub 2006 Nov 28.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr., Amarillo, TX 79106, USA.

Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to block GABA(A) receptors. The goal of this study was to test the potential role of a GABAergic mechanism for the neuroprotective activity of bilobalide. In rat hippocampal slices exposed to NMDA, release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 microM) and under low-chloride conditions. Bicuculline (100 microM), a competitive antagonist at GABA(A) receptors, reduced NMDA-induced choline release to a small extent (-23%). GABA (100 microM) partially antagonized the inhibitory action of bilobalide. Exposure of hippocampal slices to NMDA also caused edema formation as measured by increases of tissue water content. NMDA-induced edema formation was suppressed by bilobalide and by low-chloride conditions. Bicuculline exerted partial protection (by 30%) while GABA reduced bilobalide's effect by about one third. To investigate bilobalide's interaction with GABA(A) receptors directly, we measured binding of [(35)S]-TBPS to rat cortical membranes. TBPS binding was competitively inhibited by bilobalide in the low micromolar range (IC(50)=3.7 microM). As a functional test, we determined (36)chloride flux in rat corticohippocampal synaptoneurosomes. GABA (100 microM) significantly increased (36)chloride flux (+65%), and this increase was blocked by bilobalide, but with low potency (IC(50): 39 microM). We conclude that, while antagonism of GABA(A) receptors may contribute to bilobalide's neuroprotective effects, additional mechanisms must be postulated to fully explain bilobalide's actions.
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http://dx.doi.org/10.1016/j.brainres.2006.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865101PMC
January 2007

NGP1-01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated calcium channels.

Neurochem Res 2006 Mar;31(3):395-9

Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, Amarillo, TX 79106, USA.

Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 microM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 microM) also inhibited N-methyl-D: -aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P < 0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents.
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http://dx.doi.org/10.1007/s11064-005-9036-0DOI Listing
March 2006

Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients.

Neurobiol Aging 2004 Nov-Dec;25(10):1299-303

Department of Pharmacology, Johannes Gutenberg University of Mainz, Mainz 55101, Germany.

Experimental and clinical studies give evidence for breakdown of membrane phospholipids during neurodegeneration. In the present study, we measured the levels of glycerophosphocholine (GPCh), phosphocholine (PCh), and choline, that is, water-soluble metabolites of phosphatidylcholine (PtdCho), in human cerebrospinal fluid (CSF). Among 30 cognitively normal patients the average CSF levels of GPCh, phosphocholine and choline were 3.64, 1.28, and 1.93 microM, respectively; metabolite levels did not change with increasing age. When compared with age-matched controls, patients with Alzheimer's disease had elevated levels of all choline metabolites: GPCh was significantly increased by 76% (P<0.01), phosphocholine by 52% (P<0.05), and free choline (Ch) by 39%. Six patients with vascular dementia had lower choline and elevated phosphocholine levels, when compared to controls, but normal levels of GPCh. These data demonstrate that Alzheimer's disease is accompanied by an increased PtdCho hydrolysis in the brain. PtdCho breakdown seems to be mediated by phospholipase A2 and leads to significantly elevated levels of GPCh in CSF.
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http://dx.doi.org/10.1016/j.neurobiolaging.2004.02.016DOI Listing
December 2004

Stimulation of hippocampal acetylcholine release by hyperforin, a constituent of St. John's Wort.

Neurosci Lett 2004 Jul;364(3):195-8

Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, 1300 Coulter Drive, Amarillo 79106, USA.

Extracts of the medicinal plant St. John's Wort (Hypericum perforatum) are widely used in the therapy of affective disorders and have been reported to exert antidepressant, anxiolytic, and cognitive effects in experimental and clinical studies. We here report that hyperforin, the major active constituent of the extract, increases the release of acetylcholine from rat hippocampus in vivo as determined by microdialysis. Hippocampal acetylcholine levels were increased by 50-100% following the systemic administration of pure hyperforin at doses of 1 and 10 mg/kg. The effect was almost completely suppressed by local perfusion with calcium-free buffer or with tetrodotoxin (1 microM). We conclude that hyperforin releases hippocampal acetylcholine by an indirect mechanism of action which is calcium-dependent and requires intact neuronal communication and cell firing. Our findings suggest therapeutic efficacy of St. John's Wort extracts in central cholinergic dysfunction.
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http://dx.doi.org/10.1016/j.neulet.2004.04.046DOI Listing
July 2004

Effects of septal grafts on acetylcholine release from rat hippocampus after 192 IgG-saporin lesion.

Neurochem Res 2003 Apr;28(3-4):467-72

Department of Pharmacology, University of Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany.

The cholinergic inputs to the rat hippocampus were lesioned by intraseptal injections of 192 IgG-saporin. After 15 days, fetal septal cells were grafted into the hippocampus. Thirteen months later, hippocampal acetylcholine (ACh) release was studied by microdialysis. Lesioning reduced basal ACh release (100%) to 20% of normal, which was compensated for by the graft (71%). Infusion of the serotonin uptake inhibitor citalopram (100 microM) enhanced ACh release to the same extent (% of basal release) in all rat groups. Systemic injection of 8-OH-DPAT (0.5 mg/kg, SC), an agonist of 5-HT1A receptors, caused a smaller ACh release than citalopram. Acetylcholinesterase (AChE) staining and densitometric quantification revealed that the lesion-induced reduction of the AChE-staining density was compensated for by septal grafting. In conclusion, both histochemical and biochemical methods showed that cholinergic hippocampal parameters were drastically impaired by 192 IgG-saporin lesions, but were almost completely restored by septal grafting. The graft responded to intrinsic serotonergic regulation.
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http://dx.doi.org/10.1023/a:1022852819018DOI Listing
April 2003

Potential active-site residues in polyneuridine aldehyde esterase, a central enzyme of indole alkaloid biosynthesis, by modelling and site-directed mutagenesis.

Eur J Biochem 2002 Jun;269(12):2889-96

Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Johannes Gutenberg-Universität Mainz, Germany.

In the biosynthesis of the antiarrhythmic alkaloid ajmaline, polyneuridine aldehyde esterase (PNAE) catalyses a central reaction by transforming polyneuridine aldehyde into epi-vellosimine, which is the immediate precursor for the synthesis of the ajmalane skeleton. The PNAE cDNA was previously heterologously expressed in E. coli. Sequence alignments indicated that PNAE has a 43% identity to a hydroxynitrile lyase from Hevea brasiliensis, which is a member of the alpha/beta hydrolase superfamily. The catalytic triad, which is typical for this family, is conserved. By site-directed mutagenesis, the members of the catalytic triad were identified. For further detection of the active residues, a model of PNAE was constructed based on the X-ray crystallographic structure of hydroxynitrile lyase. The potential active site residues were selected on this model, and were mutated in order to better understand the relationship of PNAE with the alpha/beta hydrolases, and as well its mechanism of action. The results showed that PNAE is a novel member of the alpha/beta hydrolase enzyme superfamily.
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http://dx.doi.org/10.1046/j.1432-1033.2002.02956.xDOI Listing
June 2002
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