Konstanze Plaschke

Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus.

In sporadic Alzheimers disease (AD), a number of metabolic alterations to the brain have been observed soon after the onset of the initial clinical symptoms. In particular, impairments of glucose utilization and related metabolic pathways are prominent and well‐established findings in incipient AD, resembling metabolic abnormalities such as have been found in noninsulin‐dependent diabetes mellitus. To mimic these abnormalities, we administered an intracerebroventricular (icv) injection of streptozotocin (STZ) to rats and studied the effects on glucose and glycogen metabolism in the cerebral cortex and hippocampus compared with controls. The enzymatic activities studied dropped significantly by 10–30% in brain cortex (cort.) and hippocampus (hc) 3 and 6 weeks after icv STZ injection: hexokinase (15% 3 weeks cort.; 14% 6 weeks cort.; 12% 3 weeks hc; 28% 6 weeks hc), phosphofructokinase (15%; 15%; 24%; 15%), glyceraldehyde‐3‐phosphate dehydrogenase (10%; 12%; 30%; 19%), pyruvate kinase (22%; 13%; 22%; 28%), glucose‐6‐phosphatase (10%; 23%; 14%; 19%) and phosphorylase a (22%; 11%; 30%; 15%).

Insulin-Resistant Brain State after Intracerebroventricular Streptozotocin Injection Exacerbates Alzheimer-like Changes in Tg2576 AβPP-Overexpressing Mice

For studying rare hereditary Alzheimers disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS).We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK) alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Abeta40/42 fragments, total and phosphorylated tau protein, and GSK-3alpha/beta were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Abeta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between Abeta42 and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.

Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro

Cytokine production, neutrophil adhesion to endothelial cells, and release of reactive oxygen species are thought to be critical events in sepsis or ischemia/reperfusion. Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury under these conditions. Therefore, we investigated the effect of ketamine on the expression of CD18, CD62L, and oxygen radical production of human neutrophils in vitro and on interleukin-6 production in endotoxin-stimulated human whole blood. Ketamine inhibited both the N- formyl-methionyl-leucyl-phenylalanine- and phorbol 12-myristate 13-acetate-induced up-regulation of CD18 and shedding of CD62L, determined by flow cytometry, in a concentration-dependent manner. Ketamine also caused a significant suppression of oxygen radical generation of isolated human neutrophils. In addition, there was a significant decrease in endotoxin-stimulated interleukin-6 production in human whole blood. The inhibitory effects were similar for racemic ketamine and its isomers S(+)-ketamine and R(-)-ketamine, suggesting that the inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions. Implications Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury in sepsis or ischemia/reperfusion. Therefore, we examined the effect of ketamine on stimulated neutrophil functions in vitro. These neutrophil functions were significantly inhibited by ketamine, independent of whether the racemic mixture or isomers were tested.

Desensitization of brain insulin receptor Effect on glucose/energy and related metabolism

The overall majority of cases of Alzheimer disease are not caused by genetic abnormalities. A pluricausal etiology is assumed, and the age factor may be of pivotal significance. Aging leads to inherent changes in basic metabolic principles, including the functionally most important cerebral glucose/energy metabolism. Experimentally induced perturbation of the neuronal control over the glucose metabolism by means of intracerebroventricular administration of streptozotocin leads to cascade-like abnormalities in glucose breakdown and energy formation and in membrane phospholipid and monoaminergic catecholamine metabolism, which closely resemble the disturbances found in sporadic Alzheimer disease. It is concluded that this model is a good tool for in vivo study of the cellular events characteristic for this human neurodegenerative disorder.

Serum anticholinergic activity and cerebral cholinergic dysfunction: An EEG study in frail elderly with and without delirium

BackgroundDelirium increases morbidity, mortality and healthcare costs especially in the elderly. Serum anticholinergic activity (SAA) is a suggested biomarker for anticholinergic burden and delirium risk, but the association with cerebral cholinergic function remains unclear. To clarify this relationship, we prospectively assessed the correlation of SAA with quantitative electroencephalography (qEEG) power, delirium occurrence, functional and cognitive measures in a cross-sectional sample of acutely hospitalized elderly (> 80 y) with high dementia and delirium prevalence.Methods61 consecutively admitted patients over 80 years underwent an extensive clinical and neuropsychological evaluation. SAA was determined by using radio receptor assay as developed by Tune, and standard as well as quantitative EEGs were obtained.Results15 patients had dementia with additional delirium (DD) according to expert consensus using DSM-IV criteria, 31 suffered from dementia without delirium (D), 15 were cognitively unimpaired (CU). SAA was clearly detectable in all patients but one (mean 10.9 ± 7.1 pmol/ml), but was not associated with expert-panel approved delirium diagnosis or cognitive functions. Delirium-associated EEG abnormalities included occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states. EEG measures correlated significantly with cognitive performance and delirium severity, but not with SAA levels.ConclusionIn elderly with acute disease, EEG parameters reliable indicate delirium, but SAA does not seem to reflect cerebral cholinergic function as measured by EEG and is not related to delirium diagnosis.

The neuroprotective effect of cerebral poly(ADP-ribose)polymerase inhibition in a rat model of global ischemia.

In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on rat cortical energy state was investigated at 24 h after global cerebral ischemia induced by permanent bilateral common carotid artery ligation plus transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected 10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme activity increased from 0.425+/-0.144 to 0.794+/-0.193 units/mg protein. Cerebral ischemia was associated by a decrease in adenosine triphosphate (ATP) and phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In addition, an 1.9- and 2. 2-fold increase in adenosine monophosphate and adenosine was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected the rat energy state by preserving cortical phosphocreatine and NAD(+). Cortical ATP was not changed significantly after PARP inhibition. In conclusion, activation of the nuclear enzyme PARP plays an important role in cerebral energy metabolism during rat global ischemia. Therefore, specific PARP inhibition may offer new strategies in the therapy of vascular diseases such as stroke.

Effects of verum acupuncture compared to placebo acupuncture on quantitative EEG and heart rate variability in healthy volunteers.

OBJECTIVES The aim of this single-blind randomized crossover study was to evaluate specific effects of manual acupuncture on central and vegetative nervous system activity measured by quantitative electroencephalography (qEEG) and heart rate variability (HRV). DESIGN Twenty (20) healthy volunteers (mean: 25.2 +/- 3.6 years) were monitored simultaneously using a qEEG system and a 12-channel electrocardiogram recorder during verum acupuncture (VA) at acupuncture point Large Intestine 4 (Hegu) (LI4) or placebo acupuncture (PA) at a sham point. RESULTS In the EEG conduction of the occipital area, needle stimulation in VA increased alpha1-frequency significantly, and the ratio alpha1/theta was shifted to the benefit of alpha1 over all electrodes. The HRV parameters showed a significant increase of the low frequency/high frequency (HF) ratio during the first minute of stimulation in VA, indicating an initial increase of sympathetic activation. However, an increase of HF power in the minute after stimulation followed by a decrease in heart rate suggests delayed vagal activation. De qi (a sensation that is typical of acupuncture needling) occurred in 16 subjects during VA and in 9 volunteers during PA (80% versus 45%). CONCLUSIONS Manual stimulation on LI4 seems to lead to specific changes in alpha EEG-frequency and in HRV parameters. A linear relationship between the HRV parameters and the alpha EEG band might point to a specific modulation of cerebral function by vegetative effects during acupuncture.

EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit

The aim of this study was to examine whether serum anticholinergic activity (SAA) is a reliable indicator of delirium in the ICU, and whether there is a significant correlation between SAA and quantitative electroencephalographic (EEG) data in delirious patients. In a prospective cohort study, we assessed ICU patients diagnosed with delirium (n = 37). EEG measurements and blood analysis including SAA were performed 48 h following ICU admission. The presence of delirium was evaluated using the Confusion Assessment Method for critically ill patients in ICU (CAM‐ICU). The SAA level was measured using a competitive radioreceptor binding assay for muscarinergic receptors and quantitative EEG was measured using the CATEEM® system. We found that, under comparable conditions, patients in the delirium group showed a higher relative EEG theta power and a reduced alpha power (n = 17) than did the non‐delirious patients (n = 20). No difference in measured SAA levels were seen; therefore, there was no correlation between SAA and EEG measurements in delirious patients. We conclude that, in contrast to the EEG, the SAA level cannot be proposed as a tool for diagnosing delirium in ICU patients.

Injury of the Blood Brain Barrier and Up-Regulation of ICAM-1 in Polymicrobial Sepsis

BACKGROUND The pathogenesis and mechanisms of septic encephalopathy are not completely understood. We compared two different models of sepsis: lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP) bacteremia in rats with respect to changes in endothelial expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and of cerebral albumin extravasation as a marker for capillary breakdown of the blood brain barrier. MATERIAL AND METHODS Male Wistar rats were divided into control, endotoxemia, or CLP-group. Mean arterial blood pressure was measured via femoral artery catheterization. Brain tissue for immunohistochemistry was harvested at 1 h, 6 h, and 24 h after induction of sepsis. RESULTS The CLP-group showed a decrease in mean arterial pressure after 24 h in comparison with the sham-group (P < 0.05). Cerebral ICAM-1 expression was at its maximum 24 h after induction of sepsis, with the highest expression in the CLP-group. There was no difference in PECAM-1 expression between the groups. Cerebral albumin extravasation increased early after 6 h in both septic groups with a maximum at 24 h after induction of sepsis. CONCLUSION These results suggest that there are early changes in the integrity of the blood-brain barrier in the central nervous system in an ongoing septic progress. This provides evidence that these changes are due to inflammatory mediators, and not to the presence of live bacteria. Increased ICAM-1 expression might be an early factor involved in these pathogenic events. Although the role of PECAM-1 cannot conclusively be determined, we were able to show its expression on cerebral endothelium in all groups.

VEGF overexpression improves mice cognitive abilities after unilateral common carotid artery occlusion.

Angiogenesis and neurogenesis are adaptive responses protecting cerebral tissue from hypoxic-ischemic injury. Both processes seem to be governed by hypoxia-induced growth factors, of which vascular endothelial growth factor (VEGF) is a prominent example. The aim of this study was to investigate the influence of VEGF overexpression (V1 mice) on mice cognitive function and cerebral structure under moderate cerebral oligemia. In 33 V1 and wild-type (wt) mice, the left common carotid artery was permanently occluded (CCAO) under acute (48 h) and subchronic (12 days) conditions. Sham operation was performed in 35 mice (controls). Psychometric testing was done using holeboard test and Morris Water Maze system, immunohistochemistry was performed for detection of cerebral apoptosis, nestin and CD31 expression. The results show that under control conditions V1 mice showed better spatial cognitive abilities as compared to their wt littermates. During CCAO, time and distance to reach a hidden platform in Water Maze were shorter in V1 mice as compared to wt animals, indicative of faster learning and better spatial memory processes. While no signs of necrosis or apoptosis were detected, immunohistochemistry showed that VEGF transgenity was related to higher number of nestin-positive precursor cells. Finally, acute CCAO was paralleled by a reduction of CD31 staining in wt but not V1 mice. We conclude that VEGF overexpression led to a protective effect on cognitive function, because V1 mice showed evidence for faster spatial learning and better memory, as well as an increased number of neuronal precursor cells and a prevention of endothelial cell loss after CCAO.