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Biomedical subjects

S Hoyer

Publications and source records attributed to S Hoyer.

At least 55 records · Page 3Linked to original sources
PubMed1997

The effect of stepwise cerebral hypoperfusion on energy metabolism and amyloid precursor protein (APP) in cerebral cortex and hippocampus in the adult rat.

To study the relationship between cerebral blood flow, energy metabolism, and the formation of amyloid precursor protein (APP), an in vivo animal model was established in which stepwise long-term cerebral hypoperfusion states were induced. Adult rats underwent a stepwise chronic cerebral hypoperfusion by crosswise occlusion of the carotid and vertebral arteries with different periods and severity of hypoperfusion until the final steady-state experiment. Investigations of metabolic compounds were done in hippocampus and parietotemporal cerebral cortex. The analysis of energy-rich phosphates and adenosine was examined by HPLC analysis. Substrate concentrations of pyruvate and lactate were measured spectrophotometrically. The APP holoprotein was investigated by immunblot technique. Long-term cerebral hypoperfusion induced a decrease of energy-rich phosphates in the brain areas studied, whereas the concentration of adenosine and the ATP turnover were increased. Pyruvate decreased, and lactate was increased, pointing to a shift in the cytoplasmatic redox state. More severe changes were found in parietotemporal cerebral cortex in comparison to the hippocampus. After 2-vessel occlusion, the concentration of APP decreased, whereas the APP concentration was significantly increased in rat brain after 4-vessel occlusion. It has been demonstrated for the first time in vivo that the reduction in cerebral energy metabolism alters the formation of APP due to cerebral hypoperfusion.

Amyloid beta-Protein Precursor↗
PubMed1997

Models of Alzheimer's disease: cellular and molecular aspects.

Glucose metabolism in the brain is an important process that influences many normal cellular processes, from neurotransmitter synthesis to ATP production. While cortisol and insulin have opposing effects on glucose metabolism, desensitization of the neuronal insulin receptor results in metabolic abnormalities. In the normal aging brain, glucose/energy metabolism is decreased slightly. In the majority of cases. Alzheimer's disease is sporadic and has a late onset. Therefore, age-related variations in cellular metabolism following the principle of self-organized criticality may come into focus with respect to the etiopathogenesis of this neurodegenerative disorder. As a possible primary abnormal event in late-onset sporadic DAT, a prolonged desensitization of the neuronal insulin receptor is assumed to be responsible for cascade-like abnormalities in oxidative energy metabolism and related metabolism with impacts on amyloid formation.

Adenosine Triphosphate↗
PubMed1997

Learning abilities depend on NMDA-receptor density in hippocampus in adult rats.

The hippocampal NMDA-receptor is predominantly involved to establish long-term potentiation (LTP) which is assumed to underlie fundamental molecular mechanisms of learning and memory. In the present study, NMDA-receptor density was investigated in parietotemporal cerebral cortex and in hippocampus of commonly bred naive adult male Wistar rats which had performed well or poorly in the passive avoidance paradigm. NMDA-receptor binding was determined in saturation experiments using (3H) MK-801 as a ligand and data for KD and Bmax were calculated from Scatchard plots. In general, higher NMDA receptor density was found in the hippocampus as compared to parietotemporal cerebral cortex. This regional difference became particularly obvious in good performers but was abolished in poor performers. In the hippocampus, a significantly higher NMDA-receptor density could be found in rats which had performed well in the passive avoidance task as compared to poor performers. In contrast, no such differences could be found in parietotemporal cerebral cortex. The data may indicate that the reduction in hippocampal NMDA-receptor density is of functional importance, for cognitive abilities in both physiological and pathophysiological conditions.

Animals↗
PubMed1996

Brain glucose metabolism is controlled by amplification and desensitization of the neuronal insulin receptor.

Glucose metabolism is essential for brain function and structure. Glucose contributes to the formation of neurotransmitters and is normally the only source for energy formation. There is increasing evidence that brain glucose metabolism is under control of the neuronal insulin/insulin receptor signal transduction. The present data clearly show that intracerebroventricularly administered insulin exerts anabolic effects on cerebral glucose/energy metabolism (amplification of the neuronal insulin receptor complex) whereas cortisol (corticosterone) acts antagonistically (desensitization of the neuronal insulin receptor complex). It is also shown that short-term cortisol (corticosterone) enhanced energy turnover in temporoparietal cortex and hippocampus. In contrast, long-term cortisol (corticosterone) reduced energy turnover in both brain structures studied. This metabolic pattern is reminiscent of that found in very old age. Therefore, it is assumed that long-term cortisol accelerates the aging process in the brain and thus the risk for age-related disorders such as dementia.

Animals↗
PubMed1996

Effect of adrenalectomy and corticosterone substitution on glucose and glycogen metabolism in rat brain.

In non-nervous tissues, glucocorticoids (GCs) counteract the effects of insulin and stimulate gluconeogenesis. The present study was designed to investigate whether or not adrenalectomy (ADX) and glucocorticoid substitution influence the pathway of both glucose and glycogen metabolism in cerebral parietotemporal cortex and hippocampus, and if so how. The activities of respective key enzymes, such as hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), glucose-6-phosphatase (G6Pase) and phosphorylase a (PLa), and the concentrations of the intermediates, such as glucose (Glu), glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), fructose-1,6-bisphosphate (F16PP), pyruvate (Pyr), lactate (Lac), glycogen (Glyc) and glucose-1-phosphate (G1P), were measured in the brains of 1-year-old male Wistar rats under controlled conditions 3 days after ADX or sham operation and in a pilot study after ADX and substitution with corticosterone (CST) suspended in sesame oil or after ADX and subcutaneous administration of the vehicle only. An increase in both glycolytic flux and glycogen breakdown and a decrease in gluconeogenesis in cerebral cortex but not in hippocampus were observed after ADX. After substitution with CST in adrenalectomized rats the effect of ADX on enzyme activities was reversed: significant differences from adrenalectomized rats that received vehicle only was shown for PK and G6Pase activities in both areas of the rat brain investigated.

Adrenalectomy↗
PubMed1996

Oxidative metabolism deficiencies in brains of patients with Alzheimer's disease.

Glucose metabolism in the brain has an important influence on many normal cellular processes. It contributes to the synthesis of acetylcholine, glutamate, aspartate, gamma-aminobutyric acid, glycine, and ATP production (the driving force behind almost all cellular and molecular activity). Neuronal glucose metabolism is controlled antagonistically by insulin and cortisol. Desensitization of the neuronal insulin receptor causes abnormalities in oxidative energy metabolism. During normal aging, the cerebral energy pool is slightly diminished, but its level increases after stressful events. In age-related sporadic late-onset dementia of the Alzheimer type (SDAT), glucose metabolism and formation of cellular energy are severely reduced. Desensitization of the neuronal insulin receptor seems to be an early event in the pathogenesis or even etiology of SDAT causing disturbances in oxidative glucose metabolism and energy failure in insulin-sensitive brain structures. These abnormalities appear to induce a cascade of disturbances that leads to abnormal APP processing and amyloid formation, membrane damage, and neuronal death.

Alzheimer Disease↗
PubMed1995

Decline and preservation of reversal learning abilities and acquisition in the course of senescence.

Different types of learning and memory functions decrease at different rates in senescence. The present study examines which types of mental functions show a relatively early decline and which learning abilities are relatively preserved in late senescence by investigating different types of learning abilities in water maze tests. Two groups of senescent male Wistar rats aged 24 months (group W24) and 30 months (group W30), respectively, were compared to adult rats (12 months, group W12). Group W24 represents 'senescent' and group W30 'late-senescent' rats. Whereas acquisition showed a relatively late decline (in group W30), reversal learning was impaired relatively early (group W24).

Age Factors↗
PubMed1995

Holeboard maze-learning deficits and brain monoaminergic neurotransmitter concentrations in rats after intracerebroventricular injection of 3-bromopyruvate.

3-Bromopyruvate is a suicide inhibitor of pyruvate dehydrogenase complex in brain homogenates, and after intracerebral injection reduces acetylcholine tissue content and muscarinic cholinergic receptors in brain cortex and hippocampus for extended periods of time. A stereotaxic injection of 0.2 mumol 3-bromopyruvate was given twice into the cerebral ventricles of male Wistar rats. Ten weeks later, the animals were tested for learning deficits in a food-motivated complex holeboard test. 3-Bromopyruvate-treated rats showed an increased number of visits to nonfood-baited holes over a 5-day testing period (four trials per day) compared to sham-operated control rats, an increased number of visits to food-baited holes over the first 2 days of the testing period and an increased time for completing the task. There were no changes in brain monoaminergic neurotransmitter concentrations compared to controls. The results indicate that long-term learning deficits in a spatial discrimination paradigm are caused by 3-bromopyruvate, which might be related to a cholinergic deficit induced by a primary inhibition of brain glucose metabolism at the step of pyruvate dehydrogenase complex. This animal model may be useful for behavioral studies in relation to neurodegenerative diseases like dementia of Alzheimer type.

Animals↗
PubMed1995

Age-related changes in cerebral oxidative metabolism. Implications for drug therapy.

Glucose metabolism in the brain is of central significance. It contributes to the synthesis of the neurotransmitters acetylcholine, glutamate, aspartate, gamma-aminobutyric acid (GABA) and glycine, and yields adenosine triphosphate (ATP) as the driving force of almost all cellular and molecular work. Neuronal glucose metabolism is controlled antagonistically by insulin and cortisol via amplification and desensitisation of the insulin signal from the insulin receptor. Normal aging of mammalian brains is associated with numerous inherent metabolic changes. The metabolic changes that are of pivotal importance include probable primary inherent variations in the neuronal insulin receptor, the desensitisation of the neuronal insulin receptor by circulating cortisol and receptor dysfunction subsequent to changes in membrane structure and function. As a consequence, slight aberrations in glucose/energy metabolism become obvious under resting conditions, indicating incipient variations of neuronal homeostasis as a common path in the aging process. Subsequent to the changes in glucose metabolism and energy production, variations occur in acetylcholine synthesis and release, extracellular concentration and receptor binding of glutamate and cytosolic Ca++ homeostasis. Additionally, free radical formation and membrane structure changes must be considered as primary changes during aging. Stressful events occurring more frequently during aging aggravate and prolong these changes that are accompanied by membrane liability.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Altered regulation of brain glucose metabolism as a cause of neurodegenerative disorders?

At present, search for the causes of neurodegenerative diseases represents a major topic in brain research. Acquired disturbances of cell metabolism are supposed to be a cause of the two most important neurodegenerative disorders in ageing, like senile dementia of the Alzheimer type and Parkinson's disease, resulting in measurable decreases of in vivo and post mortem cerebral glucose metabolism. Accumulating evidence indicates that insulin plays an important role in the regulation of brain glucose homeostasis in the central nervous system and has trophic effects on neurons. It has been suggested that the reduction of brain glucose metabolism in neuro-degenerative disorders may be related to a defect of the neuronal insulin-insulin receptor-interaction. It will be the aim of our study to demonstrate whether there exist any changes in the content of insulin, its receptor and/or in the functionality of the insulin receptor and its signal transduction in neurodegenerative disorders as Alzheimer's and Parkinson's disease.

Aged↗
PubMed1994

Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat.

Evidence for an involvement of insulin in the regulation of cerebral glycolytic glucose catabolism is becoming more and more convincing. To investigate whether short-term or long-term administration of insulin to the brain influences brain energy metabolism, we determined tissue concentrations of energy-rich phosphates in cerebral parietotemporal cortex and in hippocampus of 1- (adult) and 2-year-old (aged) male Wistar rats treated with intracerebroventricular (i.c.v.) infusion of the hormone for 1, 7, and 21 days. In cerebral parietotemporal cortex, tissue concentrations of ATP, PCr, ADP, ATP/ADP ratio and energy charge potential were all unaltered. In hippocampus, however, the concentration of PCr was significantly increased. Thus, short-term and long-term i.c.v. administration of insulin are assumed to have a discrete anabolic effect on the cerebral energy pool.

Adenosine Diphosphate↗
PubMed1994

Age as risk factor for sporadic dementia of the Alzheimer type?

Normal brain aging is accompanied by a slight but persistent reduction in energy formation and an increase in energy demand. Stress conditions aggravate energy shortage particularly in old age. Mitochondrial dysfunction in both ATP formation and ATP release may be assumed to be causative for the reduced availability of energy in cerebral cells leading to diminished cellular work. In this respect, aging may be considered as a contributing risk factor for sporadic late-onset dementia of the Alzheimer type. Metabolically, this disorder seems to be characterized also by an early energy shortage in cerebral cells with the same consequences for the disturbance of cellular work. However, the causative abnormality may be seen in a perturbation of the control of cerebral glucose metabolisms, in all probability mediated by a desensitization of the neuronal insulin receptor.

Adenosine Triphosphate↗
PubMed1994

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.

Aging↗
PubMed1994

Neurodegeneration, Alzheimer's disease, and beta-amyloid toxicity.

In its majority, Alzheimer's disease is sporadic and with late onset. Therefore, age-related disturbances in cellular metabolism may come into focus with respect to the etiopathogenesis of this neurodegenerative disorder. As a possible primary abnormal event in sporadic Alzheimer's disease, a desensitization of the neuronal insulin receptor and the subsequent deficits in ATP and acetylcholine are discussed with its impact on protein processing in general and beta-amyloid formation in particular, and neurotoxicity of the latter.

Alzheimer Disease↗
PubMed1994

Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats.

The purpose of the present study was to investigate whether or not cerebral glucose utilization is changed locally after damage of the neuronal insulin receptor by means of intracerebroventricular (icv) streptozotocin (STZ) administered in a subdiabetogenic dosage (1.5 mg/kg bw.). STZ was administered at the start of the study, and 2 and 21 days later bilaterally into the cerebral ventricles in rats of a mean age of 18 months. The local distribution of cerebral glucose utilization was analyzed in conscious rats on the 42nd day after the first STZ injection using the quantitative (14C)-2-deoxyglucose method. Of the 35 brain structures investigated from autoradiograms of brain sections, 17 showed a reduction in glucose utilization. Decreases in glucose utilization were observed in the frontal, parietal, sensory motor, auditory and entorhinal cortex and in all hippocampal subfields. In contrast, glucose utilization was increased in two white matter structures. The decrease in cerebral glucose utilization observed in cortical and hippocampal areas in the present study may correspond to changes in morphobiological parameters which have been found in patients with Alzheimer's disease. The present data are in accordance with the hypothesis that an impairment in the control of neuronal glucose metabolism at the insulin receptor site may exist in sporadic dementia of Alzheimer type (DAT), and can be studied by the icv STZ animal model.

Animals↗
PubMed1993

Abnormalities in brain glucose utilization and its impact on cellular and molecular mechanisms in sporadic dementia of Alzheimer type.

Brain glucose utilization and ATP formation were found to be reduced to 54% and 81%, respectively, of control values in incipient sporadic dementia of Alzheimer type, causing reduced availability of the glucose-derived neurotransmitter acetylcholine. With respect to energy shortage, impacts on energy-dependent processes such as synaptic transmission, ion homeostasis, protein processing and degradation, extracellular transmission, and extracellular phosphorylation may be expected. Normal processing of the amyloid precursor protein was demonstrated to occur via a muscarinergic acetylcholine M1 and M3 receptor-mediated signal transduction pathway. Since both the muscarinergic acetylcholine receptors on pyramidal neurons and G proteins were found to be unaltered in DAT, the possibility is discussed that the diminution of glucose utilization and the energy shortage in DAT brain may contribute considerably to abnormal amyloid precursor protein processing and thus to secondary amyloid formation.

Adult↗