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Biomedical subjects

R Hellweg

Publications and source records attributed to R Hellweg.

At least 37 records · Page 2Linked to original sources
PubMed1998

Combined treatment of schizophrenic psychoses with haloperidol and valproate.

In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine (CBZ) on the neuroleptic treatment of schizophrenic psychoses, the effects of valproate (VPA) were tested in a randomly assigned double-blind, placebo-controlled study. Apart from a (statistically nonsignificant) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on "hostile belligerence", no overall therapeutic effects of the combination of haloperidol (HPD) with VPA were observed under controlled conditions. Unlike the results with CBZ, concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group, although these differences did not attain statistical significance. In regard to use of the sedative neuroleptic chlorprothixene, there was a trend toward lower doses in the VPA group than in the placebo group. From these results, adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study. However, the trend toward lower doses of sedative medication and observed effects on "hostile belligerence" may indicate sedative and/or antimanic properties of valproate which have recently been demonstrated in several controlled studies.

Adult↗
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

[20 years unsuccessful prevention of bipolar affective psychosis recurrence].

A now 73-year-old female patient suffered from bipolar affective disorder for the first time at the age of 28. Despite treatment with all known phase-prophylactic agents (i.e., lithium, carbamazepine, valproate, and various antidepressants) she relapsed frequently. To render matters even more difficult, she easily developed side effects with most medications, particularly anticholinergic ones. In order to reach effective longterm prophylactic treatment, we tried several not yet established therapeutic regimens like clozapine, high-dose L-thyroxine, and maintenance ECT. In this case report we discuss the available literature with special respect to clozapine and maintenance ECT.

Aged↗
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↗
PubMed1996

Increase of hypoxic tolerance in rat hippocampal slices following 3-nitropropionic acid is not mediated by endogenous nerve growth factor.

Chemical preconditioning with low dose inhibition of succinic dehydrogenase by 3-nitropropionic acid (3-np) increases tolerance against succeeding hypoxia. Supraphysiological doses of nerve growth factor (NGF) repeatedly were shown to protect against ischemic damage. We investigated whether increased tolerance against hypoxia results from increased or accelerated production of endogenous NGF. Average recovery of population spike amplitude after 15 min of hypoxia and 45 min of reoxygenation was 31 +/- 9% (mean +/- SE) in control hippocampal slices. After pretreatment with 3-np (single i.p. injection of 20 mg/kg body weight 1 h to 3 days prior to slice preparation), recovery exceeded 90% (P < 0.01). However, NGF content did not increase upon slice preparation, hypoxia in vitro, and pretreatment with 3-np in vivo 1 h to 1 day prior to slice preparation with and without additional hypoxia in vitro. We conclude that early-onset tolerance to hypoxia induced by 3-np treatment is not caused by induction of endogenous NGF production.

Animals↗
PubMed1996

NGF level in the rat sciatic nerve is decreased after long-term consumption of ethanol.

Long-term effects of ethanol consumption on endogenous nerve growth factor (NGF) level were investigated in NGF-producing target organs and tissues of the peripheral nervous system. Rats were treated with ethanol (20% v/v) for 9 months, detoxified for an additional 2 weeks and kept without ethanol for an additional month prior to sacrifice. NGF level in the NGF-producing target tissues such as iris and submandibular gland and in the trigeminal ganglion and superior cervical ganglion, where NGF-responsive perikarya are located, did not differ significantly from corresponding controls. In contrast, NGF level in the sciatic nerve was significantly reduced by 54%. This indicates that long-term ethanol consumption affects retrograde axonal transport of the neurotrophic factor NGF, suggesting that NGF deficiency may be part of the pathophysiology of peripheral neuropathy due to chronic alcoholism.

Alcoholism↗
PubMed1995

Myoclonus in patients treated with clozapine: a case series.

BACKGROUND: Various types of movement disorder have been reported to occur rarely in patients treated with clozapine. This paper describes five cases in which these phenomena appeared to be clearly associated with clozapine medication and discusses possible pharmacologic mechanisms and treatment options. METHOD: Inpatients receiving clozapine were investigated for the presence of movement disorders. We present five patients with clozapine-induced myoclonus, describe their patterns, and compare clinical features. RESULTS: Five patients treated with clozapine developed a similar pattern of movement disorder that can be described as myoclonus. The neurologic symptoms improved after the treatment was discontinued, the clozapine dose reduced, or concomitant carbamazepine administered. CONCLUSION: Clozapine can induce dose-dependent myoclonus. However, these symptoms can be relieved by reducing the dose of clozapine or giving carbamazepine so that discontinuation of clozapine treatment can be avoided.

Adult↗
PubMed1994

Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy.

There is increasing evidence that deprivation of the retrogradely transported neurotrophic protein nerve growth factor (NGF) accounts for some functional deficits known to occur in experimental diabetic neuropathy. Here we have studied changes in the axonal transport of endogenous NGF, NGF receptor (NGFR), and NGFR saturation (NGF/NGFR ratio) in the rat sciatic nerve after 2 months of streptozotocin (STZ)-induced diabetes mellitus. Compared with vehicle-treated control rats (blood glucose: 6-12 mM), there was a very clear reduction in the retrograde transport of NGF by 50% (P < 0.001) in STZ-treated, diabetic animals (blood glucose: 33-62 mM). No significant reduction in NGF axonal transport was observed in a subpopulation of STZ-treated rats (poor responders) with nearly normal glucose levels (range: 9-12 mM). No change was observed in any group in the retrograde transport of NGFR. Compared with control rats, however, the apparent NGFR saturation was reduced by 45% (P < 0.002) in STZ diabetics, whereas no change in NGFR saturation was observed in the STZ-poor responders. Moreover, the NGFR saturation and amount of retrogradely transported NGF were negatively correlated to the individual glucose concentration in diabetics (r2 = 0.47 and 0.55, respectively; P < 0.0001). These findings indicate that, while NGFR expression is normal in the STZ-diabetic neuropathy model, the marked decrease in receptor saturation observed in diabetics may reflect low peripheral NGF levels, which in consequence leads to the apparent deprivation of neuronal NGF in diabetic rats.

Animals↗
PubMed1994

Trophic factors during normal brain aging and after functional damage.

There is an increasing body of information concerning the physiological role of several target-derived neurotrophic proteins that are structurally and functionally related to the classical neurotrophic molecule NGF and which resemble a genetic family called neurotrophins. However apart from NGF, there is little knowledge about the pathophysiological role of these neurotrophins concerning aging or dementia. To our present knowledge, decreased NGF production does not seem to play a causal role in age-related cognitive impairment which is usually associated with neurodegenerative processes in the cholinergic basal forebrain system. However, there are several experimentally found indications that NGF might be of importance in the stimulation of compensatory changes and repair mechanisms. Moreover, recent findings suggest that disturbances in cerebral glucose metabolism may play an important role in cognitive disabilities during normal aging and also in dementia disorders such as Alzheimer's disease. Intracerebroventricular (ICV) injection of streptozotocin (STZ) has been reported to decrease cerebral glucose utilization and energy metabolism and to impair passive avoidance learning in adult rats. One week after ICV STZ treatment, NGF content was significantly decreased in the septal region, where NGF-responsive cell bodies are known to be located and where NGF exerts its neurotrophic action after retrograde transport from NGF-producing targets. In contrast, NGF levels were increased within 3 weeks after ICV STZ treatment by about the same magnitude as has been observed for aged learning-impaired rats in the target regions for the basal forebrain cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Neurotrophic factors in memory disorders.

Neurotrophic factors are target-derived proteins capable of affecting survival, target innervation, and/or function of neuronal cell populations. These factors are structurally and functionally related to the classical neurotrophic molecule nerve growth factor (NGF) and resemble a genetic family called neurotrophins. Besides NGF and brain-derived neurotrophic factor (BDNF), there is little knowledge whether these neurotrophins play a pathophysiological role in dementing brain disease(s). BDNF-mRNA levels are reported to be decreased in the hippocampus of individuals with Alzheimer's disease (AD). Decreased NGF production does not seem to play a causal role both in age-related cognitive impairment and AD which is usually associated with neurodegenerative processes in the cholinergic basal forebrain system. However, there are several experimental indications that NGF might be of importance for the stimulation of compensatory changes and repair mechanisms; given in pharmacological dose, NGF might be of therapeutical benefit, as reported in a preliminary clinical case study. Thus, the availability of sufficient quantities of recombinant human neurotrophins should allow comprehensive research programs in future.

Alzheimer Disease↗
PubMed1994

Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial.

Six patients with very severe forms of non-rapid cycling bipolar affective illness whose symptoms had previously been refractory to all current antidepressant and/or prophylactic medications were treated with supraphysiological doses of thyroxine (250 to 500 micrograms/day) as an adjuvant to their previous medications. The mean follow-up period was 27.8 +/- 12.8 months (range 12 to 46). The mean number of relapses during the follow-up period of each patient declined from 5.3 +/- 3.1 to 0.8 +/- 0.8 and the mean duration of hospitalization from 10.0 +/- 5.6 to 0.8 +/- 1.2 months as compared to the same length of time for each patient before the start of treatment with high-dose thyroxine (T4). Three of the patients had no further relapses at all. Thus, for these patients, who had previously been severely ill and therapy-resistant, high-dose T4 administration proved to have excellent effects on the course of the illness. However, in five of these patients the effect of the T4 was strong enough only when it was administered in combination with a prophylactic and antidepressant and/or neuroleptic drug, of which in some cases high doses were also needed. The side effects were negligible. Mechanisms that may possibly underlie the beneficial effects of high-dose T4 in bipolar affective disorder are discussed.

Adult↗
PubMed1994

Nerve growth factor: pathophysiological and therapeutic implications.

Neurotrophic factors are target-derived proteins capable of affecting survival, target innervation, and/or function of neuronal cell populations. Nerve growth factor (NGF) is the best-studied member of the genetic family called neurotrophins. There is however little knowledge whether other neurotrophins play a pathophysiological role in diseases of the peripheral and central nervous system. An increasing number of animal studies suggest that NGF plays a role in (a) peripheral nerve regeneration, (b) diabetic neuropathy, and (c) age-related neurodegenerative processes within the brain.

Animals↗
PubMed1992

Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism.

Intracerebroventricular (ICV) injection of streptozotocin (STZ) has been reported to impair cerebral glucose utilization and energy metabolism (Nitsch and Hoyer: Neurosci Lett, 128:199-202, 1991) and also to prejudice passive avoidance learning in adult rats (Mayer et al.: Brain Res 532:95-100, 1990). It is well established that the forebrain cholinergic system, whose integrity is essential for learning and memory functions, depends on the target-derived retrograde messenger nerve growth factor (NGF). Therefore, we measured NGF and choline acetyltransferase (ChAT) activity levels in the forebrain cholinergic system in adult rats that had received a single injection of either STZ or artificial cerebrospinal fluid into the left ventricle 1 or 3 weeks prior to sacrifice. One week after ICV STZ treatment, NGF content was significantly decreased (-32%) in the septal region, where NGF-responsive cell bodies are located and NGF exerts its neurotrophic action after retrograde transport from NGF-producing targets. In contrast, NGF levels in the cortex and hippocampus, which are target regions for the basal forebrain cholinergic neurons, and in the brainstem and cerebellum were increased (+12% to +47%) within 3 weeks after ICV STZ treatment. The alterations in NGF levels were not related to changes in ChAT activity that decreased in the hippocampus by only 15%. This might be due to masking effects exerted by compensatory NGF-mediated stimulation of ChAT activity in remaining functional neurons. It is suggested that impaired behavior which has been observed after STZ-induced impairment of cerebral glucose and energy metabolism may be at least partially related to a diminished capacity of central NGF-responsive neurons to bind and/or transport NGF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Diabetes mellitus-associated decrease in nerve growth factor levels is reversed by allogeneic pancreatic islet transplantation.

After an untreated 5-month duration of streptozotocin (STZ)-induced diabetes mellitus (DM), nerve growth factor (NGF) levels in BDE rats were decreased to 45-65% of control in the sympathetically innervated target organs iris and submandibular gland, in the superior cervical ganglion (containing NGF-dependent sympathetic perikarya projecting to the cranial targets), and in the NGF-transporting sciatic nerve. Successful allogeneic pancreatic islet transplantation (providing a physiological glucose homeostasis without immunosuppression) after 3-4 weeks of DM reversed the DM-related decrease in NGF levels 4 months after transplantation as compared with untreated diabetic rats. By contrast, NGF levels in the treated vas deferens (innervated by short postganglionic sympathetic neurons) remained increased as in the untreated diabetic rats (175% of control). Thus, DM-associated changes in endogenous NGF levels seem to be reversible by institution of metabolic control, at least at an early stage of DM when NGF-responsive neurons have not been deprived of NGF for a long time.

Animals↗