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Biomedical subjects

M Windisch

Publications and source records attributed to M Windisch.

At least 19 recordsLinked to original sources
PubMed1998

Neurotrophic activities and therapeutic experience with a brain derived peptide preparation.

In spite that the use of naturally occurring neurotrophic factors like NGF, BDNF, CNTF, GDNF and others for treatment of neurodegenerative disorders seems promising because of their pharmacological properties, until now no large scale clinical trials have been published. One of the reasons is that these molecules are unable to penetrate through the blood brain barrier, making invasive application strategies like intracerebroventricular infusion necessary. Another one is the fact that in first clinical studies, several undesirable side-effects like hyperalgesia or weight loss have been reported. Major efforts are now put into development of improved application procedures and in treatment protocols for avoiding the known side-effects. Already 7 years ago it has been demonstrated that Cerebrolysin, a peptidergic drug, produced from purified brain proteins by standardized enzymatic breakdown, containing biologically active peptides, is exerting nerve growth factor like activity on neurons from dorsal root ganglia. Still ongoing investigations are showing growth promoting efficacy of this drug in different neuronal populations from peripheral and central nervous system. The current findings are in accordance with several older publications, enabling now a more clear interpretation of these findings. In addition to the direct neurotrophic effect, the drug also shows clear neuroprotective properties after different types of lesion in vitro and in vivo, resembling the pharmacological activities of naturally occurring nerve growth factors. Neurotrophic and neuroprotective efficacy has been shown with a broad variety of methods in different models and it is remarkable that all biochemical and morphological drug dependent alterations are resulting in improvements of learning and memory. Because of these experimental results, clinical trials using cerebrolysin in Alzheimer's patients have been performed, demonstrating a quick improvement in the overall state of the patients, particularly enhancing the cognitive performance. It is remarkable that these effects are long lasting after cessation of the active treatment procedure. Even 6 months after stop of drug application improvements in AD-patients are detectable. Therefore it is concluded that cerebrolysin is able to induce repair phenomena, resulting in long term stabilization. In contrast to the naturally occurring growth factors, tolerability of this drug is extremely high, without any reports about serious side-effects in these clinical studies.

Aged↗
PubMed1998

The influence of Cerebrolysin and E021 on spatial navigation of 24-month-old rats.

In the present study the behavioural effects of Cerebrolysin (Cere), a peptidergic nootropic drug, and E021, the concentrated peptide fraction of Cere, were investigated in 24-month-old rats. Rats passing a pretest to exclude motor- and eye-deficits were treated with either drugs or saline as control (2.5 ml/kg, intraperitoneally i.p.) for 19 days. Animals were tested in a standard Morris water maze on day 16 after pretest for 4 consecutive days (test days 1-4), eight trials per day. No significant differences of escape latency between males and females were found, therefore, results were pooled. Both Cere and E021 treated rats showed significant lower escape latencies than saline treated controls on all four test days (p < 0.01). More pronounced effects of both drugs were found for female rats. Female rats showed no significant differences in motor activity whereas drug treated males swam quicker on test day 1 (Cere p < 0.01: E021 p < 0.05) and day 2 (Cere p < 0.01). In the present experiments it was demonstrated that i.p. administration of both Cere and E021 improves the spatial learning and memory of 24 month-old male and female rats.

Amino Acids↗
PubMed1998

Cerebrolysin protects isolated cortical neurons from neurodegeneration after brief histotoxic hypoxia.

A brief period of histotoxic hypoxia exhibits certain metabolic features resembling the in vivo situation of ischemia. In this study the neuroprotective effects of the peptidergic nootropic drug Cerebrolysin (Cere) against iodoacetate induced histotoxic hypoxia were investigated. For that purpose isolated cortical neurons from 9 day chicken embryos were precultured with 0 to 6.4 mg.Cere/ml medium. At the 8th day in vitro histotoxic hypoxia was induced by incubation with 0.01 or 0.1 mM iodoacetate. Cells were allowed to recover from toxic stress for 3, 6, 24 or 48 hours. Cere protected neurons dose dependently from delayed neuronal cell death due to 0.01 mM iodoacetate even after a recovery period of 48h. After induction of histotoxic hypoxia by 0.1 mM iodoacetate high concentrations of Cere again led to neuronal protection after the 3 and 6 h recovery period. Moreover the influence of Cere on the cytoskeletal protein MAP2 in neurons submitted to 0.01 mM iodoacetate was investigated. With Western blotting and immunohistochemical techniques it has been demonstrated that the drug clearly increased MAP2 abundance after histotoxic hypoxia. The present study points out that after severe damage of cortical neurons with iodoacetate Cere is able to protect neurons from delayed neuronal cell death maybe by maintaining neuronal plasticity due to avoidance of the cytoskeletal breakdown.

Amino Acids↗
PubMed1998

Further evidence that Cerebrolysin protects cortical neurons from neurodegeneration in vitro.

The effects of Cerebrolysin on isolated chicken cortical neurons in an iron induced oxidative stress model and in a combined iron-glutamate model have been examined. In a first part of experiments it has been shown that under low serum conditions exposure of neurons to different concentrations of ammonium-iron (III)citrate (1, 5 microM AC-Fe3+) for 8 days caused a significant reduction in neuronal survival. Cerebrolysin not only prevented iron induced neurodegeneration, demonstrating that ionic iron was responsible for the cell damage, moreover, it increased the neuronal viability up to tenfold with respect to the controls. In the second part of the study neurons pre-incubated for 8 days with AC-Fe3+ were additionally lesioned with 1 mM L-glutamate and allowed to recover for another 48 h. Under these conditions cerebrolysin again clearly counteracted the in vitro destructive effects of glutamate. Besides consequences on the viability and survival of neurons Cerebrolysin increased abundance of the microtubule-associated protein MAP2, which is known to play a an important role in maintaining normal neuronal function.

Amino Acids↗
PubMed1998

Influence of BDNF and FCS on viability and programmed cell death (PCD) of developing cortical chicken neurons in vitro.

Programmed cell death (PCD) has been proposed to occur in vitro after withdrawal of growth factors and serum deprivation. In the present study the influence of brain derived neurotrophic factor (BDNF) and different serum (FCS) concentrations on viability, survival and apoptotic cell death of cortical cells from 8 days old chicken embryos after 3, 5 or 7 DIV was investigated. Results show that BDNF as well as fetal calf serum (FCS) influence the metabolism of neurons. Furthermore, serum, but not BDNF, is able to protect neurons from cell death. For the detection of apoptosis TUNEL-staining and DNA gel electrophoresis was performed. These methods supplied contrary information about the type of cell death in neurons raised without serum. The first technique indicates the occurrence of apoptosis whereas the second suggests necrosis. In addition, by the means of DNA gel electrophoresis it was exhibited that cortical cells from 8 days old chicken embryos are committed to undergo PCD already in vivo at time of preparation.

Animals↗
PubMed1998

Dose-dependent effects of Cerebrolysin on EEG and short-term memory of healthy volunteers during control and hyperventilation induced cerebral ischemia.

Cerebrolysin, a peptidergic nootropic drug, was to be effective on learning and other cognitive functions in animal experiments as well as in clinical studies. Hyperventilation (HV) as a model of brain ischemia induces slowing of the EEG and cognitive impairment. The aim of this study was to examine the potential dose-dependent effects of Cerebrolysin on HV related EEG changes and short term memory during chronic (10 days) application and the time dependency of these effects. In this single centre, double blind, randomized, placebo-controlled, parallel group study 48 healthy males were enrolled and received either 100 ml placebo (NaCl) or Cerebrolysin (10 ml or 30 ml or 50 ml) in a volume of 100 ml (NaCl) for 10 days. EEG at baseline and during HV as well as the cognitive performance was evaluated at Day 1 (baseline, 15 min p.i., 2 h p.i., 4 h p.i., 8 h p.i., 24 h p.i.), Day 10 (baseline, 15 min p.i., 2 h p.i.,) and at day 11 (24 h. after the last infusion). The main effects found during the study can be summarized as follows: At baseline we found an increase of the EEG power ratio (PR) for the grouptrated with 10 ml Cerebrolysin. The effect was most pronounced at the parietal cortex. The effect started after 15 min, was most expressed at 2 h and was kept until 8 h. During HV we found a relative PR decrease of the group (10 ml Cerebrolysin) at 2 hours. For short term memory, there is a trend towards less effective word recall for the baseline situation during the first 4 hours for the placebo. This effect was not observed in the Cerebrolysin treated groups. If chronic effects are concerned, the PR increased over the parietal regions at 24 h for the groups treated with 10 and 30 ml Cerebrolysin. The effect remains at day 10 and 11. But at 10 and 11 days there was also a trend for a relative increase of the PR in the group treated with 50ml Cerebrolysin. Signs of overdosage occurred with the highest concentrations of Cerebrolysin. The events were only mild and caused no harm to the volunteers. The highest concentration caused a small but significant reduction of blood pressure. The effects could be interpreted as those of an atypical nootropic with anti-ischemic properties.

Adult↗
PubMed1998

Early postnatal stimulation influences passive avoidance behaviour of adult rats.

In this study, the effects of stimulation on either postnatal days 1 to 7 or 21 to 27 on the passive avoidance reaction (PAR) of 3-month-old rats were examined. Animals received tactile or visual stimulation or tactile-visual stimulation for 10 min each day, and were trained at the beginning of the 4th month of life in a step-through apparatus using a footshock of 0.5 mA. Memory retention was measured 24, 48, 72, 96, and 120 h after the acquisition trial. Step-through latencies to enter the dark compartment and the total duration of stay in the illuminated compartment were recorded up to 200 s. Rats that received tactile or a combined tactile-visual stimulation during the 1st postnatal week displayed significantly longer PAR latencies and a longer duration of stay in the illuminated compartment compared to unstimulated control animals. Visual stimulation during the postnatal days 1 to 7 and 21 to 27 resulted in a longer duration of stay in the illuminated compartment. This effect, however, was more pronounced when stimulation was applied during the 1st postnatal week. Rats that received tactile stimulation during the 4th postnatal week showed decreased PAR performance for all measured parameters when compared to animals that received stimulation during the 1st postnatal week. Furthermore, combined tactile-visual stimulation during the 4th postnatal week led to a reduced duration of stay in the illuminated compartment when compared to the stimulation during the 1st postnatal week. These findings can be attributed to the higher degree of plasticity and to a heightened sensitivity to various stimuli in the 1st postnatal week. The results suggest that tactile, visual or combined tactile-visual stimulation have a long-lasting effect on the ability of adult rats to cope with stressful tasks.

Aging↗
PubMed1997

Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion.

The effects of the peptidergic nootropic drug Cerebrolysin on spatial memory and motor activity were examined in intact and ischemic rats. Ischemic-hypoxic damage was induced by injection of Na-cyanide followed by bilateral occlusion of common carotid arteries. Immediately afterwards Cerebrolysin or saline was administered, either by continuous intraventricular (i.v.) infusion or by daily intraperitoneal (i.p.) injection. Rats were tested for spatial memory and motor activity in the Morris water maze on days 3 and 4 post-surgery. The best dose of the substance for i.p. administration was known from previous studies. Therefore we had to investigate the dose-response-relationship and tolerability of the drug after i.v. administration in intact rats. Infusion (i.v.) of a high dose of Cerebrolysin (0.57 mg/day) decreased motor activity and spatial memory of intact rats (p < 0.01 and p < 0.05, respectively) but low dose of Cerebrolysin was well tolerated in the intact animals. Ischemia led to deterioration of motor activity in control rats (p < 0.01). Cerebrolysin significantly counteracted deleterious motor changes due to ischemia up to the level of intact controls after both i.v. infusion (0.0057 mg/day) and daily i.p. drug administration (100 mg/kg bw and day) indicating an accelerating recovery after ischemia.

Amino Acids↗
PubMed1996

Death of cultured telencephalon neurons induced by glutamate is reduced by the peptide derivative Cerebrolysin.

Glutamate induced neurotoxicity has been proposed to account for the loss of neurons after ischemia as well as in the cause of neurodegenerative diseases. We have studied the effects of exogenous glutamate on survival of neurons from chick embryo telencephalon, precultured with a peptide derivative for 8 days. The peptide derivative Cerebrolysin is a drug produced by standardised enzymatic breakdown consisting of 80% peptides and 20% amino acids. Toxic effects of acute glutamate exposure were prevented by Cerebrolysin in a concentration-dependent manner. 20 and 40 microliters Cerebrolysin produce distinct neuroprotective effects. However, 80 microliters Cerebrolysin/ml nutrition medium more than doubles neuronal viability compared to untreated control cells. These concentration-dependent effects of Cerebrolysin were evident even at the light microscopic level.

Amino Acids↗
PubMed1996

Effects of two protein-free peptide derivatives on passive avoidance behaviour of 24-month-old rats.

Cerebrolysin is an aqueous protein-free solution produced by biotechnological methods, using a standardised enzymatic breakdown of lipid-free pig brain proteins. The present study investigated the behavioural effects of this peptide derivative PD (100 mg/kg b.wt.), a related experimental peptide derivative PD-exp (1 mg/kg b.wt.) and a 0.9% saline control, on passive avoidance reaction (PAR) of 24-month-old male and female rats. Rats were pre-treated chronically for 7 days. Passive avoidance procedure started one day after the last subcutaneous injection with a single PAR-acquisition training session. Animals were trained in a step-through avoidance task using an unavoidable footshock of 1 mA (2 s). PAR-extinction testing showed that PAR latencies were treatment dependent (p < 0.001) due to the fact that PD and PD-exp treated animals displayed better performance. The same was true for all other behavioural elements observed. In this study we were able to demonstrate that s.c. administration of PD and PD-exp changes the capability of old female but not of old male rats to extinguish step-through behaviour. Because there were no differences in postshock latencies between control females and males we propose different sensitivity for the substances used.

Amino Acids↗
PubMed1996

Dose-dependent behavioural effects of two protein-free peptide derivatives on the passive avoidance reaction of rats.

Cerebrolysin is an aqueous protein-free solution produced by biotechnological methods, using a standardised enzymatic breakdown of lipid-free pig brain proteins. The present study investigated the behavioural effects of various doses (0.01; 0.1; 1; 10 and 100 mg/kg b.wt.) of this peptide derivative PD, and the related experimental peptide derivative PD-exp on passive avoidance reaction (PAR) of 2-month-old rats. PD consists of 15% small peptides (< 10 kD) and 85% free amino acids. The peptide composition of PD-exp is identical to that of PD but the overall peptide concentration is five times greater than that of PD. In the presented experiments, rats were treated with only one single injection of PD, PD-exp or saline as a control. Passive avoidance procedure started 24 h after the subcutaneous injection with a single PAR-acquisition training. Animals were trained in a step-through avoidance task using an unavoidable footshock of 0.75 mA (2 s). PAR extinction testing started 24 h later and was recorded on five consecutive days. The results of our experiments demonstrate that already a single injection of PD (100 mg/kg b.wt.), but to a higher extent of PD-exp (1 mg/kg b.wt.) induce an improvement on PA reaction of 2-month-old healthy rats.

Amino Acids↗
PubMed1995

Effects of postnatal stimulation on the passive avoidance behaviour of young rats.

We examined the effects of stimulation on either postnatal days 1-7 or 21-27 on passive avoidance reaction (PAR) of young rats. Animals received tactile or visual stimulation for 10 min each day, and were trained on postnatal day 28 in a step-through apparatus using a footshock of 0.75 mA for 2 s. Retention was tested on five consecutive days beginning on day 29. Memory retention was measured for each rat 24, 48, 72, 96 and 120 h after the acquisition trial. Step-through latencies to enter the dark compartment, time spent in the illuminated compartment and number of crossings of the light beam were recorded up to 200 s. Rats that received tactile or visual stimulation during the 4th postnatal week displayed significantly lower PAR latencies, a shorter stay in the illuminated compartment and a higher number of crossings of the light beam compared to rats treated during the 1st postnatal week. The untreated control group showed a rapid decline of PAR latencies. All experimental groups remained in the illuminated compartment longer and showed PAR latencies well above those of the control group. The differences became more pronounced when visual stimulation in the first postnatal week was used. The number of crossings of the light beam was significantly reduced by the treatment, with the exception of the experimental group stimulated visually in the 4th week. The behavioural changes induced by tactile or visual stimulation have a long-lasting effect in coping with a stressful task.

Animals↗