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Biomedical subjects

E Giacobini

Publications and source records attributed to E Giacobini.

At least 73 records · Page 4Linked to original sources
PubMed1990

Cerebrospinal fluid acetylcholinesterase and choline measurements in Huntington's disease.

The caudate nucleus has the highest acetylcholinesterase (AChE) activity in the brain and it has been shown that autopsied brain tissue of patients with Huntington's disease (HD) have reduced levels of acetylcholine. Because of these findings, the cholinergic function in HD was studied by measuring cerebrospinal fluid (CSF) choline levels and AChE activity during a randomized, double-blind, cross-over, placebo-controlled clinical trial of isoniazid. While mean choline levels adjusted for age were lower compared with controls (P = 0.0007), AChE activity did not differ between HD patients and normal controls. Treatment with isoniazid had no significant effect on CSF choline levels or CSF AChE activity. CSF AChE activity showed a statistically significant increase with advancing age. The reduced level of choline in CSF of HD patients may reflect either a defect in choline transport into the brain or a decrease of choline-phospholipid output from the brain.

Acetylcholinesterase↗
PubMed1989

Modulation of acetylcholine release by nicotinic receptors in the rat brain.

Since physostigmine (Phy) is presently used in the experimental treatment of Alzheimer disease (AD) patients by means of intracerebral ventricular (i.c.v.) administration, we designed a study to determine the effect of the drug administered by the same route on the cholinergic system of the rat brain. Particularly, we studied the involvement of nicotinic cholinergic function. The specific conditions required in this experiment were achieved by a series of short-lasting periods of acetylcholinesterase (AChE) inhibition leading to short-lasting increases of acetylcholine (ACh). These were produced by periodic i.c.v. injections of Phy. At 7 days of Phy administration, a small effect on 3H-nicotine binding was seen only in the striatum of the injected side. In rats treated for 13 days, we observed a 120% increase in the stimulated release of 3H-ACh in hippocampal slices of the injected side of the brain. There also was a significant 88% increase in 3H-nicotinic binding in the hippocampus of the same side while muscarinic binding was unchanged. These results suggest a process of upregulation of presynaptic nicotinic autoreceptors in the hippocampus modulating ACh release but no effect on the muscarinic receptors. Our results also suggest that pulses of ACh in analogy to nicotinic stimulation can cause protracted desensitization and eventually inactivation of the receptor leading to its up-regulation. These results are consistent with findings on the release of ACh from cortical biopsies and of a sustained ACh release in the CSF of AD patients following the same treatment.

Acetylcholine↗
PubMed1989

Effect of huperzine A, a new cholinesterase inhibitor, on the central cholinergic system of the rat.

The present study represents the first comprehensive investigation of the effect of huperzine A (HUP-A), a new cholinesterase inhibitor (ChEI) isolated from a Lycopodium species, upon acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels and release, and cholinergic receptors in rat brain following acute i.m. or i.p. administration. The study shows that HUP-A can produce a long-term inhibition of AChE activity in brain (up to 360 min) and an increase in the ACh levels up to 40% at 60 min. There is considerable regional variation in the degree of ACh elevation after HUP-A with maximal values seen in frontal (125%) and parietal (105%) cortex and smaller increases (22-65%) in other brain regions. HUP-A at concentrations of 10(-6) to 10(-4) M does not significantly alter the electrically evoked release of 3H-ACh from cortical slices. With the exception of the highest concentrations (6 X 10(-4) M) the displacement effect of HUP-A for cholinergic ligands is stronger for 3H-(-)nicotine than for 3H-QNB. A parallel autoradiographic study in the mouse shows that 60 min after i.v. injection (183 micrograms/kg) the drug is present in all brain regions, but it is particularly concentrated in certain areas such as frontoparietal cortex, nucleus accumbens, hippocampal, and striatal cortex. Radio-activity is practically absent in the whole body at 12 hr. Our study suggests that this new ChEI has interesting cholinomimetic properties, and its effects satisfy more closely established criteria for an ideal ChEI for therapeutic use than previously tested compounds.

Acetylcholine↗
PubMed1989

The effect of heptyl-physostigmine, a new cholinesterase inhibitor, on the central cholinergic system of the rat.

Heptyl-physostigmine (Heptyl-Phy; MF-201) is a new carbamate derivative of physostigmine (Phy) with greater lipophilicity and longer inhibitory action on cholinesterase (ChE) activity than the parent compound. Following single dose administration of 5 mg/kg heptyl-Phy i.m., maximal whole brain acetylcholinesterase (AChE) inhibition (82%) if reached at 60 min. Inhibition of plasma BuChE butyrylcholinesterase (BuChE) remains close to the steady state level (60%) between 120 and 360 min. At 360 min, whole brain AChE activity is still 67% inhibited compared to controls. Inhibition of AChE activity displays brain regional differences which are more significant at 360 min. At this time point, AChe activity in cerebellum is only 40% inhibited while frontal cortex and medial septum are still 80% inhibited. Increases in acetylcholine (ACh) levels also show regional differences, however, there is no direct relationship between AChE inhibition and ACh increase. The electrically evoked [3H]ACh release in cortical slices was inhibited only by the highest concentration of heptyl-Phy tested (10(-4) M). At this concentration ChE activity was 97% inhibited in vitro. In conclusion, our results demonstrate that heptyl-Phy compares favorably to other reversible cholinesterase inhibitors (ChEI), particularly to Phy as far as producing a more long-lasting inhibition of AChE and a more prolonged increase of ACh in brain with less severe side effects. Therefore, it represents an interesting candidate for cholinomimetic therapy of Alzheimer disease (AD).

Acetylcholinesterase↗
PubMed1989

Physostigmine, tacrine and metrifonate: the effect of multiple doses on acetylcholine metabolism in rat brain.

The effects of two consecutive intramuscular doses of three cholinesterase inhibitors (physostigmine, tetrahydroaminoacridine and metrifonate) were compared in rats. The results revealed major differences in biochemical effects on the brain of the rat including the extent and duration of inhibition of cholinesterase, inhibition of release of acetylcholine and increase in levels of acetylcholine. Side effects were also markedly different in the time of appearance, duration and severity. These results suggest that there are significant differences in the mechanisms of action of various cholinesterase inhibitors. Since all three cholinesterase inhibitors are currently used in the experimental treatment of Alzheimer's disease, these findings have potential implications for the symptomatic therapy of these patients.

Acetylcholine↗
PubMed1989

CSF choline and acetylcholinesterase in early-onset vs. late-onset Alzheimer's disease patients.

Cerebrospinal fluid acetylcholinesterase (AChE) activity levels and choline (Ch) levels were studied in 52 dementia of Alzheimer type (DAT) patients and 20 age-matched controls. The AChE activity was significantly lower and Ch levels were significantly higher in DAT patients than the age-matched controls. There was no significant difference in AChE activity and Ch levels between early-onset (less than or equal to 65 years) patients and late-onset (greater than 65 years) patients. However, the AChE activity was significantly lower in early-onset patients compared with their age-matched controls but no difference was observed in late-onset patients compared with their age-matched controls. None of the biological measures (AChE, Ch) were significantly correlated with the degree of cognitive impairment, duration of the illness or the sex of these patients.

Acetylcholinesterase↗
PubMed1989

Present progress and future development in the therapy for Alzheimer's disease.

The following is a review of the present progress and future development in the experimental therapy of Alzheimer disease (AD). Four different approaches are considered, first a molecular genetic one, second neuropeptide delivery, third trophic factors administration and fourth a cholinergic approach. Advantages and disadvantages of presently applied therapeutical experiments are analyzed and discussed together with the author's own experience and results.

Alzheimer Disease↗
PubMed1989

Determination of physostigmine in plasma and cerebrospinal fluid by liquid chromatography with electrochemical detection.

Physostigmine (Phy) was determined in plasma and cerebrospinal fluid (CSF) by HPLC with electrochemical detection, with use of a normal-phase column and methanolic sodium acetate buffer, pH 4.6. The detection limit of the method was 0.5 micrograms/L for a 2-mL sample of plasma or 0.5 mL of CSF. Analytical recovery of Phy in the range from 0.5 to 40 micrograms/L was 60% (SD 5%) for plasma and 78% (SD 8%) for CSF. Excellent chromatographic separation of Phy without column deterioration during extended usage and constant recovery for a wide range of Phy concentrations makes the routine monitoring of plasma from patients with Alzheimer's disease economically feasible. Using our method, we measured Phy in 13 such patients' plasmas at 105 and 135 min after a 135-min intravenous infusion of 300, 600, and 900 micrograms of Phy per square meter of body surface. Mean values significantly increased with dose (P = 0.001), but differences between 105 and 135 min (P = 0.229) or between dose and time (P = 0.949) were not significant.

Alzheimer Disease↗
PubMed1988

Potential pharmacotherapy of Alzheimer disease. A comparison of various forms of physostigmine administration.

This paper reviews clinical trials with physostigmine administered to Alzheimer patients using three different routes of administration: oral, i.v. and intracerebroventricular (i.c.v.). It compares results obtained with three different routes by the authors as well as by other authors. Particular emphasis is given to a novel type of physostigmine administration, the i.c.v. route. Advantages and disadvantages, as well as side effects of each route are presented and discussed.

Administration, Oral↗
PubMed1988

Cortisol responses to cholinergic drugs in Alzheimer's disease.

Patients with Alzheimer's disease participated in a trial of two sessions in which they received physostigmine and neostigmine in a double-blind crossover design. Most of these patients subsequently participated in a scopolamine vs saline double-blind crossover trial using a similar design. Physostigmine increased plasma cortisol relative to neostigmine, with the greatest difference at time points greater than 90 min post drug oral administration. Physostigmine also significantly decreased plasma cholinesterase (ChE). There was a significant positive correlation between the effects of physostigmine on increasing cortisol and decreasing ChE; there was no correlation between the increase in cortisol of cholinesterase inhibitor following neostigmine administration, but neither of these chemical parameters is related to the drug's effects on cognitive functioning.

Aged↗
PubMed1987

Cholinesterases in cerebrospinal fluid. A longitudinal study in Alzheimer disease.

We measured acetylcholinesterase (AChE) and butyrylcholinesterase activities in the lumbar cerebrospinal fluid (CSF) of 39 patients with dementia of Alzheimer type and 21 age-matched controls. The mean lumbar CSF AChE activity in our patients did not differ significantly from that of controls. The 7S and 11S molecular forms were also unchanged. When CSF was analyzed at six-month intervals, there was no significant decline in AChE activity over a span of 12 months. Our results and those of previous studies demonstrate that CSF AChE is not a useful diagnostic marker of Alzheimer disease.

Acetylcholinesterase↗