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E Giacobini

Publications and source records attributed to E Giacobini.

At least 19 recordsLinked to original sources
PubMed1992

Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain.

Molecular forms of acetylcholinesterase were studied in three brain regions from Alzheimer disease patients and non-demented, age-matched controls. In Alzheimer disease patients, the membrane-bound G4 form was decreased in frontal (-71%) and parietal cortex (-45%) and in the caudate-putamen (-47%) from control levels. We also found a decrease of aqueous-soluble acetylcholinesterase molecular forms in the aqueous-soluble acetylcholinesterase molecular forms in the caudate-putamen region. The effect of three clinically significant acetylcholinesterase inhibitors, heptyl-physostigmine, physostigmine and edrophonium, on aqueous-soluble acetylcholinesterase molecular forms of the caudate-putamen was investigated. Heptyl-physostigmine, a physostigmine analogue, showed preferential inhibition for the G1 form. On the contrary, edrophonium inhibited the G4 form more potently than the G1 form. Physostigmine inhibited both forms with similar potency. The clinical implications of selective acetylcholinesterase inhibitors are discussed.

Acetylcholinesterase↗
PubMed1992

Heptyl-physostigmine enhances basal forebrain control of cortical cerebral blood flow.

This study sought to determine the effect of heptylphysostigmine (H-PHY), a reversible cholinesterase (ChE) inhibitor with greater lipophilicity and longer duration of action than physostigmine, on resting and basal forebrain (BF)-elicited increases in cortical cerebral blood flow (CBF). Laser-doppler flowmetry (LDF) was used to monitor changes in frontal cortical microvascular perfusion in urethane anesthetized rats. Responses were measured before, early after, and 1 hr following H-PHY, 3 mg/kg, i.m. Electrical stimulation (100 microA) of the BF elicited up to 220% increases in CBF at 50 Hz, an effect that was graded with frequency. At 15 min following H-PHY (3 mg/kg) resting cortical CBF was unchanged, whereas BF-elicited increases were potentiated 47% at 50 Hz. At 1 hour, resting cortical CBF remained unchanged, and the BF-elicited responses were remarkably potentiated by 354% at 10 Hz and 67% at 50 Hz. Acetylcholinesterase (AChE) activity measured in the tissue directly beneath the LDF probe was decreased by 84% at a time when these CBF responses were enhanced. These data suggest that H-PHY substantially enhances the regulation of cortical CBF by the BF, an effect that may be linked to inhibition of cortical AChE activity. This enhancement of cortical CBF may contribute to the efficacy of H-PHY as a treatment for Alzheimer's disease.

Animals↗
PubMed1992

Preferential inhibition of acetylcholinesterase molecular forms in rat brain.

The effect of eight different acetylcholinesterase inhibitors (AChEIs) on the activity of acetylcholinesterase (AChE) molecular forms was investigated. Aqueous-soluble and detergent-soluble AChE molecular forms were separated from rat brain homogenate by sucrose density sedimentation. The bulk of soluble AChE corresponds to globular tetrameric (G4), and monomeric (G1) forms. Heptylphysostigmine (HEP) and diisopropylfluorophosphate were more selective for the G1 than for the G4 form in aqueous-soluble extract. Neostigmine showed slightly more selectivity for the G1 form both in aqueous- and detergent-soluble extracts. Other drugs such as physostigmine, echothiophate, BW284C51, tetrahydroaminoacridine, and metrifonate inhibited both aqueous- and detergent-soluble AChE molecular forms with similar potency. Inhibition of aqueous-soluble AChE by HEP was highly competitive with Triton X-100 in a gradient, indicating that HEP may bind to a detergent-sensitive non-catalytic site of AChE. These results suggest a differential sensitivity among AChE molecular forms to inhibition by drugs through an allosteric mechanism. The application of these properties in developing AChEIs for treatment of Alzheimer disease is considered.

Acetylcholinesterase↗
PubMed1991

Effects of L-beta-N-methylamino-L-alanine (L-BMAA) on the cortical cholinergic and glutamatergic systems of the rat.

Neurotoxic properties of L-beta-methylamino-alanine (L-BMAA) after chronic intracerebroventricular (i.c.v.) (500 micrograms/day) administration up to 60 days were investigated in the cerebral cortex of the rat. At day 16, there was a significant decrease in acetylcholinesterase (AChE) activity, 3H-QNB binding, 3H-glutamate (GLU) binding, and 3H-glutamate binding in the presence of quisqualate (QA). Choline acetyltransferase (ChAT) activity and 3H-nicotine binding were increased at day 16; however, ChAT activity decreased below control levels at days 40 and 60. 3H-Nicotine and 3H-AMPA binding were significantly lower than controls at both days 40 and 60. These significant neurochemical differences from unoperated controls were seen in both drug-injected and non-injected sides of the cortex suggesting a generalized cortical damage to glutamatergic and cholinergic systems. In the presence of bicarbonate, L-BMAA inhibited in vitro both glutamate and AMPA binding sites. L-BMAA treatment elicited behavioral changes such as splay, jerking movements, and rigidity. These symptoms were present for a period of at least 6 days after daily administration. After this period, symptoms were gradually attenuated and at day 10 the behavior of the L-BMAA-treated animals was not different from that of Na-bicarbonate injected controls. Our results are interpreted as an activation of quisqualate (AMPA) receptors by L-BMAA involving NMDA as well as non-NMDA receptors.

Acetylcholinesterase↗
PubMed1991

Muscarinic cholinoceptive neurons in the frontal cortex in Alzheimer's disease.

The cellular distribution of muscarinic acetylcholine receptor protein in the frontal cortex of Alzheimer (AD) patients, age-matched and middle-aged controls was assessed quantitatively by means of immunohistochemistry using the monoclonal antibody M35. As shown previously in biopsy cortices, mainly layer II/III and V pyramidal neurons were immunolabeled. Neither distribution nor numbers of labeled cells displayed significant differences between the groups investigated. This is in accordance with the results of ligand binding studies that mostly failed to reveal different binding characteristics in AD compared to controls. Muscarinic and nicotinic receptor proteins have been shown to be colocalized in many cholinoceptive pyramidal neurons. Since nicotinic receptors--in contrast to muscarinic receptor proteins--are severely reduced in AD, this indicates a selective impairment of nicotinic receptor expression and not a significant death of cholinoceptive neurons per se.

Aged↗
PubMed1991

Nucleus basalis lesions decrease alpha- and kappa-bungarotoxins binding in rat cortex.

A unilateral ibotenic acid lesion of the nucleus basalis magnocellularis in the rat, which is known to produce a reduction in cortical choline acetyltransferase activity and acetylcholine release, produces a decrease of 125I-alpha-bungarotoxin and 125I-kappa-bungarotoxin binding sites in the frontoparietal cortex of the lesioned hemisphere. This decrease can be observed at two weeks following the lesion and persists for up to twelve weeks. The results suggest that a population of bungarotoxin binding sites may have a presynaptic localization.

Animals↗
PubMed1991

Cellular distribution and expression of cortical acetylcholine receptors in aging and Alzheimer's disease.

Ligand binding studies show marked reductions of nicotinic, but not of muscarinic binding sites in Alzheimer's disease. Using monoclonal antibodies we studied immunohistochemically the expression of the respective receptor proteins in the frontal cortex of middle-aged (55 +/- 5 yr) controls, age-matched controls (73 +/- 6 yr), and patients with Alzheimer's disease (74 +/- 5 yr). Density of nicotinic cholinoceptive neurons was 8000/mm3 for middle-aged controls and 4000/mm3 for age-matched controls, but only 900/mm3 in Alzheimer's brains (p less than 0.0001). Densities of muscarinic cholinoceptive and of Nissl-stained neurons were not significantly different between the groups, pointing to a selective decrease of nicotinic receptor protein expression in cortical neurons with aging and in Alzheimer's disease.

Aging↗
PubMed1990

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Acetylcholine↗
PubMed1990

Cerebrospinal fluid choline levels are decreased in Parkinson's disease.

We examined acetylcholinsterase (AChE) activity and choline levels in cerebrospinal fluid (CSF) in 16 patients with idiopathic Parkinson's disease and 9 control subjects of corresponding age: 8 were untreated Parkinson's patients; 4 were treated with carbidopa-levodopa (100/1,000 mg/day) for 20 +/- 3 months; and 4 were treated with carbidopa-levodopa (110/1,100 mg/day) for 28 +/- 18 months plus amantadine (200 mg/day) for 16 +/- 8 months. CSF choline levels (nmol/ml) were 2.97 +/- 0.79 (control subjects); 1.31 +/- 0.29 (untreated patients); 1.00 +/- 0.29 (carbidopa-levodopa treated); and 1.26 +/- 0.19 (carbidopa-levodopa/amantadine treated). Choline levels were significantly lower in untreated and treated patients compared to control subjects (p = 0.0001). AChE activity did not differ in Parkinson's disease patients as compared to control subjects. The reduced level of choline in CSF may reflect a deficit in choline transport into the brain or a decrease of choline-phospholipid output from the brain.

Acetylcholinesterase↗
PubMed1990

Brain regional distribution of physostigmine and its relation to cerebral blood flow following intravenous administration in rats.

3H-labeled physostigmine (50 micrograms.kg-1) was administered intravenously to rats, and its concentration in brain tissue and spinal cord was assessed by quantitative autoradiography. Regional cerebral blood flow (rCBF) was measured with iodo-14C-antipyrine autoradiography in control rats and in animals injected i.v. with a dose of physostigmine similar to that used for the distribution studies. Tissue concentration of 3H-physostigmine was correlated with rCBF for 37 brain regions. A high degree of correlation was found at 0.5 min after drug injection, r (correlation coefficient) = 0.87. This association decreased at later times (5 min r = 0.73, 12 min r = 0.24). Structures with high cholinesterase activity (caudate-putamen, amygdala, hippocampus) showed greater retention of physostigmine over time. The highest initial physostigmine concentrations were found in regions lacking a blood-brain barrier (pineal bland, median eminence, choroid plexus) (range = 10.4-23.8 nCi/mg) and the lowest in white matter (corpus callosum, internal capsule, hippocampus commisure, spinal cord dorsal column) (range = 1.2-2.6 nCi/mg). Initial concentrations of the drug in the areas in which physostigmine induced vasodilatation (motor, sensory, temporal and occipital cortex, claustrum, and superior collicullus) were not different from concentrations in areas of comparable basal rCBF in which no such effect was observed. Variations in drug access to brain regions, then, do not explain the topographical variations of the cerebrovascular action of physostigmine.

Animals↗
PubMed1990

Nicotinic acetylcholine receptor subtypes in human frontal cortex: changes in Alzheimer's disease.

Molecular genetic and pharmacological studies have suggested that several subtypes of nicotinic acetylcholine receptors exist in the mammalian and avian brain. Combining 3H-(-)-nicotine, 125I-alpha-bungarotoxin, and 125I-kappa-bungarotoxin as ligands, we report here the first evidence for the existence in human frontal cortex of at least three different subtypes of nicotinic receptors. Autoradiographic analysis shows that specific 125I-kappa-bungarotoxin binding sites are concentrated mainly in several cortical layers. We also show that kappa-bungarotoxin, but not alpha-bungarotoxin decreases the evoked release of 3H-acetylcholine in rat cortical slices, indicating a likely presynaptic localization for some of the alpha-bungarotoxin-insensitive kappa-bungarotoxin sites in mammalian brain. The brains of patients with Alzheimer's disease show marked decreases in Bmax values for low-affinity 125I-kappa-bungarotoxin sites and both high- and low-affinity 3H-nicotine sites, whereas 125I-alpha-bungarotoxin sites are not significantly different in number from age-matched control brains. We conclude that Alzheimer's disease does not affect all subtypes of nicotinic receptors in the frontal cortex to the same extent.

Acetylcholine↗
PubMed1990

Cholinergic receptors in human brain: effects of aging and Alzheimer disease.

A general review of cholinergic receptors in human brain is presented. The paper focuses upon changes in normal aging brain and in Alzheimer disease. Studies from five different approaches are reported: 1) molecular biology; 2) receptor binding studies; 3) studies with specific neurotoxins; 4) immunocytochemistry; and 5) PET scan. These studies document profound and characteristic differences between the normal aging and the pathological Alzheimer brain with regard to cholinergic receptor localization, distribution, and function.

Aging↗
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↗