Alzheimer disease, from molecular biology to therapy.
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Alzheimer Disease↗
Biomedical subjects
E Giacobini
Publications and source records attributed to E Giacobini.
The effect of cholinesterase inhibitors on the secretion of APPS from rat brain cortex.
In this study we examined the question whether cholinesterase inhibitors (ChEI) could alter the release of amyloid precursor protein (APP) from superfused brain cortical slices of the rat following electrical as well as pharmacological stimulation with bethanechol (BETHA). Three ChEI, both reversible and irreversible were tested for their ability to enhance the release of non-amyloidogenic soluble derivatives (APPs). These included physostigmine (PHY), heptyl-physostigmine (HEP) and 2,2-dichlorovinyldimethyl phosphate (DDVP), at the concentrations producing cholinesterase (ChE) inhibition ranging from 5% to 95%. All three ChEI elevated APPs release significantly above control levels. Electrical field stimulation significantly increased the release of APPs within 50 min. Similar increase was observed after muscarinic receptor stimulation with BETHA. Tetrodotoxin (TTX) completely blocked the effect of electrical stimulation. These findings suggest that long-term administration of ChEI to Alzheimer's disease (AD) patients may have a neuroprotective effect by activating normal APP processing and decreasing the formation of amyloidogenic APP products.
Amyloid beta-Protein Precursor↗
Effects of MF-268, a new cholinesterase inhibitor, on acetylcholine and biogenic amines in rat cortex.
MF-268 bitartrate [(3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol- 5-ol[8-(cis2,-6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate; Mediolanum Farmaceutici, Milan, Italy] is a pseudo-reversible carbamate-type cholinesterase inhibitor (ChEI) which interacts with the catalytic and regulatory anionic site of the enzyme. Its effects on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5-HT, 5-hydroxytryptamine) were studied in rat cortex by using a microdialysis technique coupled with high-performance liquid chromatography-electrochemical detection (HPLC-ECD). Conscious, freely moving rats were systemically [per os (p.o.) and subcutaneously (s.c.)] administered MF-268 with no ChEI in the probe. Cholinesterase inhibition in brain was assayed in parallel experiments. Oral administration of MF-268 (0.5, 2.0, and 5.0 mg/kg) produced a significant increase of extracellular ACh in cortex; the maximal increase was 300% [not significant (n.s.)], 460% and 1,200%, respectively. Maximal cholinesterase (ChE) inhibition was 2.3% (n.s.) at 9 hr and 9.7% (P < .05) at 12 hr after the 2.0 and 5.0 mg/kg doses, respectively. Norepinephrine and DA levels were increased 180% and 100% after the 5.0 mg/kg dose, respectively; 100% and 60% after the 2.0 mg/kg dose, respectively; and 70% for both amines after the 0.5 mg/kg dose, respectively. The elevation lasted at least 5 hr with the 2.0 and 5.0 mg/kg doses. There were no major changes in 5-HT levels at these three doses. Subcutaneous administration (0.5 and 2.0 mg/kg) produced a maximal 360% (5.5 hr) and 2,500% (5 hr) increase in extracellular ACh, respectively. Maximal ChE inhibition was 13% (0.5 mg/kg) and 41% (2.0 mg/kg). Neither 0.5 nor 2.0 mg/kg produced a consistent modification of NE. Only a transient increase in DA was seen with the 0.5 mg/kg dose. There were no changes in 5-HT levels at these two doses. MF-268-treated animals showed slight cholinergic side effects (chewing, tremor) at both doses. MF-268 administered intracortically through the microdialysis probe at a concentration of 50 microM induced a 5,900% increase in ACh levels at 6 hr. This effect started 30 min after injection and continued throughout the period of administration. MF-268 produced a significant decrease in NE levels (-44%) starting at 30 min, and a slight but significant increase in DA levels of 45% at 2.5 hr. A significant increase of 5-HT (58%) was also observed starting at 4 hr. Slight symptoms of cholinergic toxicity were observed during intracortical administration.
Acetylcholine↗
A microdialysis study of the effects of the nicotinic agonist RJR-2403 on cortical release of acetylcholine and biogenic amines.
Transcortical dialysis was employed to investigate the effects of subcutaneous (s.c.) injections of RJR-2403 (1.2-7.2 mumol/kg) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in rat. Systemic administration of RJR-2403 produced a 90% increase of cortical extracellular ACh levels that persisted for up to 90 minutes after injection. Norepinephrine and DA release were increased 124% and 131% above basal values, respectively. Serotonin (5-HT) levels in the dialysate were also significantly elevated by RJR-2403 (3.6 mumol/kg, s.c.) 70% above baseline at 90 minutes post-injection. Comparison of these responses to those of (-)nicotine from a previous study reveals little difference between the two compounds in their ability to influence cortical neurotransmitter release following systemic administration.
Acetylcholine↗
The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex.
E2020 is a piperidine cholinesterase inhibitor (ChEI) which is structurally distinct from other compounds presently under study for treatment of Alzheimer's disease. We studied the effect of this compound on acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT; 5-hydroxytryptamine) by means of transcortical microdialysis in the cortex of awake rats with no ChEI in the probe. We also compared the inhibition of brain cholinesterase (ChE) by two different approaches. Following 0.5 and 2.0 mg/kg s.c. administration, the increase in ACh was 200% (30 min) and 2100% (1 hr), respectively. The maximal ChE inhibition at 30 min was 35.5% (2.0 mg/kg) and 15.6% (0.5 mg/kg) when measured as ACh hydrolysis in the diluted homogenate. After the 2.0 mg/kg dose, phosphorylation by DFP was completely blocked at 30 min. After 0.5 mg/kg, ChE phosphorylation was maximally inhibited at 30 min (56%) and declined thereafter to negligible levels by 3 hr. In addition, E2020 increased extracellular levels of catecholamines in cortex in agreement with our previous findings with carbamate ChEI. Following 2.0 mg/kg, both NE (100%) and DA (80%) were elevated, whereas after 0.5 mg/kg only NE (50%) was affected. Neither dose affected extracellular 5-HT. Thus, E2020, which inhibits brain ChE by a novel, reversible mechanism, elevates extracellular ACh in a comparable manner to other centrally-active ChEI, and this elevation of ACh is associated with stimulation of catecholamine release.
Acetylcholine↗
New trends in cholinergic therapy for Alzheimer disease: nicotinic agonists or cholinesterase inhibitors?
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Adrenergic Agonists↗
Second generation cholinesterase inhibitors: effect of (L)-huperzine-A on cortical biogenic amines.
L-Huperzine-A (Hup-A), a natural cholinesterase inhibitor (ChEI) derived from the Chinese herb Huperzia serrata, was administered systemically (i.p.) or locally through the microdialysis probe into the rat cortex. Systemic Hup-A significantly increased acetylcholine (ACh) levels above baseline at doses of 0.1, 0.3, and 0.5 mg/kg; the increases were 54%, 129%, and 220%, respectively. Norepinephrine (NE) and dopamine (DA) levels were also increased 121% and 129% above baseline at 0.3 mg/kg, and 143% and 153% at 0.5 mg/kg. Peak cholinesterase (ChE) inhibition was 23% at 60 min with the 0.3 mg/kg dose. Huperzine-A, perfused through the microdialysis probe, produced a maximal increase of ACh levels of 3090% and 7790% at concentrations of 5 and 50 microM. The ACh increase seen at both concentrations lasted at least 6 hr. At the 5-microM dose, NE and DA were increased by 214% and 386%; at the 50-microM dose, NE and DA were increased by 216% and 1141%. There were no changes of 5-HT levels. With local administration (via the probe), both doses produced facial-forelimb seizures that lasted throughout the perfusion. Our results show that Hup-A is a potent inhibitor of ChE which penetrates into the brain and produces a dose-dependent increase of ACh, NE, and DA in rat cortex. This effect is seen with both systemic and local intracerebral administration, suggesting cortical as well as subcortical effects of the drug.
Acetylcholine↗
Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex.
We postulate that the effect of cholinesterase inhibitors to ameliorate the cholinergic deficit in Alzheimer's disease is related to their ability to maintain long-lasting, non-toxic steady-state levels of acetylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone), on the extracellular levels of acetylcholine, norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat by high-performance liquid chromatography coupled with electrochemical detection. The drug significantly increased acetylcholine levels above the baseline at 2 and 10 mg/kg s.c., but not at the 1 mg/kg dose. At both 2 and 10 mg/kg there was a good correlation between cholinesterase inhibition and acetylcholine increase in cortex. At the 2 and 10 mg/kg doses, the maximal cholinesterase inhibition was 64% and 77%, respectively, and the increase in acetylcholine release was 481% and 1016%, respectively. Norepinephrine and dopamine, but not 5-hydroxytryptamine levels, were also significantly increased by the 10 mg/kg dose. The increases of norepinephrine and dopamine levels reached a maximum of 124% and 370%, respectively, and continued for a period of at least 8 h. Cholinergic side-effects were most marked at the 10 mg/kg dose but were also noticeable at the 2 mg/kg dose in the form of fasciculations, tremor and splay.
Acetophenones↗
Cholinesterase inhibitors increase secretion of APPs in rat brain cortex.
We examined whether cholinesterase inhibitors (ChEI) could alter the release of amyloid precursor protein (APP) from superfused brain cortical slices of the rat. Three ChEI, both reversible and irreversible, were tested for their ability to enhance the release of nonamyloidogenic soluble derivatives (APPs). These included: physostigmine (PHY), heptyl-physostigmine (HEP) and 2,2-dichloro-vinyldimethyl phosphate (DDVP), at concentrations producing cholinesterase (ChE) inhibition ranging from 5% to 95%. All three ChEI elevated APPs release significantly above control levels. Electrical field stimulation significantly increased the release of APPs within 50 min. Similar increase was observed after muscarinic receptor stimulation with bethanechol (BETHA). Tetrodotoxin (TTX) completely blocked the effect of electrical stimulation. These findings suggest that administration of ChEI to Alzheimer's disease (AD) patients may have a neuroprotective effect by activating normal APP processing.
Amyloid beta-Protein Precursor↗
Metrifonate effects on acetylcholine and biogenic amines in rat cortex.
The effect of systemic and local administration of metrifonate (MTF), a long-acting cholinesterase inhibitor (ChEl) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) was investigated in the rat cortex by using transcortical microdialysis. Metrifonate (20, 40, and 80 mg/kg, s.c.) increased ACh levels in a dose-dependent manner above the baseline. Two consecutive administrations (80 mg/kg) enhanced ACh levels producing two similar patterns of elevation. A significant increase in NE was also seen at 80 mg/kg. Systemic administration (20 mg/kg) of MTF produced a significant increase of DA levels. Local cortical perfusion of MTF through the probe caused a significant but slow increase of ACh as well as an increase of NE levels. Compared to NE, the elevation of DA was more rapid and more long-lasting. The cortical levels of 5-HT were not modified by MTF given by either route. These results support the concept of MTF being a potential drug for treatment of Alzheimer disease (AD).
Acetylcholine↗
5-fluoronicotine, noranhydroecgonine, and pyridyl-methylpyrrolidine release acetylcholine and biogenic amines in rat cortex in vivo.
The effects of nicotinic receptor agonists 5-fluoronicotine, noranhydroecgonine and pyridyl-methylpyrrolidine on the cortical release of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were investigated with microdialysis in rat. 5-Fluoronicotine significantly elevated ACh to 76% above basal values and DA to 69% above baseline. Pyridyl-methylpyrrolidine significantly increased the release of ACh to 39% above basal values and NE to 63% above baseline. Noranhydroecgonine significantly elevated NE to 64% above basal values and DA to 147% above baseline. 5-Fluoronicotine did not affect NE release; pyridylmethylpyrrolidine did not alter DA release; and noranhydroecgonine did not significantly elevate ACh release. None of these agonists increased the release of 5-HT. All responses were blocked by prior administration of mecamylamine, a nicotinic receptor antagonist. The distinctive neurotransmitter-related profiles for the three agonists are suggestive of activity at subtypes of nicotinic receptors, an effect that may be related to the structural diversity of these compounds.
Acetylcholine↗
Effects of local and repeated systemic administration of (-)nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex.
Systemically administered (-)nicotine (0.2-1.2 mg/kg, s.c.) significantly increased the release of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in rat cortex. The lowest dose of (-)nicotine examined (0.2 mg/kg, s.c.) also significantly elevated extracellular serotonin (5-HT) levels, and the maximal increases of extracellular ACh (122% at 90 min post injection) and DA levels (249% at 120 min post-injection) were observed following this dose. In contrast, the maximal increase of NE release (157% at 30 min post-injection) was observed following the highest dose of (-)nicotine injected (1.2 mg/kg, s.c.). This higher dose consistently produced generalized seizures. Repeating the (-)nicotine (0.58 mg/kg, s.c.) injection four hours after the first administration significantly elevated extracellular NE levels and also appeared to increase DA and ACh release. In addition, extracellular ACh and DA levels increased significantly in the dialysate after (-)nicotine was administered directly to the neocortex through the microdialysis probe membrane. Norepinephrine levels appeared to be elevated in the cortex following local administration as well.
Acetylcholine↗
Effects of cholinesterase inhibitors and clonidine coadministration on rat cortex neurotransmitters in vivo.
In previous investigations, we have demonstrated that cholinesterase inhibitors such as physostigmine (PHY) and heptylphysostigmine (HEP) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels in the rat cortex. This effect is enhanced by idazoxan, a selective alpha-2 antagonist. These data suggest that a combination of cholinergic and adrenergic drug may improve the pharmacological effect of the cholinesterase inhibitor on cortical neurotransmitters such as ACh-NE. In order to obtain additional information on cortical cortical neurotransmitter interaction, we tested, in the cerebral cortex of the rat, the effect of PHY and HEP in animals pretreated with clonidine (CLO), a selective alpha-2 agonist, on ACh, NE, dopamine and 5-hydroxytryptamine) extracellular levels. We detected no effect of systemic or intracortical CLO administration of ACh levels, but NE, dopamine and 5-hydroxytryptamine levels were all decreased. Systemic coadministration of CLO and PHY significantly elevated ACh levels and decreased NE, dopamine and 5-hydroxytryptamine levels. Systemic coadministration of CLO and HEP produced a significant elevation in ACh levels. Comparison between the two treatment combinations shows that, although CLO coadministration reduces the effect of PHY on ACh levels, HEP administered to animals pretreated with CLO produces a stronger effect than HEP alone. A possible explanation for this difference is the variation in duration of the two drugs on ACh elevation and muscarinic receptor desensitization. As a result of the alpha-2 agonist cholinesterase inhibitor coadministration, our data suggest that such a combination does not represent an advantage as a therapeutical alternative for treatment of cognitive impairment in Alzheimer disease patients.
Acetylcholine↗
Coadministration of cholinesterase inhibitors and idazoxan: effects of neurotransmitters in rat cortex in vivo.
Based on previous results indicating that cholinesterase inhibitors (ChEI) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels, we studied whether the NE elevation could down-regulate ACh levels and possibly decrease the therapeutical effect of these drugs. A modified microdialysis technique without ChEI in the probe was used to study the putative interaction of these neurotransmitters in cerebral cortex of freely moving rats. We administered physostigmine (PHY) (0.03 mg/kg) and heptylphysostigmine (HEP) (2 mg/kg) subcutaneously to animals pretreated with idazoxan (IDA) (i.p. or in the probe), a selective alpha-2 antagonist. IDA (20 mg/kg i.p. and 10(-4) M in the probe) did not modify the basal release of ACh. On the other hand, NE and dopamine (DA) were increased after both types of administration. PHY administered to rats pretreated with IDA (systemically or locally) induced a similar increase in the ACh levels as demonstrated for PHY alone. Conversely, coadministration of HEP with IDA i.p. produced a more sustained effect on ACh cortical levels than did HEP alone. These data suggest that a combination of cholinergic-adrenergic drugs may improve the pharmacological effect of ChEI.
Acetylcholine↗
Trimethylsilylated trifluoromethyl ketones, a novel class of acetylcholinesterase inhibitors: biochemical and pharmacological profile of MDL 73,745.
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Acetophenones↗
Therapy of Alzheimer disease: symptomatic or neuroprotective?
Therapeutic strategies aimed to treat Alzheimer disease (AD) may either produce an attenuation of symptoms or slow down deterioration by attenuating progression of the disease. Presently, cholinesterase inhibitors (ChEI) have shown the most promising therapeutical effects. The best documented clinical efficacy of ChEI are studies of THA (tacrine, tetrahydroaminoacridine). The results of five recent studies in a total of 1,242 patients are reported here. Based on differences from placebo in scoring, a gain of 2-12 (MMSE) or 5-6 (ADAS) months in deterioration can be seen for a THA treatment of 2-3 months duration. This suggests that if treatment with THA will be extended to a longer period, the drug effect may not be only a symptomatic improvement but a slow-down of disease course. A similarity of THA's effect in AD with L-deprenyl effects in Parkinson is suggested.
Alzheimer Disease↗
Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo.
A microdialysis technique was used to investigate the effect of physostigmine (PHY) and heptylphysostigmine (HEP), administered systemically or locally, on the extracellular levels of acetyl-choline (ACh), norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat. Levels of these neurotransmitters in dialysates were assayed simultaneously with two different high pressure liquid chromatography systems. No cholinesterase inhibitor was added into the probe to increase detection of ACh after systemic administration. Cholinesterase inhibition and its relation to ACh levels were also studied. Systemic administration of two doses of cholinesterase inhibitor [PHY (30 and 300 micrograms/kg) and HEP (2 and 5 mg/kg)] produced a dose-dependent increase in ACh levels. Local perfusion of these drugs through the probe elicited a strong increase in extracellular ACh. HEP produced a longer lasting inhibition of cholinesterase and a more prolonged elevation of ACh in cerebral cortex than PHY. After systemic administration of PHY (both doses), we observed a significant increase of norepinephrine levels. This effect was weaker after HEP. Local administration through the probe did not modify norepinephrine concentration. Dopamine levels were also increased after systemic administration. ONly HEP perfused into the probe elicited a significant increase in extracellular dopamine. Systemic or local administration did not modify 5-hydroxytryptamine levels. These observations suggest a more favorable pharmacological profile for HEP as a potential drug for Alzheimer disease, as compared to PHY.
Acetylcholine↗
Muscarinic receptors mediate attenuation of extracellular acetylcholine levels in rat cerebral cortex after cholinesterase inhibition.
Muscarinic autoregulation of extracellular acetylcholine levels was investigated by microdialysis in the cerebral cortex of freely moving rats under basal conditions as well as following systemic administration of a reversible cholinesterase inhibitor. Atropine (2.2 mg/kg s.c. or 0.2 microM via the dialysis probe) did not affect basal extracellular acetylcholine levels in the cerebral cortex. However, it did potentiate the elevation of extracellular acetylcholine levels produced by a dose of systemic heptylphysostigmine which inhibited 25% of cortical and 40% of plasma cholinesterase activity. These observations suggest that the extracellular concentration of acetylcholine following moderate acetylcholinesterase inhibition is regulated through muscarinic receptors.
Acetylcholine↗