Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes

Nielsen, Jann A.; Mena, E. Edward; Williams, Ian H.; Nocerini, Mark R.; Liston, Dane

doi:10.1016/0014-2999(89)90008-3

Cited by 100 publications

(56 citation statements)

References 31 publications

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“…Tacrine (positive control) inhibited acetylcholinesterase activity with an IC 50 of 334 ng / ml, which is consistent with previously published data (49). Our in vitro study showed that COE also inhibited acetylcholinesterase activity in a dose-dependent manner with an IC 50 of 81.6 µg / ml.…”

Section: Discussionsupporting

confidence: 92%

The Seed Extract of Cassia obtusifolia Ameliorates Learning and Memory Impairments Induced by Scopolamine or Transient Cerebral Hypoperfusion in Mice

et al. 2007

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Abstract. In the present study, we assessed the effect of the ethanolic extract of the seeds of Cassia obtusifolia (COE) on the learning and memory impairments induced by scopolamine or transient bilateral common carotid artery occlusion (2VO). In a study of the cholinergic dysfunction induced by scopolamine, single COE (25, 50, or 100 mg / kg, p.o.) administration significantly attenuated scopolamine-induced cognitive impairments as determined by the passive avoidance and Y-maze tasks (P<0.05) and also reduced escape-latency on the Morris water maze task (P<0.05). In the 2VO study, COE (50 mg / kg, p.o.) significantly reversed 2VO-induced cognitive impairments in mice by the passive avoidance and the Y-maze tasks (P<0.05). Moreover, COE (50 mg / kg, p.o.) also reduced escape-latency and prolonged swimming time in the target quadrant during a probe trial of the Morris water maze task (P<0.05). In an in vitro study, COE was found to inhibit acetylcholinesterase activity in a dose-dependent manner (IC 50 value: 81.6 µg / ml). Furthermore, COE also inhibited acetylcholinesterase activity in an ex vivo study. These results suggest that COE attenuates memory impairment induced by scopolamine or 2VO and that these effects are mediated by enhancing the cholinergic nervous system via acetylcholinesterase inhibition.

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Section: Discussionsupporting

confidence: 92%

The Seed Extract of Cassia obtusifolia Ameliorates Learning and Memory Impairments Induced by Scopolamine or Transient Cerebral Hypoperfusion in Mice

et al. 2007

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“…On the other hand, tremor, hypothermia, hypersalivation, chewing and yawning induced by muscarinic agonists are well-recognized central or peripheral cholinomimetic side effects (27 -29). It has been reported that tacrine causes serious side effects in humans (30,31) and animals (20,32). In the present study, although E2020 and tacrine increased the ACh concentration more potently than T-82 in the rat hippocampus and striatum, these drugs also produced cholinomimetic symptoms, such as hypothermia and hypersalivation.…”

Section: Discussioncontrasting

confidence: 40%

“…Therefore, drugs that activate central cholinergic neurotransmission may be effective for treating amnesia symptoms. In fact, AChE inhibitors, such as tacrine and E2020, are thought to augment cholinergic neurotransmission by preventing the hydrolysis of extracellular ACh (20,21). These compounds have been reported to improve the cognitive dysfunction in patients with Alzheimer's disease (22 -24) and in animal models of amnesia (20,25,26).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, AChE inhibitors, such as tacrine and E2020, are thought to augment cholinergic neurotransmission by preventing the hydrolysis of extracellular ACh (20,21). These compounds have been reported to improve the cognitive dysfunction in patients with Alzheimer's disease (22 -24) and in animal models of amnesia (20,25,26). On the other hand, tremor, hypothermia, hypersalivation, chewing and yawning induced by muscarinic agonists are well-recognized central or peripheral cholinomimetic side effects (27 -29).…”

Section: Discussionmentioning

confidence: 99%

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Effects of T-82, a New Quinoline Derivative, on Cholinesterase Activity and Extracellular Acetylcholine Concentration in Rat Brain

Isomae¹,

Ishikawa²,

Ohta³

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-The effects of T-82 (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo [3,4-b]quinolin-1-one hemifumarate), a new quinoline derivative, on acetylcholinesterase (AChE) activity and acetylcholine (ACh) release were compared with those of the well-known cholinesterase inhibitors tacrine and E2020. T-82, tacrine and E2020 all concentration-dependently inhibited AChE in rat brain homogenate (IC 50s = 109.4, 84.2 and 11.8 nM, respectively). In addition, although tacrine strongly inhibited butyrylcholinesterase (BuChE), T-82 and E2020 showed only weak activity on BuChE in human plasma. In ex vivo experiments, intraperitoneal administration of T-82 at a dose of 30 mg/ kg inhibited AChE activity in the hippocampus, frontal cortex and parietal cortex of rats. The effect of T-82 on the extracellular ACh concentration in rat brain was measured using in vivo microdialysis. T-82 at doses of 10 and 30 mg /kg, i.p. increased the extracellular ACh concentration in the hippocampus and striatum in a dose-dependent manner. These findings suggest that T-82 activates the central cholinergic system by selectively inhibiting AChE activity, while weakly affecting peripheral BuChE activity, and that T-82 increases the extracellular ACh concentration in the brain, which is followed by inhibited AChE activity.

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“…It has been reported, however, that galanthamine, physostigmine and tacrine accumulate in the brain tissue of small animals. If this occurs to an equal extent in humans, physostigmine might be increased 2-fold (23,24) and tacrine 8 -12-fold (25), resulting in an estimated acetylcholinesterase inhibition of 65% and 75% respectively. In the case of galanthamine (26), the accumulation factor of 2 would only lead to a 25 -35% enzyme inhibition in the human brain.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Thomsen¹,

Kaden²,

Fischer³

et al. 1991

Clinical Chemistry and Laboratory Medicine

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Summary:Galanthamine, physostigmine and 9-amino-l,2,3,4-tetrahydroacridine (tacrine) were evaluated s inhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortex biopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues by physostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a half maximal effect (IC 50 ) on acetylcholinesterase in postmortem human brain frontal cortex were 14nmol/l, 1.0 μιηοΐ/ΐ and 3.2 μηιόΐ/ΐ versus 15 nmol/1, 1.1 μτηοΐ/ΐ and 2.8 μιηοΐ/ΐ in the hippocampus region. In addition, the Inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain cortical biopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 h after death probably did not influence the measurement of acetylcholinesterase Inhibition. While physostigmine and tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potent in inhibiting the enzyme activity from human brain than from human erythrocytes. Comparison with issues from mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in human erythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn for further clinical studies.in Alzheimer's disease were determined: the frontal Reversible cholinesterase inhibitors are currently used cortex and the hippocampus. Since measurement of for symptomatic treatment of cognitive deficits and red-cell acetylcholinesterase Inhibition ex vivo may memory impairment in Alzheimer's disease. One pos-predict enzyme Inhibition in the brain (6, 7), it seemed tulated mechanism is restoration of the cholinergic useful to perform additional in vitro experiments with deficit at synaptic sites in the brain by inhibition of erythrocytes. Postmortem acetylcholinesterase activacetylcholine metabolisipti (1), b t severalother mech^ ity has been shown to be stable (8) for at least 31 h. anisms have also been discussed (2 -5). It was the It has also been reported, however, that the 4S and purpose of this study to measure the inhibition of 10S molecular forms in the brain are extremely labile acetylcholinesterase 1 ) from various sources by galan-and that freezing of either subcellular or intact tissue thamine, physostigmine and tacrine. A series of con-causes dramatic shifts in the level of the molecular centration response trials was performed using human forms (9), although the molecular shift was not asbrain tissue; and, prior to further specified analysis soeiated with any change of total acetylcholinesterase currently in progress, two separate regions of interest activity. To identify possible alterations in postmortem tissue, the inhibition of acetylcholinesterase by 1 ) Enzymes: Acetyl holinesterase, EC 3.1.1.7 galanthamine in fresh human brain cortex samplesEur.

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Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes

Cited by 100 publications

References 31 publications

The Seed Extract of Cassia obtusifolia Ameliorates Learning and Memory Impairments Induced by Scopolamine or Transient Cerebral Hypoperfusion in Mice

The Seed Extract of Cassia obtusifolia Ameliorates Learning and Memory Impairments Induced by Scopolamine or Transient Cerebral Hypoperfusion in Mice

Effects of T-82, a New Quinoline Derivative, on Cholinesterase Activity and Extracellular Acetylcholine Concentration in Rat Brain

Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

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