Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in this laboratory have demonstrated that the centrally-acting alpha 2-adrenergic agonist clonidine can offer significant protection against both the acute and chronic toxicity following irreversible cholinesterase inactivation with soman. The purpose of this study was to estimate the contribution of central mechanisms to soman toxicity in a rat model; and to determine the effectiveness of clonidine and a series of related agonists to offer protection against the acute and chronic manifestations of this toxicity. To investigate the central component of soman toxicity, animals were pretreated with the peripherally selective reversible cholinesterase inhibitor pyridostigmine, a standard protective agent. Pyridostigmine pretreatment resulted in significant improvement in survival following soman administration. However, pyridostigmine was not able to inhibit the signs of central soman toxicity, including convulsive behavior. Clonidine and several related drugs produced both a further reduction in lethality and a significant reduction in the central signs of soman toxicity. Signs of delayed toxicity to soman were apparent in rats surviving 48 h after administration as measured in open-field locomotor monitoring. Again, pyridostigmine did not offer protection against such delayed toxicity. When clonidine was included in the regimen, however, significant improvement in performance in this measure was observed. These results are consistent with our earlier findings of significant protection provided by clonidine and related drugs against acute and chronic manifestations of soman toxicity and provide further evidence that 1) central toxicity is an important contributor to soman's actions, and 2) stimulation of central alpha 2-adrenergic receptors limits the expression of this central toxicity.
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PMID:Effectiveness of alpha 2-adrenergic receptor stimulation in reducing the central toxicity following cholinesterase inhibition. 135 46

Physostigmine and other centrally-acting acetylcholinesterase inhibitors are currently being examined for their potential in the treatment of Alzheimer's Disease. The ability to employ this class of agents is limited by the potential for debilitating and dangerous side effects. Clonidine and related drugs have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. Seven adult macaque monkeys performing a delayed matching-to-sample (DMTS) task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the 'best dose' of each agent in terms of enhanced memory performance. The best doses were combined as a single administration and performance compared to that using the two drugs alone. The combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability to employ significantly higher doses of physostigmine in the combination regimen. A single injection of the combination resulted in enhanced performance both on the day of administration as well as on the following day. These results are consistent with the ability of clonidine to limit the expression or intensity of certain physostigmine-induced autonomic side effects, while allowing the cognitive beneficial effects of the cholinesterase inhibitor.
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PMID:Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by primates. 161 76

Intrathecal (i.t.) injection of neostigmine was employed to activate spinal cholinergic neurons mediating a hypertensive response in freely-moving rats. Our earlier studies have demonstrated that stimulation of central alpha-adrenergic receptors inhibits the pressor response following inhibition of brain cholinesterase. Clonidine (0.5-5 micrograms) pretreatment by i.t. injection did not alter the magnitude of the pressor response to i.t. injection of neostigmine, but did significantly delay the onset of the response. Since systemic administration of clonidine abolished the pressor response to i.t. neostigmine, clonidine was administered by the intracisternal (i.c.) route to determine whether higher centers mediated the inhibitory response. In this situation, clonidine pretreatment significantly inhibited the pressor response to i.t. injection of neostigmine. I.t. injection of norepinephrine (1-10 micrograms) was more effective, but i.c. pretreatment less effective than clonidine in inhibiting the pressor response to i.t. neostigmine. In order to confirm the ascending nature of the spinal cholinergic system, hemicholinium-3 was injected i.c. to deplete medullary levels of acetylcholine. Carbachol was then injected i.t. (since carbachol is a direct-acting agonist, it is not affected by local depletion of acetylcholine). Depletion of medullary acetylcholine significantly blocked the pressor response to i.t. injection of carbachol. These findings are consistent with the concept of an ascending spinal cholinergic pressor pathway. The pressor response to activation of spinal cholinergic receptors is not sensitive to local injection of clonidine, but, the medullary cholinergic component of the system is inhibited by alpha-receptor stimulation.
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PMID:Modification of spino-bulbar autonomic cholinergic systems by activation of alpha-adrenergic receptors. 257 71

Studies in our laboratory have demonstrated that alpha 2-adrenergic agonists such as clonidine inhibit acetylcholine synthesis and release. The effect of clonidine is so marked, that pretreatment reduces both the accumulation of brain acetylcholine, and the toxicity caused by cholinesterase inhibitors such as soman. In this study rats were pretreated with regimens which included known protective doses of clonidine or atropine. The dose of soman was adjusted to allow for the 24 hr survival of 50% of the animals in each group. Behavioral toxicity was assessed by observational techniques and by employing an automated animal activity monitor. Clonidine pretreatment resulted in a significant degree of protection from the lethal effects of soman in the rat. In addition, the ability of soman to inhibit normal ongoing behavior as well to elicit the expression of several abnormal behaviors, including convulsive behavior were inhibited by clonidine pretreatment. While clonidine pretreatment resulted in a similar degree of protection as atropine pretreatment against the acute phase of soman toxicity, only clonidine was effective in preventing the expression of chronic behavioral toxic manifestations to soman. Thus, animals pretreated with clonidine exhibited a significantly improved prognosis 24 or 48 hr following soman injection as compared with saline- or atropine-pretreated animals.
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PMID:Protection afforded by clonidine from the acute and chronic behavioral toxicity produced by the cholinesterase inhibitor soman. 272 39

Studies in our laboratory have demonstrated that alpha 2-adrenergic agonists such as clonidine offer protection against the toxicity caused by cholinesterase inhibitors such as soman. Experiments were designed to determine whether central catecholaminergic systems are implicated in the toxic and lethal manifestations of soman toxicity and whether the protection afforded by clonidine involves such pathways. Clonidine pretreatment resulted in a significant degree of protection from the lethal effects of soman in the mouse. Depletion of brain catecholamines did not alter soman-induced lethality or behavioral toxicity. Furthermore, catecholamine depletion was not effective in blocking clonidine-induced protection against soman toxicity. In contrast, elevation of brain catecholamines using the monoamine oxidase inhibitor, pargyline, resulted in significant protection against soman toxicity which was additive with that of clonidine.
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PMID:Role of central biogenic amines on the protection afforded by clonidine against the toxicity of soman, an irreversible cholinesterase inhibitor. 317 58

Clonidine, an alpha-2 adrenergic agonist can inhibit the release of acetylcholine from central and peripheral cholinergic neurons. This study was designed to examine the ability of clonidine to protect animals from the toxic manifestations of cholinesterase poisoning. Physostigmine, a central and peripheral cholinesterase inhibitor produced tremors, and at high doses death, by respiratory paralysis. Mice were injected with physostigmine at a dose (0.75 mg/kg) which evoked tremors in 100% and death in 90% of the animals. Clonidine pretreatment (0.3 mg/kg) increased the onset latency to tremor from 5 to 20 min, increased the onset latency to death from 12 to 24 min and increased the percentage of survivors to 50%. Yohimbine (1 mg/kg) reversed these protective effects of clonidine. The physostigmine-induced accumulation of forebrain and hindbrain acetylcholine also was reduced by 50% in both brain regions in clonidine-pretreated mice. Neostigmine, a selective peripheral cholinesterase inhibitor, induced respiratory paralysis which was not affected by clonidine pretreatment. These findings indicate that central cholinergic neurons involved in the regulation of respiration and fine motor control, but not peripheral motor neurons, are inhibited by clonidine acting on alpha receptors.
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PMID:Mechanism of the clonidine-induced protection against acetylcholinesterase inhibitor toxicity. 628 26

Possible mechanisms of the ability of clonidine to correct bupivacaine-induced ventricular electrophysiologic impairment were evaluated in an electrophysiologic model on closed-chest dogs. Nine groups (n = 6) of pentobarbital-anesthetized dogs were given atropine, 0.2 mg/kg intravenously (i.v.), and bupivacaine, 4 mg/kg i.v., over a 10-s period. Group 1 was then given only saline solution. Group 2 was given clonidine, 0.01 mg/kg i.v., over a 1-min period. Group 3 was given clonidine followed by i.v. administration of yohimbine, 1 mg/kg, an alpha 2-antagonist. Group 4 was given carbachol, 1 mg/kg i.v., a long-lasting cholinergic agonist, over a 1-min period. Group 5 was given electrical stimulation of the left vagus nerve. Group 6 was given physostigmine, 0.1 mg/kg i.v., known to inhibit cholinesterase degradation, 5 min before bupivacaine administration, and Group 7 received a combination of physostigmine pretreatment and electrical vagal stimulation. Group 8 was given physostigmine, 0.1 mg/kg i.v., and pancuronium bromide, 1 mg/kg i.v., known to inhibit nicotinic receptors, 5 min before bupivacaine administration. Then electrical stimulation of the left vagus nerve was performed. Group 9 was given nicotine, 0.1 mg/kg i.v., 1 min after bupivacaine injection over 1 min. Bupivacaine induced bradycardia, markedly increased the His-Purkinje conduction time (HV interval) and QRS duration. Bupivacaine decreased the peak of first derivative of left ventricle pressure (LVdP/dtmax) and increased left ventricular end-diastolic pressure (LVEDP). Clonidine improved QRS duration and HV interval. Yohimbine did not modify the effects of clonidine. QRS duration and HV interval were significantly improved in Groups 4-7. In Group 8, pancuronium pretreatment inhibited the beneficial effects of the combination of physostigmine pretreatment and electrical vagal stimulation. In contrast, in Group 9, like clonidine, nicotine improved QRS duration and HV interval. Three other groups of anesthetized dogs (n = 6) were then studied. All dogs were given hexamethonium, 10 mg/kg i.v. Then, Group 10 was given only saline solution; Group 11 was given bupivacaine, 4 mg/kg, and Group 12 was given bupivacaine and nicotine as in Group 9. In Group 11, bupivacaine induced its usual alterations. In contrast, nicotine did not modify the cardiotoxic profile of bupivacaine after hexamethonium pretreatment. We conclude that the beneficial effect of clonidine on the variables of ventricular conduction altered by bupivacaine 1) is not mediated by central alpha 2-activation, 2) is mediated by the activation of parasympathetic pathways, and 3) is indirect and not mediated by acetylcholine release but is mediated by the activation of parasympathetic ganglionic nicotinic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor mechanisms for clonidine reversal of bupivacaine-induced impairment of ventricular conduction in pentobarbital-anesthetized dogs. 790 46

In rats, the injection of soman (70 micrograms/kg, SC) resulted in a 90% inhibition of the cholinesterase (ChE) activities in three brain regions. The density (Bmax) for muscarinic acetylcholine receptors (mAChRs) following a single injection of soman was significantly reduced at 2 h after injection in the cortex and hindbrain. Bmax values, however, returned to baseline within 24 h. Subacute (repeated injection every 15 min) treatment with a sublethal dose of soman over 2 h also decreased the density of mAChRs. In both cases the density of mAChRs was reduced by about 15% for the cortex and 17% for the hindbrain (the midbrain was also reduced by 18% for subacute injections). Chronic administration (once daily for 7 days) of soman (20 micrograms/kg, SC) produced maximal inhibition of ChE activity but did not significantly downregulate mAChRs. Clonidine pretreatment reversed the soman-induced mAChR downregulation in cortex and hindbrain produced by acute soman administration. Thus, marked reduction in the levels of brain ChE is not the only factor involved in the production of mAChR downregulation to cholinesterase inhibitors.
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PMID:Regulation of central muscarinic receptors after cholinesterase inhibition: effect of clonidine. 822 Nov 66

We investigated the effects of a single administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 25 and 50 mg, orally), and an alpha 2-agonist, clonidine (0.5 and 2 micrograms/kg, orally), on neuropsychologic performance in two groups of patients with Alzheimer's disease (AD). Clonidine enhanced a spatial working memory and verbal fluency, but had no effect on spatial span or word priming. THA enhanced word priming, but had no effect on other performance measures. Our data suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia.
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PMID:THA improves word priming and clonidine enhances fluency and working memory in Alzheimer's disease. 1008 36