Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GEA 857 [2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate], a structural analogue of the 5-HT uptake blocker alaproclate, was tested for its ability to modify tremor and salivation induced by muscarinic agonists (oxotremorine, arecoline) and acetylcholinesterase inhibitors (physostigmine, THA) in the male rat. These agents were employed at submaximal doses. GEA 857, similarly to alaproclate (Ogren et al. 1985a & b), produced a dose-dependent, statistically significant (in the 5-20 mg/kg dose range) enhancement of the tremor response induced by all four cholinergic stimulants. However, unlike alaproclate, GEA 857 failed to enhance salivation in a consistent manner. GEA 857 itself did not produce tremor in the absence of the muscarinic agonists or the acetylcholinesterase inhibitors. The potentiation of oxotremorine tremor by GEA 857 could be fully blocked by atropine (1 mg/kg intraperitoneally). Unlike alaproclate, GEA 857 failed to affect 5-HT uptake or 5-HT metabolism in the 10-20 mg/kg dose range. However, similarly to the action of alaproclate, the potentiating effect of GEA 857 on muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of GEA 857 to enhance responses evoked by muscarinic agonists involves inhibitory properties of GEA 857 at certain membranal Ca(2+)-dependent K+ channels, the blockade of which can potentiate or prolong muscarinic cholinergic actions.
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PMID:GEA 857, a putative blocker of potassium conductance, enhances muscarinic agonist-evoked responses: dissociation from an action on 5-HT mechanisms. 143 27

Tetrahydroaminoacridine (THA) and metrifonate are cholinesterase inhibitors used in the treatment of Alzheimer's disease. In experimental animals they inhibit acetylcholinesterase activity and have been reported to increase levels of brain acetylcholine. This paper presents results from studies of their effect at two dose levels on the dynamics of acetylcholine in mouse brain. Metrifonate at two doses (10 and 30 mg/kg intraperitoneally), known to cause cholinesterase inhibition, had no effect on levels of acetylcholine or choline or on the rate of synthesis of acetylcholine. THA (3 mg/kg intraperitoneally) had no effect on levels of acetylcholine and choline but had a shortlasting decreasing effect on the synthesis rate of acetylcholine. THA (10 mg/kg intraperitoneally) increased levels of acetylcholine and choline and markedly decreased the synthesis rate of acetylcholine. At this dose, the animals showed severe cholinergic effects, e.g. tremor and salivation. It is suggested that a moderate cholinesterase inhibition in brain facilitates cholinergic nerve transmission which is obtained at a broader dose range for metrifonate than for THA.
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PMID:Metrifonate and tacrine: a comparative study on their effect on acetylcholine dynamics in mouse brain. 143 50

Studies were performed to bring out a serotoninergic involvement in physostigmine tremor, hitherto known to be working via the cholinergic system. 5-Hydroxytryptamine (5-HT) was estimated fluorimetrically after isolation on Sephadex G-10 and acetylcholinesterase (AChE) was assayed spectrophotometrically. The dose-dependent tremor was quantified by a double-blind study. No correlation (r = 0.01) existed between tremor and AChE inhibition since the non-tremoring dose of physostigmine caused the same degree of enzyme inhibition. An increase of 5-HT was found to be correlated (r = 0.59) with the duration and intensity of tremor. Cholinergic antagonists atropine (2 and 5 mg/kg, i.p.), scopolamine (0.5, 1.0, 2.0 mg/kg, i.p.) and mecamylamine (1 mg/kg, i.p.) failed to block the tremor while the 5-HT antagonists methysergide (5 mg/kg, i.v.) and cyproheptadine (10 and 30 mg/kg, s.c.) could afford more than 60% protection. These results suggest a serotoninergic rather than a cholinergic component in the genesis of physostigmine tremor.
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PMID:Tremorogenesis by physostigmine is unrelated to acetylcholinesterase inhibition: evidence for serotoninergic involvement. 229

Repeated application of hexachlorocyclohexane (HCH; 50 and 100 mg/kg) and malathion (200 and 400 mg/kg) alone or in combination daily for 30 days on the skin of male guinea pigs caused mild to severe signs of toxicity and death of animals. The experimental animals exhibited tremor, dyspnea, salivation, convulsion, diarrhea and paralysis of the limbs. These were associated with significant biochemical and morphological changes in skin, liver, kidney and testes. The inhibition of acetylcholinesterase appeared highly significant in the combined treatment, but was not suggestive of any HCH and malathion potentiation. The highest level of HCH residue was seen in fatty tissue after low dose treatment. This was in contrast to the high level seen in liver after larger doses of HCH. This study suggests that HCH and malathion did not elicit any potentiation effects in the parameters monitored and at the doses tested.
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PMID:Interaction of hexachlorocyclohexane and malathion in male guinea pigs after repeated dermal application. 243 88

1. The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2. Administration of THA (5-20 mg kg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg-1) administration. 3. THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4. In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 +/- 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 +/- 10 nM) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 +/- 1.4 nM). 5. Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600 nM) and M2 (Ki: 880 nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors. 6. It is concluded that THA is a reversible non-competitive inhibitor of cholinesterase with a long half life (compared with physostigmine). It also may antagonize muscarinic receptors at high doses. The long half life may account for its reported efficacy in the treatment of Alzheimer's disease.
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PMID:The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro. 280 55

We examined two sets of genes expressed early in the developmental cycle of Dictyostelium discoideum that appear to be regulated by cyclic AMP (cAMP). The transcripts of both sets of genes were not detectable in vegetative cells. During normal development on filter pads, RNA complementary to these genes could be detected at about 2 h, peaked around 6 to 8 h, and decreased gradually thereafter. Expression of these genes upon starvation in shaking culture was stimulated by pulsing the cells with nanomolar levels of cAMP, a condition that mimics the in vivo pulsing during normal aggregation. Expression was inhibited by caffeine or by continuous levels of cAMP, a condition found later in development when in vivo expression of these genes decreased. The inhibition of caffeine could be overcome by pulsing cells with cAMP. These results suggest that the expression is mediated via the cell surface cAMP receptor, but does not require a rise in intracellular cAMP. mRNA from a gene of the second class was induced upon starvation, peaked by 2.5 h of development, and then declined. In contrast to the other genes, its expression was maintained by continuous levels of cAMP and repressed by cAMP pulses. These and other results on a number of classes of developmentally regulated genes indicates that changing levels of cAMP, acting via the cell surface cAMP receptor, are involved in controlling these groups of genes. We also examined the structure and partial sequence of the cAMP pulse-induced genes. The two tandemly duplicated M3 genes were almost continuously homologous over the sequenced portion of the protein-coding region except for a region near the N-terminal end. The two M3 genes had regions of homology in the 5' flanking sequence and showed slight homology to the same regions in gene D2, another cAMP pulse-induced gene. D2 showed extremely significant homology over its entire sequenced length to an acetylcholinesterase. The results presented here and by others suggest that expression of many early genes in D. discoideum is regulated via the cell surface cAMP receptor. We expect that many of these genes may play essential roles in early Dictyostelium development and could code for elements of the cAMP signal transduction pathway involved in aggregation.
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PMID:Cyclic AMP regulation of early gene expression in Dictyostelium discoideum: mediation via the cell surface cyclic AMP receptor. 303 75

The spinal cord is capable of initiating a significant and long-lasting pressor response following intrathecal injection of cholinergic agonists in freely moving rats. The magnitude of the pressor response to the cholinesterase inhibitor, neostigmine, was greatest when the site of injection was restricted to the thoracic level. Intrathecal (i.t.) injection of neostigmine (1-10 micrograms) elicited a dose-related increase in mean arterial pressure of up to 45 mm Hg which remained elevated for almost 2 h. Significant inhibition of acetylcholinesterase was localized to the spinal cord, with the thoracic region exhibiting the greatest degree of inhibition. Also, depletion of spinal acetylcholine levels following i.t. injection of hemicholinium-3 (HC-3) resulted in a significant reduction in the magnitude of the neostigmine-induced pressor response. Carbachol, a direct-acting cholinergic receptor agonist also increased mean arterial pressure following i.t. injection. However, the pressor response to carbachol was not reduced following HC-3. For both agonists, cardiovascular changes were accompanied by significant behavioral changes characterized by tremor, scratching, tail biting and chewing. The appearances of these behaviors following neostigmine injection were reduced in frequency and intensity in HC-3-pretreated animals. These findings demonstrate the ability of spinal cholinergic neurons to mediate a significant hypertensive response. The presence of marked behavioral changes accompanying the cardiovascular response suggests the possibility that cholinergic neurons may be part of an ascending spinal system.
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PMID:Hypertension following intrathecal injection of cholinergic agonists in conscious rats: role of endogenous acetylcholine. 322 83

Tri-o-cresyl phosphate (TOCP), which produces a delayed neurotoxic syndrome in humans and some animal species, was given to Fischer 344 (F344) male (18 week old) rats to determine if it causes biochemical, sensorimotor, and neuropathological effects. Animals were given TOCP by gavage in doses ranging from 10 to 100 mg of TOCP/kg daily for a period of 63 days. The rats were subjected to a series of neurobehavioral tests including fore- and hindlimb grip strength, motor activity, tremor, and latency to respond to a thermal stimulus. Central and peripheral nervous tissues were examined for damage characteristic of organophosphorous compound-induced delayed neurotoxicity (OPIDN). Brain neurotoxic esterase and acetylcholinesterase activities were inhibited in a dose-dependent fashion. A group of three chickens treated with 100 mg of TOCP/kg/day for 18 days was included as the positive control for enzymatic and histopathological alterations associated with OPIDN. Rats showed no consistent neurobehavioral changes or evidence of neuropathological damage in nervous tissues associated with treatment. In contrast, chickens treated with TOCP developed delayed neurotoxicity characterized by ataxia, which progressed to paralysis. These neurological changes included swelling, fragmentation, and degeneration of the axon and myelin in both central and peripheral nervous tissues. This study concludes that the F344 rat is not sensitive to the delayed neurotoxic effects of TOCP. When studying OPIDN in rats, care must be exercised in choosing the experimental animal since some strains, e.g., F344, are not sensitive.
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PMID:Lack of delayed neurotoxic effect after tri-o-cresyl phosphate treatment in male Fischer 344 rats: biochemical, neurobehavioral, and neuropathological studies. 335 6

Acetylcholinesterase (AChE)-induced chewing movements, tremors, convulsions and hind limb abduction at doses of 50-85% LD50 in rats were monitored in order to determine whether the severity of these different signs would correlate with brain AChE levels and the time course of such a relationship. 30 min after subcutaneous (s.c.) injection of Soman, the intensities of toxic signs were significantly correlated with the degree of striatal AChE inhibition. In the case of Sarin, the corresponding r-values were not significant except for tremors. For Tabun-induced chewing, tremor and hind-limb abduction, the r-values were significant. The neurotoxicity was most intense between 15 min to 2 h after treatment, but at 2 or 6 h, the r-values were well below 0.5. The inhibition of brain AChE was maximal by 30 min and was still high at 24 h.
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PMID:Relationship between the neurotoxicities of Soman, Sarin and Tabun, and acetylcholinesterase inhibition. 370

Mice pretreated with the centrally active alpha-2 adrenergic agonist, clonidine, were protected from several of the toxic manifestations of soman, an organophosphate acetylcholinesterase inhibitor. The protection resulted in increased survival rates and a reduction in centrally mediated symptoms of soman, including tremor and straub tail, as well as one peripheral muscarinic symptom, excessive salivation. Doses of clonidine between 0.1 and 1 mg/kg, administered between 5 and 40 min before LD80 to LD90 doses of soman, produced significant protection. Pretreatment with atropine (25 mg/kg) also protected against soman toxicity. When atropine was combined with clonidine, the degree of protection afforded by the combination was greater than that predicted for a simple additive effect. Mice protected by atropine from the initial toxicity of soman frequently died within 24 h; no such delayed lethality was observed with protective doses of clonidine. Clonidine noncompetitively inhibited acetylcholinesterase activity in vitro and after in vivo administration at protective doses. At brain concentrations obtained after in vivo administration in protective doses, clonidine also inhibited ligand binding to cortical muscarinic receptors in vitro. The protective effects of clonidine are likely to involve multiple effects, including blockade of acetylcholine release and postsynaptic muscarinic receptors and transient inhibition of acetylcholinesterase.
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PMID:Clonidine protection from the toxicity of soman, an organophosphate acetylcholinesterase inhibitor, in the mouse. 376 Nov 96


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