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)

The neurophysiological effects of 2 novel AMPA/kainate receptor antagonists, GYKI 52466 and LY 293558, on the high pressure neurological syndrome have been investigated in the rat and baboon (GYKI 52466) and rat (LY 293558). Rats were exposed to increasing ambient pressures of helium and oxygen at 3 ATA/min, on one occasion each. GYKI 52466 at 20 mumol/kg i.v. immediately before, followed by 70 mumol/kg/hr i.v. during compression delayed tremor by 85% and myoclonus by 30%, compared with control vehicle, and no side effects were observed. Seizure activity was not affected by any of the doses used. LY 293558 at 36 mumol/kg i.p. delayed tremor and myoclonus (44% and 12%), LY 293558 72 mumol/kg additionally delayed seizure activity (21%). Side effects, principally tranquilization at the higher dose, were also noted. Six baboons were exposed to a maximum pressure of 91 ATA at 0.3 ATA/min, in the same environment, on two occasions. One exposure was treated with an i.v. infusion of GYKI 52466 15.2 mumol/kg/hr, the other with the same volume of control vehicle. Limb and face tremor and myoclonus were delayed and the severity of signs reduced. No seizures were observed in the drug treated group before 91 ATA. EEG changes associated with exposure to pressure were not affected. It is concluded that antagonism at the AMPA/kainate receptor by GYKI 52466 and LY 293558 beneficially alters HPNS signs but in a manner which is dependent on both the drug and species being studied.
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PMID:Protection from high pressure induced hyperexcitability by the AMPA/kainate receptor antagonists GYKI 52466 and LY 293558. 793 94

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.
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PMID:New non competitive AMPA antagonists. 1100 58

Huntingtin interacting protein 1 (HIP1) is a recently identified component of clathrin-coated vesicles that plays a role in clathrin-mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1(-/-)). HIP1(-/-) mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1-containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dose-dependent defect in clathrin-mediated internalization of GluR1-containing AMPA receptors was observed in neurons from HIP1(-/-) mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor trafficking in the central nervous system through its function in clathrin-mediated endocytosis.
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PMID:Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking. 1283 88

This study examined the nociceptive effects of the intrathecal administration of various doses of the following endogenous excitatory sulphur-containing amino acids (SAAs): L-cysteic acid (L-CA), L-cysteine sulfinic acid (L-CSA), L-homocysteic acid (L-HCA) and L-homocysteic sulfinic acid (L-HCSA). For a period of 10min, rats were observed for spontaneous nociceptive behaviours (SNBs), including: tail elevation, twitching or licking; hindpaw elevation, licking or shaking; and caudally directed biting or scratching. The amount of time each rat spent eliciting these individual behaviours was recorded and a total time (in seconds) spent exhibiting SNBs was then calculated. To determine which glutamate receptors are primarily responsible for these nociceptive behaviours, we pretreated additional groups of rats with selective antagonists for N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid/kainate (AMPA/KA) and group I metabotropic glutamate receptors (mGluR1 and 5). Results indicate that SAAs dose-dependently produce SNBs that are attenuated by NMDA receptor and group I mGluR antagonists.
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PMID:Nociceptive effects of intrathecal administration of sulphur-containing amino acids. 1294

Transient synapse formation between thalamic axons and subplate neurons is thought to be important in thalamocortical targeting. Shaking rat Kawasaki (SRK), having reversed cortical layering similarly observed in reeler mouse, provides an interesting model system to test this idea. The spatial and temporal pattern of excitation was investigated using optical recording with voltage-sensitive dyes in thalamocortical slice preparations from SRK. At postnatal day 0 (P0), a strong optical response was elicited within the superplate of the SRK in the cell layer corresponding to subplate in wild-type (WT) rats. By P3, this response rapidly descended into deep cortical layers comprised of layer IV cells, as identified with 5-bromo-2'-deoxyuridine birthdating at embryonic day 17. During the first 3 postnatal days, both the subplate and cortical plate responses were present, but by P7, the subplate response was abolished. Tracing individual axons in SRK revealed that at P0-P3, a large number of thalamocortical axons reach the superplate, and by P7-P10, the ascending axons develop side branches into the lower or middle cortical layers. Synaptic currents were also demonstrated in WT subplate cells and in SRK superficial cortical cells using whole-cell recording. These currents were elicited monosynaptically, because partial AMPA current blockade did not modify the latencies. These results suggest that the general developmental pattern of synapse formation between thalamic axons and subplate (superplate) neurons in WT and SRK is very similar, and individual thalamic arbors in cortex are considerably remodeled during early postnatal development to find layer IV equivalent neurons.
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PMID:Functional thalamocortical synapse reorganization from subplate to layer IV during postnatal development in the reeler-like mutant rat (shaking rat Kawasaki). 1570 93

The mechanism of blocking effect of phenylcyclohexyl derivative, IEM-1925, on ionotropic glutamate receptors of the NMDA and AMPA types has been studied on the rat isolated brain neurons. The whole-cell configuration of patck clanp recording technique was used equilibrium conditions and -80 mV holding potential, the IEM-1925 manifests nonselective action on open channels of both receptors. However, the prominent differences in the mechanism of the blocking effect were revealed. Although IEM-1925 can not enter the closed channels of both types, its molecule are able to leave closed channels of the AMPA but not the NMDA receptors. Hyperpolarization reduces removal of blocker from the open channels of the NMDA receptors. Contrary to that, hyperpolarization facilitates going out of the IEM-1925 to cytozol from both open and closed channels. Evidently, the bloker can pass through the AMPA receptor channels into the cell, and the gating mechanism of these channels is located above the binding site for the blocker. The blocking action of the IEM-1925 on the NMDA and AMPA receptors was compared with its potency to weaken the tremor evoked by subcutaneous injection of arecoline to mice. The observed differences in the mechanisms of action help to explain the ambiguous effects of channel blocking drugs on experimental models of pathological processes.
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PMID:[Mechanisms of blockade of glutamate receptors channels: the significance for structural and physiological investigations]. 1661 55

The mechanism of the blocking action of phenylcyclohexyl derivative IEM-1925 on ionotropic NMDA and AMPA glutamate receptors was studied. Experiments on isolated rat brain neurons (hippocampal pyramidal cells and striatal cholinergic interneurons) were performed using local voltage clamping in the "whole cell" configuration. In equilibrium conditions at a membrane potential of -80 mV, there was no selectivity in the action of IEM-1925 on the open channels of either type of glutamate receptor. However, data were obtained showing significant differences in the mechanisms of the blocking actions. Although IEM-1925 was unable to penetrate into closed channels of either receptor type, molecules were able to leave closed AMPA receptor channels but not closed NMDA receptor channels. In hyperpolarization, the departure of the blocker from open NMDA receptor channels was slowed, while departure from open and closed AMPA receptor channels was accelerated. The blocker thus appeared able to penetrate AMPA receptor channels to enter cells, the gating mechanism of these channels being located above the blocker binding site. The actions of IEM-1925 on NMDA and AMPA receptors were compared with its ability to suppress tremor in mice induced with s.c. doses of arecoline. The results indicated that both types of receptors have a role in producing tremor. The differences in the mechanisms of action on AMPA and NMDA receptors may explain the ambiguous nature of the effects of the glutamate channel blocker in experimental therapy.
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PMID:Mechanisms of the blockade of glutamate channel receptors: significance for structural and physiological investigations. 1729 4

The muscarinic agonist arecoline (6 mg/kg, subcutaneously in mice) induced a long-lasting tremor. The inhibitory potency of non-competitive antagonists of ionotropic glutamate receptors has been studied. These antagonists are the derivatives of adamantane and phenylcyclohexyl. A part of them: monocationic compounds, selectively block the NMDA-receptor channels, their dicationic analogues affecting both channels of the NMDA- and the AMPA-glutamate receptors. Monocationic blockers effectively reduced the arecoline-evoked tremor and their potency correlated with ability to block the NMDA-receptor channels. Dicationic blockers revealed protective effect only in low range doses (0.0001-0.01 microM/kg). Further increase of the dose reduced or completely abolished this effect. This suggests that the NMDA-receptors are involved in the genesis of arecoline-evoked tremor. The only moderate blockade of the AMPA-receptors potentiates the drug blocking action but the prevalent blockade of these receptors impedes the effect on arecoline-evoked tremor.
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PMID:[Involvement of ionotropic glutamate receptors in the genesis of arecoline-induced tremor]. 1759 70

Development of the mammalian CNS requires formation and stabilization of neuronal circuits and synaptic connections. Sensory stimulation provided by the environment orchestrates neuronal circuit formation in the waking state. Endogenous sources of activation are also implicated in these processes. Accordingly we hypothesized that sleep, especially rapid eye movement sleep (REMS), the stage characterized by high neuronal activity that is more prominent in development than adulthood, provides endogenous stimulation, which, like sensory input, helps to stabilize and refine neuronal circuits during CNS development. Young (Y: postnatal day (PN) 16) and adolescent (A: PN44) rats were rapid eye movement sleep-deprived (REMSD) by gentle cage-shaking for only 4 h on 3 consecutive days (total 12 h). The effect of REMS deprivation in Y and A rats was tested 3-7 days after the last deprivation session (Y, PN21-25; A, PN49-53) and was compared with younger (immature, I, PN9-12) untreated, age-matched, treated and normal control groups. REMS deprivation negatively affected the stability of long-term potentiation (LTP) in Y but not A animals. LTP instability in Y-REMSD animals was similar to the instability in even the more immature, untreated animals. Utilizing immunoblots, we identified changes in molecular components of glutamatergic synapses known to participate in mechanisms of synaptic refinement and plasticity. Overall, N-methyl-d-aspartate receptor subunit 2B (NR2B), N-methyl-d-aspartate receptor subunit 2A, AMPA receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD-95), and calcium/calmodulin kinase II tended to be lower in Y REMSD animals (NR2B, GluR1 and PSD-95 were significantly lower) compared with controls, an effect not present in the A animals. Taken together, these data indicate that early-life REMS deprivation reduces stability of hippocampal neuronal circuits, possibly by hindering expression of mature glutamatergic synaptic components. The findings support a role for REMS in the maturation of hippocampal neuronal circuits.
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PMID:Rapid eye movement sleep deprivation decreases long-term potentiation stability and affects some glutamatergic signaling proteins during hippocampal development. 1835 75

Administration of the muscarinic cholinoreceptor agonist arecoline (6 mg/kg, s.c.) to mice induced long-lasting tremor. The ability of non-competitive antagonists of ionotropic glutamate receptors to suppress the onset of tremor was studied. These antagonists, i.e., adamantane and phenylcyclohexyl derivatives, selectively blocked NMDA-type receptor channels (monocations) or both NMDA-and AMPA-type channels (dications). Both types of blocker weakened arecoline tremor, though the dose-response relationships were different for mono-and dications. The effects of dications appeared only at low blocker doses (0.0001-0.01 micromol/kg) but gradually disappeared on dose elevation. These data lead to the conclusion that the mechanism of pathogenesis of arecoline tremor predominantly involves NMDA-type receptors. Moderate blockade of AMPA-type receptors could potentiate the preventive effect of mixed-action antagonists (anti-NMDA+anti-AMPA), though predominance of blocking action against AMPA-type receptors prevented this effect.
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PMID:Involvement of ionotropic glutamate receptors in the appearance of arecoline tremor in mice. 1840 36


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