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)

Effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, have been investigated on the ethanol withdrawal syndrome in rats. Adult male Wistar rats were used in the study. Ethanol (7.2% v/v) was given to the rats by a liquid diet for 21 days. Agmatine (20, 40, 80 and 160 mg/kg) and saline were injected to rats intraperitoneally 30 min before ethanol withdrawal testing. After 30th min, 2nd and 6th h of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Agmatine caused dose-dependent and significant inhibitory effects on stereotyped behaviors, wet dog shakes and tremors during the observation period. It did not cause any significant change in motor coordination of naive (not ethanol-dependent) rats. Our results suggest that agmatine attenuates withdrawal syndrome in ethanol-dependent rats; thus, this drug may be beneficial in the treatment of ethanol dependence.
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PMID:Effects of agmatine on ethanol withdrawal syndrome in rats. 1062 39

Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant.
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PMID:The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist. 1119 34

Shaking behavior, so-called wet dog shakes (WDS), in rats is characteristic behavior indicating morphine abstinence in morphine-dependence and central excitation in relation to seizures elicited by chemicals or electrical stimulation. We have found that paraquat (PQ), a nonselective herbicide, administered systemically to rats induces WDS in a dose-dependent manner. PQ-induced WDS are suppressed by nitric oxide (NO) synthase (NOS) inhibitors, but this suppression is not reversed by an NO precursor, L-arginine (L-Arg). The present study was performed to determine whether the NO system is associated with PQ-induced WDS in rats. A time-course study on the frequency of WDS for each 30-min period up to 120 min after PQ administration (70 mg/kg, s.c.) revealed that significant induction of WDS occurred during the first and second 30-min periods, that is within 60 min of PQ administration. A nonselective NOS inhibitor, Nomega-nitro-L-arginine (L-NA; 30 mg/kg, i.p.), reduced the frequency of the PQ-induced WDS during both of these periods, but the reduced frequency was not reversed by L-Arg (500 mg/kg, i.p.) in either period. Significant induction of WDS occurred when PQ (50 nmol) was administered directly into the ventral or dorsal hippocampus, but not when administered into the amygdala or the caudate putamen, indicating that the hippocampus plays an important role in PQ-induced WDS. The WDS after the administration of PQ into the dorsal hippocampus was significantly suppressed by pretreatment with L-NA (30 mg/kg, i.p.). The extracellular levels of nitrite (NO2-) and nitrate (NO3-), the oxidative products of NO, in the dorsal hippocampus determined by in vivo microdialysis, were stimulated after systemic PQ administration (70 mg/kg, s.c.) in urethane-anesthetized rats. The increases in extracellular NO2- and NO3- were inhibited by L-NA (30 mg/kg, i.p.), and this inhibition was partly reversed by L-Arg (500 mg/kg, i.p.). The increases in extracellular NO2- and NO3- in the dorsal hippocampus appeared 60 min after PQ administration, when the WDS had occurred and disappeared. These findings suggest that NO production in the hippocampus plays a minor role in PQ-induced WDS in rats and that the suppression of PQ-induced WDS by NOS inhibitors might be mediated though complex mechanisms in the brain.
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PMID:No parallel relationship between nitric oxide production and wet dog shakes susceptible to nitric oxide synthase inhibitors following systemic administration of paraquat in rats. 1130 80

The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta1-AR and beta2-AR-have been identified in most species. Although beta2-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype, beta3-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression of beta3-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta3-AR subtype and only 1.5% and 1.4% by the beta1-AR and beta2-AR subtypes, respectively. Functionally, selective beta3-AR agonists relax human isolated detrusor, whereas selective beta1-AR/beta2-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta3-AR antagonists but not by selective beta1-AR or beta2-AR antagonists. In animal models, beta3-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta3-AR agonists as therapy for overactive bladder, clinical trials of beta3-AR agonists identified in animal models as antiobesity agents indicate side effects of tremor and tachycardia. Development of compounds with high selectivity for the human beta3-AR, identified by screening techniques using cell lines transfected with the human beta1-AR, beta2-AR, and beta3-AR genes, may mitigate such problems. Together with the preliminary finding that 49% (21 of 43) of patients with idiopathic detrusor instability have a tryptophan 64 arginine mutation of the beta3-AR gene, which may be a useful genetic marker, evidence points toward beta3-AR being a therapeutic target for treatment of overactive bladder disorder.
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PMID:Beta3-adrenoceptors in human detrusor muscle. 1200 19

Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.
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PMID:MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. 1459 36

Human hereditary hyperekplexia ("startle disease") is a neurological disorder characterized by exaggerated, convulsive movements in response to unexpected stimuli. Molecular genetic studies have shown that this disease is often caused by amino acid substitutions at arginine 271 to glutamine or leucine of the alpha1 subunit of the inhibitory glycine receptor (GlyR). When exogenously expressed in Xenopus oocytes, agonist responses of mutant alpha1(R271Q) and alpha1(R271L) GlyRs show higher EC50 values and lower maximal inducible responses (relative efficacies) compared with oocytes expressing wild-type alpha1 GlyR subunits. Here, we report that the maximal glycine-induced currents (I(max)) of mutant alpha1(R271Q) and alpha1(R271L) GlyRs were dramatically potentiated in the presence of the anesthetic propofol (PRO), whereas the I(max) of wild-type alpha(1) receptors was not affected. Quantitative analysis of the agonist responses of the isofunctionally substituted alpha1(R271K) mutant GlyR revealed that saturating concentrations of PRO decreased the EC50 values of both glycine and the partial agonist beta-alanine by >10-fold, with relative efficacies increasing by 4- and 16-fold, respectively. Transgenic (tg) mice carrying the alpha1(R271Q) mutation (tg271Q-300) have both spontaneous and induced tremor episodes that closely resemble the movements of startled hyperekplexic patients. After treatment with subanesthetic doses of PRO, the tg271Q-300 mutant mice showed temporary reflexive and locomotor improvements that made them indistinguishable from wild-type mice. Together, these results demonstrate that the functional and behavioral effects of hyperekplexia mutations can be effectively reversed by drugs that potentiate GlyR responses.
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PMID:Propofol restores the function of "hyperekplexic" mutant glycine receptors in Xenopus oocytes and mice. 1499 83

We previously showed that systemic administration of a nitric oxide (NO) precursor, L-arginine (L-Arg), failed to reverse suppression by NO synthase (NOS) inhibitors of chemically induced shaking behavior in rats, leading to the hypothesis that exogenous L-Arg might be non-uniformly supplied to brain regions susceptible to NOS inhibitors. In the present study, therefore, we examined the effect of exogenous L-Arg on the extracellular levels of the oxidative nitric oxide (NO) products, nitrite (NO2-) and nitrate (NO3-), in two different brain regions, the hippocampus and the striatum, of conscious rats by means of in vivo brain microdialysis. The basal NO2- levels in the two brain regions were comparable, while the NO3- level was significantly lower in the hippocampus than the striatum. The addition of 10 mM L-Arg, but not D-Arg, to the perfusing solution significantly increased NO2- and NO3- in the hippocampus and NO2- alone in the striatum. These increases were abolished by 1 mM N(omega)-nitro-L-arginine, an NOS inhibitor. L-Arg at 1mM was able to significantly increase NO2-, but not NO3-, in the hippocampus to a level comparable with that at 10 mM L-Arg, while it had no effect in the striatum. L-Arg (500 mg/kg, i.p.) induced a significant increase in NO2- and NO3- in the hippocampus, but not in the striatum. These results suggest that the striatum may have a lower ability to enhance NO production by utilising exogenous L-Arg than the hippocampus, despite higher basal NO production.
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PMID:Different response to exogenous L-arginine in nitric oxide production between hippocampus and striatum of conscious rats: a microdialysis study. 1528 39

Human tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) is a member of the tumor necrosis factor (TNF) family of ligands which has been reported in 1995. The TRAIL protein induces apoptosis of certain types of target cells, such as transformed cells that include but are not limited to cancer cells and virus-infected cells but the normal cells. It is a type II transmembrane protein and the extracellular domain of TRAIL is the functional domain in induction of cell apoptosis. A gene fragment encoding for the active domain of TRAIL was modified with oligo-nucleotide directed mutagenesis according to the characters of Pichia pastoris expressing vector. Arginine at the position of 149 corresponding to the amino acid residue 531 which might be a potential Kex2 protease processing sites was substituted with Lysine to prevent the expressed protein from the digestion by the protease. After proved with DNA sequencing. the modified gene fragment coding soluble TRAIL domain was inserted into the Pichia pastoris expression vector pPIC9K in the same reading frame with alpha-factor secreting signal peptide. The recombinant plasmid pPIC9K - TRAIL was transferred into P. pastoris cell by spheroplast transformation. The recombinant yeasts were identified by antibiotic G418 and Southern dot blot. The transformants (His+ Mut(s)) containing multi-copy gene fragment of TRAIL were selected with increasing concentration of G418 and induced with 0.5% methanol in shaking flask to expression the active domain of TRAIL. After inducing for 3 - 4 days, the proteins in the culture supernatant was assayed with SDS-PAGE and Western blot. Two expressed protein bands whose appearant molecular weight were 19kD and 38kD, respectively, could be specifically recognized by polyclonal antibodies against human TRAIL. The 38kD protein might be a dimers of TRAIL in the culture supernatant. The amount of expressed foreign protein made up to 36% of the total proteins in the culture suprenatant. Biological activity assay, in vitro, indicated that the expressed protein could induce tumor cells apoptosis.
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PMID:[Expression of a DNA fragment encoding the active domain of human TNF related apoptosis inducing ligand in pichia pastoris]. 1596 15

The effects of demineralized water (DEMI H(2)O) and 0.5 M ammonium acetate (0.5 M AAc) on losses of L-glutamic acid and L-arginine in the course of shaking and filtration at low temperature (6 degrees C) were tested. The concentration of L-glutamic acid decreased by 6.3% in DEMI H(2)O and by 4.9% in 0.5 M AAc, whereas the L-arginine concentration decreased by 6.0% (DEMI H(2)O) and 10.7% (0.5 M AAc). We found a significantly (P < 0.05) higher degradation of L-arginine in 0.5 M AAc compared with that of DEMI H(2)O.
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PMID:The effect of extractants on degradation of L-glutamate and L-arginine in the course of shaking and filtration at low temperature. 1707 65

Neonatal encephalopathy with seizures (NEWS) is a previously undescribed autosomal recessive disease of standard poodle puppies. Affected puppies are small and weak at birth. Many die in their first week of life. Those surviving past 1 week develop ataxia, a whole-body tremor, and, by 4 to 6 weeks of age, severe generalized clonic-tonic seizures. None have survived to 7 weeks of age. Cerebella from affected puppies were reduced in size and often contained dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons. We used deoxyribonucleic acid samples from related standard poodles to map the NEWS locus to a 2.87-Mb segment of CFA36, which contains the canine ortholog of ATF2. This gene encodes activating transcription factor 2 (ATF-2), which participates in the cellular responses to a wide variety of stimuli. We amplified and sequenced all coding regions of canine ATF2 from a NEWS-affected puppy and identified a T > G transversion that predicts a methionine-to-arginine missense mutation at amino acid position 51. Methionine-51 lies within a hydrophobic docking site for mitogen-activated protein kinases that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2 activation. All 20 NEWS-affected puppies in the standard poodle family were homozygous for the mutant G allele. The 58 clinically normal family members were either G/T heterozygotes or homozygous for the ancestral T allele. There are no previous reports of spontaneous ATF2 mutations in people or animals; however, atf2-knockout mice have cerebellar lesions that are similar to those in puppies with NEWS.
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PMID:A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. 1807 59


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