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)

Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 microM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50S of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to linopirdine, both compounds show greater in vivo potency and duration of action. Although 5 mg/kg (p.o.) linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter release.
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PMID:Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine. 958 Jun 19

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc). The symptoms are resting tremor, slowness of movement, rigidity and postural instability. Evidence that an imbalance between dopaminergic and cholinergic transmission takes place within the striatum led to the utilization of DA precursors, DA receptor agonists and anticholinergic drugs in the symptomatic therapy of PD. However, upon disease progression the therapy becomes less effective and debilitating effects such as dyskinesias and motor fluctuations appear. Hence, the need for the development of alternative therapeutic strategies has emerged. Several observations in different experimental models of PD suggest that blockade of excitatory amino acid transmission exerts antiparkinsonian effects. In particular, recent studies have focused on metabotropic glutamate receptors (mGluRs). Drugs acting on group I and II mGluRs have indeed been proven useful in ameliorating the parkinsonian symptoms in animal models of PD and therefore might represent promising therapeutic targets. This beneficial effect could be due to the reduction of both glutamatergic and cholinergic transmission. A novel target for drugs acting on mGluRs in PD therapy might be represented by striatal cholinergic interneurons. Indeed, the activation of mGluR2, highly expressed on this cell type, is able to reduce calcium-dependent plateau potentials by interfering with somato-dendritic N-type calcium channel activity, in turn reducing ACh release in the striatum. Similarly, the blockade of both group I mGluR subtypes reduces cholinergic interneuron excitability, and decreases striatal ACh release. Thus, targeting mGluRs located onto cholinergic interneurons might result in a beneficial pharmacological effect in the parkinsonian state.
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PMID:Striatal metabotropic glutamate receptors as a target for pharmacotherapy in Parkinson's disease. 1724 17

Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing alpha4 and beta2 subunits (alpha4beta2*) functionally interact with G-protein-coupled dopamine (DA) D(2) receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9'Ala) rendering alpha4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D(2)-receptor agonist. When challenged with the D(2)R agonist, quinpirole (0.5-10 mg/kg), Leu9'Ala mice, but not wild-type (WT) littermates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole-induced DA depletion did not differ between Leu9'Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c-Fos expression in choline acetyltransferase (ChAT)-positive interneurons. Highlighting the importance of the cholinergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson's disease, and the data suggest that a D(2)R-alpha4*-nAChR functional interaction regulates cholinergic interneuron activity.
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PMID:Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive {alpha}4 nicotinic receptors via a cholinergic-dependent mechanism. 1972 Jun 21


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