Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The behavioral and pharmacologic profiles of [Ser1]histogranin ([Ser1]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [3H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [3H]CGP 39653 binding to membrane preparations of rat brain with an IC50 of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [3H]CGP 39653 in the absence and presence of [Ser1]HN (2 microM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (Bmax of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (Kd of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser1]HN (10-100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser1]HN (2.5-100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser1]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.
 ...
PMID:N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin. 770 Sep 54

Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.
 ...
PMID:Behavioral studies on FR115427, a novel selective N-methyl-D-aspartate antagonist. 775 64

The glycine B receptor partial agonists L 687,414, D-cycloserine and (+)-HA 966, and the glycine B receptor antagonists MDL 29,951 and 5,7-dichloro-2,4 dihydroxy-3-phenyl-quinoline dione (DCPQ) dose-dependently inhibited the late phase (LP) of formalin-induced licking (FIL) elicited by intraplantar formalin in mice at doses exerting little motor disruption in the rotarod test. In distinction, the early phase (EP) of FIL and the writhing response to intra-abdominal acetic acid were little influenced and, irrespective of stimulus intensity, they failed to modify the tail-flick response to phasic, thermal or mechanical stimulation of the tail. In contrast to glycine B ligands, competitive antagonists at the NMDA receptor recognition site (CPP, CGS 19755, CGP 34879 and 39551) and blockers of the associated ion channel ((+)-MK 801, (-)-MK 801, memantine and ketamine) all blocked both the LP and EP of FIL and induced ataxia at comparable doses. In conclusion, normalization of transmission at NMDA receptors by inhibition of the coupled glycine B site preferentially elicits antinociception against prolonged (chemical) noxious stimulation in the absence of a marked influence upon motor coordination.
 ...
PMID:Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice. 781 23

1. A single administration of the ganglion blocker, chlorisondamine (10 mg kg-1, s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this persistent action is not known. It is also unclear whether chlorisondamine can block neuronal responses to excitatory amino acids and whether chronic blockade of nicotinic responses also occurs in the periphery. 2. Acute administration of chlorisondamine (10 mg kg-1, s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostration) when tested 1 to 14 days later, but caused no detectable cell death in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3. Long-term blockade of central nicotinic effects by chlorisondamine was not associated with significant alterations in the density (Bmax) of high-affinity [3H]-nicotine binding to forebrain cryostat-cut sections. 4. In cultured dissociated mesencephalic cells of the foetal rat, chlorisondamine and mecamylamine inhibited [3H]-dopamine release evoked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concentrations (IC50 approx. 600 and 70 microM, respectively). A high concentration of chlorisondamine (10(-3) M) had no effect on responses to quisqualate (10(-5) M) and only slightly reduced responses to kainate (10(-4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5. In adult rat hippocampal slices, chlorisondamine depressed NMDA receptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were mediated by non-NMDA excitatory amino acid receptors were less affected. 6. In rat isolated superior cervical ganglion, electrically-evoked synaptic transmission was reduced 1 h after acute in vivo administration of chlorisondamine (0.1 mg kg-1, s.c.). However, in vivo administration of a higher dose (10 mg kg-1, s.c.) did not significantly affect ganglionic transmission when tested two weeks later, despite the continued presence of central nicotinic blockade.7. These results indicate that the persistent CNS nicotinic blockade by chlorisondamine is not accompanied by changes in nicotinic [3H]-nicotine binding site density or by neuronal degeneration in the brain; that at doses sufficient to produce nicotinic receptor blockade, chlorisondamine acts in a pharmacologically selective manner; and that chronic central blockade is not accompanied by long-term peripheral ganglionic blockade.
 ...
PMID:The pharmacology of the nicotinic antagonist, chlorisondamine, investigated in rat brain and autonomic ganglion. 791 13

Systemic administration of kainic acid in the rat results in the development of a characteristic excitotoxic syndrome, consisting of automatisms (wet dog shakes, WDS), sustained limbic seizures and brain damage. Since kainate increases the release of excitatory amino acid neurotransmitters such as glutamate, this syndrome is thought to be due, at least in part, to excessive activation of glutamate receptors, particularly of the N-methyl-D-aspartate (NMDA) subtype. We examined the effect of D-cycloserine, a partial agonist for the NMDA receptor-associated glycine binding site, in the kainate model of limbic seizures in rats. For comparison, the uncompetitive NMDA antagonist MK-801 (dizocilpine) and the GABAmimetic anticonvulsant diazepam were used. D-Cycloserine exerted a potent, dose-dependent and long-lasting anticonvulsant effect against kainate-induced seizures. At 160 mg/kg, seizures were almost completely suppressed by D-cycloserine over a 3 h observation period. No adverse effects were observed at anticonvulsant doses of D-cycloserine. In contrast to its potent effect on kainate-induced seizures, D-cycloserine did not significantly alter the number of automatisms (WDS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effect was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked ataxia was observed at this dosage. In contrast to D-cycloserine, both MK-801 and diazepam reduced WDS behaviour caused by kainate. The data demonstrate that pharmacological manipulation of the strychnine-insensitive glycine site is a powerful means of protecting against kainate-induced seizures.
 ...
PMID:The glycine/NMDA receptor partial agonist D-cycloserine blocks kainate-induced seizures in rats. Comparison with MK-801 and diazepam. 795 30

Some non-competitive antagonists of N-methyl-D-aspartate (NMDA) were evaluated for potency to antagonize audiogenic seizures in genetically epilepsy-prone rats, following intraperitoneal administration. Phencyclidine (PCP), dizocilpine (MK-801), ketamine, ifenprodil and dextromethorphan, displayed anticonvulsant activity at doses similar to those which impaired performance in the rotarod equilibrium procedure. The noncompetitive NMDA receptor antagonists, at doses which slightly overlapped with the doses required for a full anticonvulsant protection against audiogenic seizures in genetically epilepsy-prone rats, induced profound untoward behavioural effects. This behavioural syndrome was characterized by marked ataxia, hyperactivity, stereotypes and wet dog shakes. In contrast, the effective anticonvulsant dose of 3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) was less than that required to impair rotarod performance and did not produce the PCP-like syndrome. A potential use in antiepileptic therapy, of CPPene or other new selective NMDA antagonists, with fewer neurotoxic effects but not for non-competitive antagonists such as MK-801, is suggested.
 ...
PMID:Anticonvulsant properties of non-competitive antagonists of the N-methyl-D-aspartate receptor in genetically epilepsy-prone rats: comparison with CPPene. 809 34

Anxiolytic-like and antinociceptive activities of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine) were compared with sedative and ataxic side effects in primates. Administration of MK-801 (0.1 mg/kg) caused taming in cynomolgus monkeys and increased tail withdrawal latencies in squirrel monkeys; both effects were accompanied by sedation and ataxia. These findings are discussed in relation to the possible therapeutic uses of NMDA antagonists and differences in the behavioural effects of such compounds in primate and rodent species.
 ...
PMID:Anxiolytic-like and antinociceptive effects of MK-801 accompanied by sedation and ataxia in primates. 809 50

This behavioral study was performed in order to delineate the antinociceptive effects of and the influence on motor function of a highly potent, competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). After intrathecal (i.t.) administration of CPP to chronically catheterized rats, antinociception was studied in 3 different nociceptive tests: the tail-flick test, the hot-plate test, and the formalin test. The lowest dose producing visible motor dysfunction was 1 nmol, with 2 of 8 animals showing slight ataxia. Dose-related motor dysfunction and apparent sedation was present after 5 and 10 nmol. Dose-related antinociception was evident in the thermal tests following doses that produced little or no motor dysfunction. In the tail-flick test, the antinociceptive effect was attenuated at higher doses, resulting in a bell-shaped dose-response relationship. Dose-related antinociception was found in both the first and second phase of the formalin test following doses from 0.25 up to 1 nmol. The present study shows that the competitive NMDA antagonist CPP has an antinociceptive effect in doses that do not affect motor function. Furthermore, antinociception was evident in both phasic and tonic nociceptive tests. Finally, the dose-response relationship in the tail-flick test was bell-shaped. As discussed this indicates that NMDA receptors may be involved in functionally divergent nociceptive systems.
 ...
PMID:The NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) has antinociceptive effect after intrathecal injection in the rat. 815 42

Recent studies have provided evidence that excitatory amino acid antagonists can exert analgesic effects in animals. These studies, however, have focused primarily on phasic pain or hyperalgesia rather than tonic pain. The present study evaluates the effects of systemic administration of Memantine (1-amino-3,5-dimethyl-adamantane), a clinically used N-methyl-D-aspartate (NMDA) receptor antagonist, on formalin-induced phasic and tonic pain behavior in the rat. Memantine (2.5, 5.0, 10.0 and 20.0 mg/kg) or normal saline was injected i.p. 1 h prior to a s.c. injection of formalin (5%, 50 microliters) into the vibrissal pad of adult rats (n = 5/group). Pain behavior was measured by the number of seconds of formalin-induced face grooming during a 42-min post-injection observation period. Saline-injected animals displayed a biphasic face-grooming response, consisting of an early, phasic phase (0-6 min) and a delayed, prolonged tonic phase (12-42 min). Memantine at doses of 2.5-10 mg/kg produced a significant dose-related inhibition of the second phase (65-93%) and a much smaller inhibition of the first phase (up to 52%). A higher dose (20 mg/kg) further inhibited both phases but also produced other motor effects (increased exploratory and decreased freezing behavior, hind-paw weakness and gait ataxia) which were not observed at the lower doses. These results suggest that the NMDA receptor antagonist Memantine can block formalin-induced tonic and, to a lesser extent, phasic pain, at doses that do not alter observed motor behaviors.
 ...
PMID:The NMDA antagonist Memantine blocks pain behavior in a rat model of formalin-induced facial pain. 823 44

The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 microM. F-721 had no effect on adenosine uptake, gamma-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.
 ...
PMID:Characterization of the anticonvulsant properties of F-721. 839 82


<< Previous 1 2 3 4 5 6 7 8 9 Next >>