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)

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
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PMID:Oxidative stress and antioxidant therapy in Parkinson's disease. 883 Mar 46

The present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.
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PMID:Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions. 890 Oct 1

Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.
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PMID:Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain. 937 98

The lipophilic t-butyl analog of 1-alkyl-4,4-diphenyl piperidine, budipine, possesses a polyvalent spectrum of mechanisms of action. Budipine experimentally increased the brain content of norepinephrine, serotonine, dopamine and histamine in reserpine treated rats. Budipine did not alter the receptor affinity of these neurotransmitters but antagonizes the effect of NMDA at its receptor binding site in vitro. Budipine reduced MPP+ toxicity in the nigrostriatal system of mice. This complex pharmacologic profile is not comparable to the one of convenient antiparkinsonian drugs. In clinical trials budipine reduced tremor, akinesia and rigidity. Budipine induced a relevant additional positive effect in patients with an optimal dopaminergic therapy based on levodopa and dopamine agonists, such as bromocriptine. Current available data suggest that the need for levodopa application in early stages of the disease may be postponed by budipine and that the long-term application of budipine may induce a levodopa-sparing effect.
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PMID:Clinical efficacy of budipine in Parkinson's disease. 1037 Sep 3

High pressure induced locomotor and motor hyperactivities (LMA), tremor and myoclonia in rat. The LMA has been reported to be reduced by intracerebroventricular (i.c.v.) administration of dopaminergic receptor antagonists. Moreover, the LMA but not myoclonia correlate with pressure induced striatal dopamine increase. Nevertheless the role of dopaminergic and NMDA receptor activities at striatal level in the development of LMA remained unclear. In this study, the microdialysis technique associated to a behavioural device was used to test the effects of intra-striatal administration of D1 antagonist SCH23390 (1 microM), D2 antagonist sulpiride (1 microM) and NMDA antagonist AP-5 (10 microM) on LMA, tremor and myoclonia expression. Data clearly showed that LMA was drastically reduced by each treatment. In contrast, tremor and myoclonia were poorly affected. These data suggest that both dopaminergic and NMDA receptor activities at striatal level are needed for the full expression of the pressure-induced LMA and confirm that striatal neurotransmission changes are principally involved in this behavioural disorders. At the light of recent studies on dopaminergic neurotransmission and glutamate evoked-NMDA activity, we suggest that blockage of D1 or D2 receptors should reduced the LMA by reducing glutamate-evoked activity.
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PMID:The full expression of locomotor and motor hyperactivities induced by pressure requires both striatal dopaminergic and N-methyl-D-aspartate receptor activities in the rat. 1038 Sep 98

Our previous report suggested that antagonists acting at NMDA receptors attenuate discriminative stimulus effects of naloxone in morphine dependent rats. Nitric oxide (NO) is a putative second messenger which mediates NMDA receptor activation. The present study evaluated behavioral effects of NO synthase inhibitor, 7-nitroindazole in morphine-dependent rats trained to discriminate 0.1 mg/kg naloxone from saline. 7-Nitroindazole did not significantly affect naloxone's discriminative stimulus effects but decreased naloxone-induced weight loss and abolished expression of several withdrawal signs--diarrhea, scream on touch, tremor and 'wet dog'-like shaking suggesting different mechanisms for subjective and somatic components of opioid withdrawal.
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PMID:Differential effects of nitric oxide synthase inhibitor, 7-nitroindazole, on discriminative stimulus and somatic effects of naloxone in morphine-dependent rats. 1045 28

Pregnant Sprague--Dawley rats were treated once daily with 40-mg/kg cocaine or saline from gestation days (GD) 12 to 21. A third group of pregnant dams was used as a pairfed control. Male and female offspring were examined for stress endurance response as determined by the cold-water swim test on postnatal days (PND) 21, 30, 40, and 60. Male and female offspring exposed to cocaine in utero were found to have diminished tolerance and altered hormonal response to stress. Moreover, prenatal cocaine exposure has been associated with significant increases in severity of N-methyl-D-aspartate (NMDA; 35 mg/kg) behavioral responses (tail twitches, wetdog shaking, and convulsion) as compared to control. Examining the experimental groups for pain sensitivity using the tail-flick and the hot-plate methods indicated that prenatal cocaine exposure altered pain sensitivity. NMDA receptor binding studies showed an increase in receptor density in the hippocampus and hypothalamus of the cocaine-treated group. These results indicate that gestational cocaine exposure is associated with long-term alterations in response to stress, NMDA receptor, and pain sensitivity in the rat offspring.
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PMID:Altered responsiveness to stress and NMDA following prenatal exposure to cocaine. 1123 96

The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg x kg(-1). In the second 3 days the initial dose was doubled (20 mg x kg(-1)) and in the last 3 days the dose of M was raised to 40 mg x kg(-1). On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg x kg(-1)M, 2 mg x kg(-1) 4-AP 105 min after 80 mg x kg(-1) M, and 80 mg x kg(-1) M 105 min before 2 mg x kg(-1) 4-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg x kg(-1) 4-AP 105 min prior to M administration, which was increased every 3 days (10 mg x kg(-1), 20 mg x kg(-1), 40 mg x kg(-1)). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg x kg(-1) 4-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg x kg(-1) M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg x kg(-1) 4-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg x kg(-1) NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named 'total number of others'. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.
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PMID:The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence. 1140 16

Reflex sympathetic dystrophy (RSD) is composed of five major features: pain, swelling, autonomic dysregulation, movement disorders, and atrophy and dystrophy. RSD is caused by an injury to a specific nerve or the C- and A-delta fibers that innervate the involved tissue. It is a progressive illness that spreads with time and may encompass the entire body. There is no psychological disposition to the problem, but all patients are severely depressed because of the constant pain, lack of sleep, and complete disruption of their lifestyle. The continuing pain is usually secondary to the process of central sensitization. The autonomic dysregulation has a major central nervous system component. Atrophy and dystrophy are partly due to loss of nutritive blood supply to the affected tissues. The movement disorder is partly due to deficiency of GABAergic mechanisms; the tremor is an exaggeration of the normal physiologic tremor. Treatment consists of decreasing the afferent pain, maintaining barrage from the underlying defect, and blocking the sympathetic component of the process. New developments include the use of neurotrophic factors to reverse the phenotypic changes that occur in the dorsal horn and the use of pharmacologic agents to block the activity-dependent NMDA channels that appear to be instrumental in maintaining central sensitization.
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PMID:Reflex sympathetic dystrophy. 1189 Aug 82

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and 80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.
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PMID:Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test. 1260 Jul 94


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