Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemically administered 3-nitropropionic acid (3-NPA) that inhibits the mitochondrial oxidative phosphorylation induces selective lesions in the striatum. To investigate the nature of these selective lesions, we administered 3-NPA (20 mg/kg, s.c. daily for 2 or 3 days) to Wistar rats and investigated the behavioral disturbance, striatal lesions and their variations after modulating the activity of nitric oxide synthase (NOS). On the second or third day of 3-NPA administration, half the animals manifested behavioral disturbances (paddling, rolling, tremor, abnormal gait, and recumbence). A strong extravasation of immunoglobulin G (IgG) and a decrease in immunoreaction for glial fibrillary acidic protein (GFAP) were detected, and iNOS-like (iNOS-L) immunoreactive small cells appeared in the lateral and central striatum especially around the vessels. A week later, lesions lacking GFAP-immunoreaction were detected in the striatum in survived animals. Pretreatment with N-nitro-L-arginine methyl ester (L-NAME) along with each injection of 3-NPA did not improve the behavioral disturbances nor the survival rate, but attenuated the extravasation of IgG and iNOS-L immunoreaction. Pretreatment with aminoguanidine or FK506 improved the behavioral symptoms and survival rate. Extravasation of IgG and expression of iNOS-L immunoreactivity were attenuated, and the striatal lesion was reduced. Data indicate the involvement of NO in the high vulnerability of the striatum, and that iNOS, one of inflammatory markers, is induced following exposure to 3-NPA.
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PMID:3-Nitropropionic acid produces striatum selective lesions accompanied by iNOS expression. 881 25

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

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
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PMID:Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset. 918 19

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.
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PMID:Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. 1583 70

Icilin is a cold channel agonist that produces vigorous wet-dog shaking in rats. The shaking is accompanied by an increase in the level of extracellular glutamate in the brain. Hence, we hypothesized that icilin-induced wet-dog shakes are dependent on increased glutamatergic transmission and nitric oxide (NO) production. Rats injected with icilin (0.5, 1, 2.5, 5 mg/kg, i.p.) displayed a dose-related increase in wet-dog shakes. Pretreatment with LY 235959 (1, 2 mg/kg, i.p.), a NMDA receptor antagonist, or L-NAME (50 mg/kg, i.p.), a NO synthase (NOS) inhibitor, attenuated icilin-induced wet-dog shakes. The shaking was also reduced by intracerebroventricular L-NAME (1 mg/rat, i.c.v.) administration, indicating that the stimulant effect of icilin is dependent on central NO production. Pretreatment with 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) (10, 20 mg/kg, i.p.), an AMPA receptor antagonist, or ceftriaxone (200 mg/kg, i.p. for 5 days), a beta-lactam antibiotic and glutamate transporter subtype 1 (GLT-1) activator, did not alter the incidence of icilin-induced shaking. The present data reveal that icilin produces behavioral stimulation by a mechanism requiring NMDA receptor activation and nitric oxide production and suggest that glutamate and NO signaling play important roles in cold channel pharmacology.
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PMID:Icilin-induced wet-dog shakes in rats are dependent on NMDA receptor activation and nitric oxide production. 1924