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)

The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that includes sustained axial twisting movements. The syndrome is correlated with increased glutamic acid decarboxylase activity in the deep cerebellar nuclei and increased cerebellar norepinephrine levels in comparison with phenotypically normal littermates. Biochemical, behavioral, and anatomical techniques were used to investigate the possibility that the abnormalities noted in the cerebellum of the dt rat were indicative of altered function of the major projection neurons of the cerebellar cortex, the Purkinje cells. Phenotypically normal rats showed tremor in response to harmaline, a drug that acts on the inferior olive to produce bursting in the climbing fiber pathway. Dystonic rats were insensitive to the effects of harmaline but did respond to oxotremorine. Levels of the cyclic nucleotide 3',5'-cyclic guanosine monophosphate, a biochemical marker for Purkinje cells, increased in response to harmaline in normal rats but were significantly lower in dystonic rats under both basal and harmaline-stimulated conditions. Purkinje cell soma size was reduced in the dystonic rats but no other morphological correlates of the behavioral or biochemical deficits were noted. Taken together with other observations on this mutant, the results suggest an impairment in the cerebellum or in its connections with lower brainstem and spinal cord sites.
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PMID:Decreased cerebellar 3',5'-cyclic guanosine monophosphate levels and insensitivity to harmaline in the genetically dystonic rat (dt). 299 3

A mutant strain of Wistar rats which carries an autosomal gene defect is characterized by a progressively developing hyperexcitability, tremor, olfactory and gustatory movements, bradykinesia, ataxia and a pathologically increased muscle tone of hindlimbs which can be measured by recording tonic activity in the electromyogram (EMG) of the gastrocnemius-soleus muscle. The activity of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the receptor binding of GABA as estimated by [3H]GABA binding to synaptic membranes were examined in olfactory bulbs, frontal cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, tectum, substantia nigra, medulla oblongata, cerebellum, and pons of mutant rats. Mutant rats exhibit a lower activity of GAD in synaptosomal fractions of olfactory bulbs and substantia nigra whereas GAD activity within the pons was increased. The changes in the activity of GAD were accompanied by alterations in [3H]GABA binding to synaptic membranes: GABA binding was significantly elevated in the olfactory bulbs and the substantia nigra, but it was markedly reduced in the pons. The functional importance of impaired nigral GABAergic transmission in mutant rats was demonstrated by the fact that intranigral injection of the GABA agonist muscimol reduced the tonic extension of the hindlimbs as indicated by reduced tonic EMG activity of the gastrocnemius-soleus muscle, while intranigral injection of the GABA antagonist bicuculline increased the disturbance.
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PMID:Disturbed GABAergic transmission in mutant Han-Wistar rats: further evidence for basal ganglia dysfunction. 299 53

Adult male rats were administered 75 mg/kg of the neurotoxin 3-acetylpyridine to produce lesions of the inferior olive-climbing fiber projection to the cerebellum. At selected times ranging from 6 h to 43 days postlesion, rats were evaluated for motor dysfunction, and glutamic acid decarboxylase (GAD) activity was determined in the deep cerebellar nuclei and cerebellar vermis. In the deep nuclei non-monotonic changes in GAD activity were found following climbing fiber destruction. Initially, there was a steady increase in GAD activity which peaked at 38% above control values 14 days postlesion. GAD activity then slowly declined, although it remained significantly above control levels at 43 days postlesion, the latest time point examined. In the vermis, GAD activity was significantly increased at 4 days postlesion (+8%) and remained at approximately this level throughout the experiment. The initial behavioral effects of climbing fiber loss included hypotonia and ataxia with severely reduced mobility. With time, the ataxia and hypotonia decreased and movements such as mud-walking and pivoting developed. As these behaviors diminished, other novel conditions such as movement-associated tremor and hopping appeared. These results are discussed in the context of the previously reported effects of climbing fiber lesions on the firing rates of Purkinje cells and deep nuclei cells.
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PMID:Temporal sequence of motor disturbances and increased cerebellar glutamic acid decarboxylase activity following 3-acetylpyridine lesions in adult rats. 369 Mar 21

In an attempt to elucidate the mechanism of wet dog shakes (WDS) produced by carbachol administered into the rat lateral brain ventricle, the effects of blockade of muscarinic and nicotinic receptors on shaking response and the effects of carbachol on central catecholaminergic, serotonergic (5-HT) and GABAergic functions were studied in rats. The muscarinic receptor antagonists, atropine and scopolamine attenuated WDS produced by carbachol, whilst a peripherally active muscarinic receptor antagonist, scopolamine methyl nitrate, failed to influence WDS. The nicotine antagonist, mecamylamine, did not affect WDS caused by carbachol either. Carbachol dose dependently decreased brain concentration of noradrenaline (NA) but failed to affect the concentration of dopamine (DA). While the brain concentration of 5-HT was unchanged, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) was increased in a dose-related manner. The catecholamine turnover times were unaffected whereas 5-HT turnover time was significantly prolonged. Atropine, but not mecamylamine, prevented the decrease in brain NA induced by carbachol. Consequently, the carbachol-induced enhancement in the level of 5-HIAA was completely blocked by atropine and only slightly influenced by mecamylamine. Neither brain GABA concentration nor glutamic acid decarboxylase activity were affected by carbachol. Behavioral and biochemical data suggest that WDS produced by carbachol may be mediated through the stimulation of central muscarinic receptors. The anatomical localization and exact mechanism of carbachol-induced WDS remain to be elucidated.
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PMID:Studies on the mechanism of wet dog shakes produced by carbachol in rats. 620 Aug 91

Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.
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PMID:Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. 893 92

This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.
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PMID:Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. 1152 46

Involuntary movements of the mouth can present as palatal tremor, which is frequently associated with hypertrophy of the inferior olivary nucleus and can be accompanied by contraction of other muscles of the head. We report the case of a 39-year-old man with autoimmune thyroiditis and diabetes who complained of involuntary rhythmic tremor involving the muscles of the floor of the mouth, which interfered with breathing and swallowing. Cerebrospinal fluid (CSF) examination showed the presence of oligoclonal bands and screening for anti-neuronal antibodies revealed high titres of anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). Tremor responded to treatment with benzodiazepines. The correlation between the tremor and antibody positivity is unclear although an alteration of the gabaergic system mediated by the antibodies may be hypothesised on the basis of an inflammatory CSF profile.
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PMID:Tremor of the mouth floor and anti-glutamic acid decarboxylase autoantibodies. 1294 Aug 31

A 58-year-old woman complaining of finger tremor was referred to our hospital. The diagnosis of Graves' disease was made based on increased free triiodothyronine (18.88 pg/ml) and free thyroxine (7.47 ng/dl), low TSH (<0.005 microIU/ml) and increased TSH receptor binding antibody activity (70.9%). Serum level of AST (62 U/l) and ALT (93 U/l) were increased and liver biopsy revealed linkage of adjacent portal areas by lymphoplasmacytic infiltrates and fibrosis with piecemeal necrosis. Although antinuclear antibody was negative, these findings indicated that she had autoimmune hepatitis (AIH) according to the criteria of the International Autoimmune Hepatitis Scoring System. Slowly progressive type 1 diabetes mellitus (DM) was confirmed by a diabetic response pattern due to 75 g-oral glucose tolerance test, and seropositivity towards anti-glutamic acid decarboxylase (725 U/ml) and islet cell (80 JDF Units) antibodies. This case exhibited an extremely rare combination of three different autoimmune diseases, including Graves' disease, slowly progressive type 1 DM and AIH, and had no known sensitive human leukocyte antigen (HLA) typing or haplotype for these disorders. Although it is common for patients with Graves' disease to exhibit abnormal liver function, it is important to make an accurate diagnosis of AIH because of this life-threatening disorder.
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PMID:A case of polyglandular autoimmune syndrome type III complicated with autoimmune hepatitis. 1694 65

Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious. Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.
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PMID:Gene therapy in Parkinson's disease: rationale and current status. 2015 94

Anoxia induced by exposure to N(2) gas for 15, 30, 50 and 60 s showed appearance of varying degrees of restlessness, tremor and convulsive behaviour resulting in mortality of adult rats. Diazepam treatment in pre- and post-anoxic conditions (10 and 20 mg/kg, respectively) has been found to decrease the anoxia-induced mortality rate along with suppression of other abnormal behaviours. In anoxic rats an increase in glutamate (Glu) level was noted. There was no change in the activity of glutamic acid decarboxylase (GAD), but GABA-aminotransferase (GABA-T) activity decreased significantly. In diazepam-treated (pre- and post-anoxic) rats there was an increase in the GAD activity with concomitant increase in ?-aminobutyric acid (GABA) level. GABA-T activity as well as Glu level became normalized. Results indicate that diazepam treatment may have some protecting ability from anoxia-induced imbalance in rat brain glutamatergic and GABAergic functions.
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PMID:Effect of pre- and post-treatments with diazepam on the rat brain GABAergic system during anoxic stress and recovery. 2050 83


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