Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.
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PMID:The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography. 228 39

Tetrahydroisoxazolopyridinol (THIP), a GABA receptor agonist, gamma-acetylenic-GABA(GAG) and gamma-vinyl-GABA(GVG), two GABA transaminase inhibitors were given in single parenteral doses to three Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol. High doses of THIP temporarily abolished dyskinesias but also caused bradykinesia, ataxia, dystonia and myoclonic jerks. GAG and GVG reduced dyskinesias to a lesser extent and with fewer side effects. Whether the observed antidyskinetic effect is secondary to the concomitant general toxic effects or if these drugs have a specific antidyskinetic action remains an open question.
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PMID:GABA agonists in cebus monkeys with neuroleptic-induced persistent dyskinesias. 289 37

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

In eight monkeys (Cercopithecus aethiops), previously treated with haloperidol for 4-14 months, we have examined the behavioral effect of: (1) methylphenidate vs apomorphine; (2) 4,5,6,7-tetrahydroisoxazolo-(5,4-c)-pyridin-3-ol(THIP, a GABA agonist) vs diazepam; and (3) THIP and diazepam in methylphenidate-induced behavior. Methylphenidate (0.5-5.0 mg/kg) and apomorphine (0.1-0.5 mg/kg) both increased locomotion, but otherwise exhibited different behavioral profiles. Methylphenidate induced repetitive movements of head, limbs, and trunk, and hallucinatory-like behavior, but not oral hyperkinesia (licking and gnawing), whereas apomorphine preferentially caused oral hyperkinesia. THIP produced a syndrome of bradykinesia, dystonia, ataxia, myoclonus, sedation, and decreased responsiveness, whereas diazepam produced only bradykinesia, ataxia, sedation, and decreased responsiveness, but not dystonia and myoclonus. Methylphenidate-induced locomotion and repetitive movements were reduced by THIP and diazepam, whereas hallucinatory-like behavior was markedly aggravated by THIP, but not by diazepam.
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PMID:Methylphenidate, apomorphine, THIP, and diazepam in monkeys: dopamine-GABA behavior related to psychoses and tardive dyskinesia. 642 Aug 23

Muscimol is a potent agonist at GABA-inhibitory synapses in mammalian brain. Given systemically at 7 mumol per kilogram, it blocks topical penicillin seizures and delays the onset of generalized metrazol convulsions in rats. It has no effect against generalized seizures caused by picrotoxin or strychnine. Higher doses of muscimol cause bradykinesia, ataxia, catatonic posturing, and slowing of the electroencephalogram. When applied topically to cortex, muscimol blocks focal penicillin, bicuculline, and picrotoxin discharges in a dose-response relationship. It has no effect against topical strychnine. Muscimol offers a potential new approach to the treatment of epilepsy.
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PMID:Anticonvulsant effects of muscimol. 718 34

We observed transient parkinsonism in 2 young epileptic patients with valproate (VPA) therapy. Complete recovery from extrapyramidal disorder occurred spontaneously in a few weeks. The lack of apparent susceptibility related to age and to VPA dosage, the rapid recovery from the extrapyramidal reaction, and the prevalence of negative signs such as bradykinesia and bradyphrenia can be considered the main clinical findings of this disease process. Pathophysiologic mechanisms of this rare "toxic" reaction remain unknown, although a transient imbalance between functionally reciprocal subgroups of GABA pathways leading to remediable dopamine inhibition might be hypothesized.
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PMID:Reversible valproate-induced extrapyramidal disorders. 815 62

Neurosurgical treatment of Parkinson's disease (PD) frequently employs chronic high-frequency deep brain stimulation (DBS) within the internal segment of globus pallidus (GPi) and can very effectively reduce L-dopa-induced dyskinesias and bradykinesia, but the mechanisms are unknown. The present study examined the effects of microstimulation in GPi on the activity of neurons close to the stimulation site. Recordings were made from GPi using two fixed or independently controlled microelectrodes, with the electrode tips usually approximately 250 or >600 micrometer apart in PD patients undergoing stereotactic exploration to localize the optimal site for placement of a lesion or DBS electrode. The spontaneous activity of nearly all of the cells (22/23) recorded in GPi in three patients was inhibited by microstimulation at currents typically <10 microA (0.15-ms pulses at 5 Hz). The inhibition had a duration of 10-25 ms at threshold. These findings suggest that microstimulation within GPi preferentially excites the axon terminals of striatal and/or external pallidal neurons causing release of GABA and inhibition of GPi neurons.
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PMID:Microstimulation-induced inhibition of neuronal firing in human globus pallidus. 1089 28

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

Ablative and chronic stimulation procedures targeting the internal pallidum (GPi) and the subthalamic nucleus (STN) have led to major advancements in the treatment of Parkinson's disease and other movement disorders. Although these procedures have evolved to primarily target the posterior ventrolateral sensorimotor portion of GPi and to less selectively target STN, centrally, the ideal targets within these structures remain to be fully established. In this study, we sought to identify the optimal targeting sites in GPi and STN for reversal of parkinsonian signs through a series of reversible injections of the GABA(A) agonist muscimol in these nuclei in parkinsonian primates. Akinesia and bradykinesia were strongly ameliorated by discrete inactivation within the centromedial extent of the sensorimotor territory in GPi and the lateral portion of the sensorimotor territory in STN. This suggests that akinesia and bradykinesia might, in fact, originate from abnormalities in the same, or at least overlapping, motor circuits in the parkinsonian state. Inactivation of areas outside of the motor territories did not improve parkinsonism but induced circling and behavioral abnormalities. The segregation of basal ganglia-thalamocortical circuits appears to be therefore maintained, at least to a large extent, in the parkinsonian state. These results underscore that inactivation of discrete regions in the central territory of GPi and the lateral portion of STN are sufficient to ameliorate parkinsonian motor signs and that extension of lesions into nonmotor territories may be deleterious. Surgical outcomes might therefore be optimized by placing more discrete lesions and by restricting the extent of chronic stimulation.
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PMID:Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. 1178 7

The levels of mRNA encoding the two isoforms of glutamic acid decarboxylase (GAD(65) and GAD(67)) were measured throughout the pallidal complex in normal and acutely (i.e., 1 month duration) and chronically (i.e., 5 years duration) parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated monkeys as well as in monkeys exposed to MPTP but asymptomatic for parkinsonism. GAD(65) mRNA labeling was modestly increased in the mid/caudal internal globus pallidus (GPi) but not in the external globus pallidus (GPe) in parkinsonian monkeys, compared with normal and asymptomatic monkeys. GAD(67) mRNA expression was highly increased in the mid/caudal GPi, and modestly increased in the GPe in parkinsonian monkeys compared with normal and asymptomatic animals. Infusion of GAD(67) antisense oligodeoxynucleotides bilaterally into the GPi resulted in a transient reversal of akinesia and bradykinesia that was not produced by infusion of missense oligodeoxynucleotides. These data emphasize the role of GAD enzyme (particularly GAD(67)) and GABA in the GPi for the expression of parkinsonian motor signs and suggest that selective manipulation of GABAergic neurotransmission in the GPi may have therapeutic potential for treating parkinsonism.
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PMID:Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site-directed antisense gene therapy. 1251 98


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