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The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt... more
The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt continued degeneration of nigral dopaminergic neurons. Considerable effort has been devoted to the search for neurotrophic factors with survival-promoting activities on dopaminergic neurons that could potentially be of therapeutic value in the treatment of PD. One such candidate is glial cell line-derived neurotrophic factor (GDNF).
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Research Interests: Neuroscience, Neurochemistry, Medicine, FMRI, Dopamine, and 6 moreAnatomy, Substantia nigra, Basal ganglia, Putamen, Neurochemical, and MPTP
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A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model... more
A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model by de novo treatment with levodopa, or selective D1 or D2 agonists, provided the drugs are short acting and administered in the pulsatile mode. Biochemical analysis of the brains revealed several alterations in dopamine receptor-binding and messenger RNA message following denervation and dopaminergic treatment, but none that clearly correlated with the presence of dyskinesias. On the other hand, gamma-aminobutyric acid (GABA)A binding was increased in the internal segment of the globus pallidus of dyskinetic MPTP monkeys. This was observed consistently and could be associated with an exaggerated response to GABAergic inhibitory inputs in this strategic structure. Increased preproenkephalin message was also found to correlate with dyskinesias and may be linked to changes in GABA receptors. Treatments that caused dyskinesias induced, in the striatum, chronic Fos proteins of the deltaFosB family which, when coupled with Jun-D, form AP-1 complexes that can affect several genes, including enkephalin and N-methyl-D-aspartate receptor. We suggest that levodopa-induced dyskinesias represent a form of pathological learning, which results from deficient gating of glutamatergic inputs to the striatum by dopamine.
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Research Interests: Neuroscience, Cognitive Science, Biology, Medicine, Gene expression, and 15 moreSignal Transduction, Dopamine, Neuropeptides, Glutamate receptors, GABA receptors, Animals, Dopamine Receptors, Levodopa, Basal ganglia, Stimulation, Neurosciences, Mono, Parkinsonism, parkinsonian disorders, and Haplorhini
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Research Interests: Endocrinology, Biology, Gene expression, In Situ Hybridization, Dopamine, and 15 moreInternal Medicine, HPLC, Female, Animals, Deoxyribonucleic Acid, Liquid Chromatography, cDNA, Macaca fascicularis, Biological activity, Long Term, Growth Factor, Agonist, binding sites, Cabergoline, and Medical and Health Sciences
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We investigated the effect of MPTP‐induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABAB receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The... more
We investigated the effect of MPTP‐induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABAB receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of 125I‐RTI‐121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABAB receptors in mice brain were evaluated using 3H‐CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABAB(1a+b), GABAB(1a), GABAB(1b), GABAB(2) subunits. In monkeys, 125I‐CGP64213 and selective probes for GABAB(1a+b) and GABAB(2) mRNAs were used. In mice, dopamine content, 125I‐RTI‐121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABAB receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of 3H‐CGP54626 binding (−10%) and of the expression of GABAB(1a+b) mRNA (−13%). The decrease of the expression of GABAB(1a+b) mRNA was correlated with dopamine content, 125I‐RTI‐121 binding and DAT expression. In MPTP‐treated monkeys, 125I‐CGP64213 binding (−40%), GABAB(1a+b) mRNA (−69%) and GABAB(2) mRNA (−66%) were also significantly decreased in the SNpc. Our results suggest that MPTP‐induced denervation is associated with a decrease of GABAB receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease. Synapse 40:225–234, 2001. © 2001 Wiley‐Liss, Inc.
Research Interests: Endocrinology, Cognitive Science, Chemistry, Medicine, Dopamine, and 15 moreInternal Medicine, Mice, Female, Animals, Cocaine, Male, Organophosphorus Compounds, Membrane transport proteins, Dopamine Transporter, Basal ganglia, Macaca fascicularis, Neurosciences, dopaminergic, Corpus striatum, and MPTP
Research Interests: Endocrinology, Chemistry, Medicine, Dopamine, Brain, and 15 moreInternal Medicine, Female, Animals, Organophosphorus Compounds, Clinical Sciences, Globus Pallidus, Basal ganglia, Autoradiography, Macaca fascicularis, Experimental Neurology, Neurosciences, Agonist, Corpus striatum, binding sites, and MPTP
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Research Interests: Endocrinology, Neurochemistry, Medicine, Dopamine, Internal Medicine, and 15 moreFemale, Animals, Dyskinesia, Denervation, Globus Pallidus, Basal ganglia, Autoradiography, Macaca fascicularis, Neurosciences, Flunitrazepam, Ovariectomy, GABAA receptor, Cabergoline, MPTP, and Medical biochemistry and metabolomics
Considerable effort has been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and potentially be of therapeutic value in the treatment of Parkinson’s disease. One such candidate is... more
Considerable effort has been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and potentially be of therapeutic value in the treatment of Parkinson’s disease. One such candidate is glial cell line-derived neurotrophic factor (GDNF). GNDF is distantly related to the transforming growth factor-β superfamily and is widely expressed in many neuronal and non-neuronal
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UK PubMed Central is a service of the UKPMC Funders Group working in partnership with the British Library, University of Manchester and the European Bioinformatics Institute in cooperation with the National Center for Biotechnology... more
UK PubMed Central is a service of the UKPMC Funders Group working in partnership with the British Library, University of Manchester and the European Bioinformatics Institute in cooperation with the National Center for Biotechnology Information at the US National ...
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Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis... more
Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized "hot spots" in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA.
Research Interests: Neuroscience, Cognitive Science, Immunohistochemistry, Medicine, Dopamine, and 15 moreCerebellum, Female, Animals, Male, Amphetamine, High Pressure Liquid Chromatography, Children and Adolescents, Microdialysis, Hot Spot, Analysis of Variance, Dopamine Transporter, Macaca Mulatta, Brain Chemistry, Attention deficit disorder with hyperactivity, and Attention deficit hyperactivity disorder
Research Interests: Magnetic Resonance Imaging, Biology, Medicine, Brain, Humans, and 15 moreCollagen, Female, Animals, Eating, Huntingtin, Analysis of Variance, Glial Fibrillary Acidic Protein, Body Weight, Macaca Mulatta, Huntington disease, Gene Expression Regulation, Motor activity, Psychomotor Performance, Psychology and Cognitive Sciences, and Medical and Health Sciences
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To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson's disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative... more
To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson's disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed. We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300μg, suggestive of a stimulative effect of the dopaminergic system. Additionally, a protective effect was observed following repeated intranasal administration in 6-OHDA lesioned rats, as suggested by: a significant decrease in d-amphetamine-induced rotation at 2 weeks; a decrea...
Research Interests: Cognitive Science, Neurochemistry, Medicine, Neuroprotection, Dopamine, and 15 moreAnimals, Male, HT, Analysis of Variance, Autoradiography, GDNF, Intranasal Administration, Neurosciences, Parkinson Disease, Dextroamphetamine, Gfr, Functional Laterality, dopaminergic, Corpus striatum, and Neuroscience Methods
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Background: Chronic treatment with l-3,4-dihydroxyphenylalanine (l-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including... more
Background: Chronic treatment with l-3,4-dihydroxyphenylalanine (l-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so far, the A2A subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors might be used in PD.Objective: To evaluate the antiparkinsonian effect of a new selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.Methods: In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting l-dopa–induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) o...
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Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6‐hydroxydopamine (6‐OHDA) lesions of the medial... more
Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6‐hydroxydopamine (6‐OHDA) lesions of the medial forebrain bundle produces a prolonged (>3 months) elevation of Fos‐like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Foslike immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6‐OHDA‐lesioned rats to determine the nature of Fos‐immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6‐OHDA lesion, expression of two Fos‐related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated ex...
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BACKGROUND Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases. NEW METHOD We used a series of techniques, to in effect,... more
BACKGROUND Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases. NEW METHOD We used a series of techniques, to in effect, maintain positive pressure inside the catheter relative to the outside, that included a hollow stylet, a high volume bolus of solution to clear the line, a low andslow continuous flow rate during implantation, and heat sealing the catheter at the time of implantation. RESULTS 120 catheters implanted into brain parenchyma of 89 adult female rhesus monkeys across four sets of experiments. After experiencing a high delivery failure rate - non patent catheters - (19%) because of tissue entrapment and debris and/or blood clots in the catheter tip, we developed modifications, including increasing the bolus infusion volume from 10 to 20 µl such that by the third experiment, the failure rate was 8% (1 of 12 implants). Increasing the bolus volume to 100 µl and maintaining positive pressure in the catheter during preparation and implantation yielded a failure rate of 0% (0/12 implants) by the fourth experiment. COMPARISON WITH EXISTING METHODS We provide a retrospective analysis to reveal how several different manipulations affect catheter patency and how post-op MRI examination is essential for assessing catheter patency in situ. CONCLUSIONS The results of the present study identified that the main cause of the catheter blockages were clots that rendered the catheter non-patent. We resolved this by modifying the surgical procedures that prevented these clots from forming.
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Research Interests:
Involuntary movements, or dyskinesias, represent a debilitating complication of levodopa therapy for Parkinson's disease. Dyskinesia is, ultimately, experienced by the vast majority of the patients. Despite the importance of this... more
Involuntary movements, or dyskinesias, represent a debilitating complication of levodopa therapy for Parkinson's disease. Dyskinesia is, ultimately, experienced by the vast majority of the patients. Despite the importance of this problem, little was known about the cause of dyskinesia, a situation that has dramatically evolved in the last few years. The present review presents: 1) the current understanding of dyskinesia pathophysiology and 2) the therapeutic modalities, mainly non-dopaminergic, available or in development. We here show that the questions raised by the dyskinesia may have a clinically-driven pharmacological answer: the symptomatic treatment of dyskinesia, the prevention of the priming and the de-priming of the neural networks.
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BACKGROUND Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases. NEW METHOD We used a series of techniques, to in effect,... more
BACKGROUND Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases. NEW METHOD We used a series of techniques, to in effect, maintain positive pressure inside the catheter relative to the outside, that included a hollow stylet, a high volume bolus of solution to clear the line, a low andslow continuous flow rate during implantation, and heat sealing the catheter at the time of implantation. RESULTS 120 catheters implanted into brain parenchyma of 89 adult female rhesus monkeys across four sets of experiments. After experiencing a high delivery failure rate - non patent catheters - (19%) because of tissue entrapment and debris and/or blood clots in the catheter tip, we developed modifications, including increasing the bolus infusion volume from 10 to 20 µl such that by the third experiment, the failure rate was 8% (1 of 12 implants). Increasing the bolus volume to 100 µl and maintaining positive pressure in the catheter during preparation and implantation yielded a failure rate of 0% (0/12 implants) by the fourth experiment. COMPARISON WITH EXISTING METHODS We provide a retrospective analysis to reveal how several different manipulations affect catheter patency and how post-op MRI examination is essential for assessing catheter patency in situ. CONCLUSIONS The results of the present study identified that the main cause of the catheter blockages were clots that rendered the catheter non-patent. We resolved this by modifying the surgical procedures that prevented these clots from forming.
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ABSTRACT Trophic factors are proteins with enormous therapeutic potential in the treatment of neurodegenerative diseases like Parkinson's disease (PD), including the potential to (1) slow the degeneration of nigral dopaminergic... more
ABSTRACT Trophic factors are proteins with enormous therapeutic potential in the treatment of neurodegenerative diseases like Parkinson's disease (PD), including the potential to (1) slow the degeneration of nigral dopaminergic neurons, (2) enhance the function of residual dopamine neurons or (3) restore function to injured neurons. Novel methods for sustained delivery of glial cell line-derived neurotrophic factor (GDNF) into the nigrostriatal pathway have been studied in non-human primates, including the use of computer-controlled infusion pumps. Using this approach, we have demonstrated that chronic, intracerebral infusions of GDNF promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in rhesus monkeys with neural deficits modeling PD. However, translational studies from the laboratory to the clinic for the treatment of PD have been problematic. On one hand, GDNF was not efficacious when delivered intraventricularly in PD patients, likely failing because of poor drug penetration through the ventricular wall into the parenchyma of the basal ganglia. On the other hand, two independent open label Phase-1 studies have reported marked functional improvements in advanced PD patients receiving chronic intraputamenal infusion of GDNF, whereas a separate, randomized, blinded multicenter trial of intraputmenal GDNF infusion did not achieve the primary study endpoint. In addition, safety concerns have arisen including the presence of neutralizing antibodies to GDNF in some patients. The major difficulty with risk assessment at this time is the failure to have a Phase-2 trial replicating the successful Phase-1 trials in dose and methods of trophic factor delivery. Thus, before any definitive conclusions could be made regarding the use of GDNF as a therapy for PD, a properly designed, adequately powered multicenter Phase-2 clinical trial should be conducted in PD patients.
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Research Interests: Medicine and Huntingtin
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Research Interests: Psychology, Artificial Intelligence, Photography, Aging, Locomotion, and 15 moreMedicine, Movement disorders, Object Tracking, Female, Animals, Clinical Sciences, Infrared, Rhesus Monkey, Motor Function, Rhesus macaques, Locomotor Activity, Macaca Mulatta, Neurobiology of Aging, Task Performance and Analysis, and Neurosciences
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Research Interests:
Research Interests:
Parkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two trophic factors with demonstrated... more
Parkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. However, GDNF and neurturin Phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls. Insufficient drug distribution in the brain parenchyma has been proposed as a major contributing factor for the lack of clinical efficacy in the Phase-2 trial patients. To address this issue, a novel mammalian cell-derived variant form of GDNF (GDNFv) was designed to promote better tissue distribution by reducing its heparin binding to the extracellular matrix and key amino acids were substituted to enhance its chemical stability. Administration of this fully glycosylated GDNFv in the normal rat striatum increased dopamine tu...
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OBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like... more
OBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like Parkinson's disease. Whether chronic intranigral delivery of an infusate could be achieved without causing motor dysfunction or marked pathology remains unclear. The authors evaluated the tolerability of continuously delivering an infusate directly into the rhesus monkey substantia nigra via a programmable pump coupled to a novel intraparenchymal needle-tip catheter surgically implanted using MRI-guided techniques. METHODS The MRI contrast agent gadopentetate dimeglumine (Magnevist, 5 mM) was used to noninvasively evaluate catheter patency and infusion volume associated with 2 flow rates sequentially tested in each of 3 animals: 0.1 µl/min for 14 days into the right substantia nigra and 0.1 µl/min for 7 days plus 0.2 µl/min for an additional 7 days into th...
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We assessed the antiparkinsonian response in MPTP-treated monkeys after acute or repeated treatment with oral L-Dopa, subcutaneous administration of L-Dopa methyl ester (LDME) or apomorphine, alone and in combination with D1 antagonists... more
We assessed the antiparkinsonian response in MPTP-treated monkeys after acute or repeated treatment with oral L-Dopa, subcutaneous administration of L-Dopa methyl ester (LDME) or apomorphine, alone and in combination with D1 antagonists SCH 23390 (SCH) or NNC 01-0112 (NNC). When given alone, the L-Dopa effect occurred within the first hour after treatment. Coadministration of SCH or NNC with L-Dopa significantly delayed the onset of action. The response duration remained unchanged, as did the extent of the antiparkinsonian effect, after SCH, whereas the former became shorter at the higher doses of NNC tested. Bypass of the gastrointestinal tract using parenteral injections of LDME and apomorphine allowed the rapid turning "on" of the animals. Both D1 antagonists administered with LDME delayed the onset and shortened the duration of the therapeutic effect as the dose increased. Pretreatment with SCH failed to block the antiparkinsonian effect induced by apomorphine, but reduced the response duration markedly in a dose-related fashion. Repeated treatment of one monkey with SCH combined with the same dopaminergic drugs produced results similar to those obtained after acute treatment in four animals. The results obtained with parenteral administration of LDME and apomorphine most probably involve pharmacodynamic actions resulting in increased threshold of response. The delay observed with L-Dopa suggests pharmacokinetic interference possibly mediated via dopamine receptors located at the level of the gut.
Research Interests: Behavior, Drug interactions, Medicine, Applied Animal Behavior, Female, and 14 moreAnimals, dopamine receptor D4, Levodopa, Digestive System, Time Factors, Combination drug therapy, Macaca fascicularis, Biological activity, Long Term, Neurosciences, Mono, Apomorphine, Dopamine antagonists, and Pharmacology and pharmaceutical sciences
UK PubMed Central is a service of the UKPMC Funders Group working in partnership with the British Library, University of Manchester and the European Bioinformatics Institute in cooperation with the National Center for Biotechnology... more
UK PubMed Central is a service of the UKPMC Funders Group working in partnership with the British Library, University of Manchester and the European Bioinformatics Institute in cooperation with the National Center for Biotechnology Information at the US National ...
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Parkinson&am... more
Parkinson's disease is characterized by a progressive degeneration of the substantia nigra pars compacta dopamine neurons that innervate the striatum. Unlike current treatments for PD, GDNF administration could potentially slow or halt the continued degeneration of nigral dopaminergic neurons. GDNF does not cross the blood-brain barrier and needs to be administered directly into the brain. Due to the progressive nature of PD, sustained delivery of trophic factors may be necessary for optimal, long-term neuronal effects. Novel methods for sustained delivery of GDNF into the nigrostriatal pathway are currently being studied in non-human primates, including computer-controlled infusion pumps. Using this approach, we have demonstrated that chronic infusions of nominally 7.5 or 22.5 microg/day GDNF into the lateral ventricle, the putamen or the substantia nigra, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in MPTP-lesioned rhesus monkeys with neural deficits modeling the terminal stages of PD and in aged rhesus monkeys modeling the early stages of PD. Based on the promising studies of the chronic effects of GDNF in non-human primate models of PD, a study was recently conducted in England on five advanced PD patients. Chronic GDNF infusion into the dorsal putamen, via programmable pumps, resulted in improved motor function in all patients and limited side effects were observed. However, while the data from this intraparenchymal clinical trial in humans look encouraging, extensive blinded efficacy trials will need to be conducted before it can be determined if chronic treatment with GDNF or other trophic molecules will prove useful in treating patients with PD.
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One possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied... more
One possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied the suppression of huntingtin mRNA achievable with short infusion times, and investigated how long suppression may persist after infusion ceases. Rhesus monkeys received 3 days of infusion of Magnevist into the putamen to confirm catheter patency and fluid distribution. After a 1-week washout period, monkeys received radiolabeled siRNA targeting huntingtin. After 1 or 3 days of siRNA delivery, monkeys were either terminated, or their pumps were shut off and they were terminated 10 or 24 days later. Results indicate that the onset of huntingtin mRNA suppression in the rhesus putamen occurs rapidly, achieving a plateau throughout the putamen within 4 days. Conversely, loss of huntingtin suppression progresses slowly, persisting an estimated 27-39 days ...
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Parkinson's disease is characterized by a progressive degeneration of the substantia nigra pars compacta dopamine neurons that innervate the striatum. Unlike current treatments for PD, GDNF administration could potentially slow or... more
Parkinson's disease is characterized by a progressive degeneration of the substantia nigra pars compacta dopamine neurons that innervate the striatum. Unlike current treatments for PD, GDNF administration could potentially slow or halt the continued degeneration of nigral dopaminergic neurons. GDNF does not cross the blood-brain barrier and needs to be administered directly into the brain. Due to the progressive nature of PD, sustained delivery of trophic factors may be necessary for optimal, long-term neuronal effects. Novel methods for sustained delivery of GDNF into the nigrostriatal pathway are currently being studied in non-human primates, including computer-controlled infusion pumps. Using this approach, we have demonstrated that chronic infusions of nominally 7.5 or 22.5 microg/day GDNF into the lateral ventricle, the putamen or the substantia nigra, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor fu...
Research Interests:
Research Interests:
A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model... more
A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model by de novo treatment with levodopa, or selective D1 or D2 agonists, provided the drugs are short acting and administered in the pulsatile mode. Biochemical analysis of the brains revealed several alterations in dopamine receptor-binding and messenger RNA message following denervation and dopaminergic treatment, but none that clearly correlated with the presence of dyskinesias. On the other hand, gamma-aminobutyric acid (GABA)A binding was increased in the internal segment of the globus pallidus of dyskinetic MPTP monkeys. This was observed consistently and could be associated with an exaggerated response to GABAergic inhibitory inputs in this strategic structure. Increased preproenkephalin message was also found to correlate with dyskinesias and may ...
Research Interests:
Changes in the functional dynamics of dopamine release and regulation in the basal ganglia have been posited to contribute to age-related slowing of motor functions. Here, we report the effects of glial cell line-derived neurotrophic... more
Changes in the functional dynamics of dopamine release and regulation in the basal ganglia have been posited to contribute to age-related slowing of motor functions. Here, we report the effects of glial cell line-derived neurotrophic factor (GDNF) on the stimulus-evoked release of dopamine and motor speed in aged monkeys (21-27 years of age; n = 10). Although no changes were observed in the vehicle controls (n = 5), chronic infusions of 7.5 microg of GDNF per day for 2 months into the right lateral ventricle initially increased hand movement speed up to 40% on an automated hand-reach task. These effects were maintained for at least 2 months after replacing GDNF with vehicle, and increased up to another 10% after the reinstatement of GDNF treatment for 1 month. In addition, upper-limb motor performance times of the aged GDNF-treated animals (n = 5) recorded at the end of the study were similar to those of five young adult monkeys (8-12 years of age). The stimulus-evoked release of do...
Research Interests:
The prevalence of both parkinsonian signs and... more
The prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, and aged animals (>20 years old) with declines in motor function. All animals underwent the same behavioral and pharmacologic magnetic resonance imaging (phMRI) procedures to measure changes in basal ganglia function in response to dopaminergic drug challenges consisting of apomorphine administration followed by either a D1 (SCH23390) or a D2 (raclopride) receptor antagonist. Significant functional changes were predominantly seen in the external segment of the globus pallidus (GPe) in aged animals and in the striatum (caudate nucleus and putamen) in MPTP-lesioned animals. Despite significant differences seen in the putamen and GPe between MPTP-lesioned versus aged animals, a similar response profile to dopaminergic stimulations was found between these 2 groups in the internal segment of the GP. In contrast, the pharmacologic responses seen in the control animals were much milder compared with the other 2 groups in all the examined areas. Our phMRI findings in MPTP-lesioned parkinsonian and aged animals suggest that changes in basal ganglia function in the elderly may differ from those seen in parkinsonian patients and that phMRI could be used to distinguish PD from other age-associated functional alterations in the brain.
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Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6-8 years... more
Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6-8 years old) and 6 aged (20-25 years old) female Rhesus monkeys (Macaca mulatta) were behaviorally characterized from standardized video records. Additionally, we measured mitochondrial bioenergetics along with calcium buffering capacity in the substantia nigra and putamen (PUT) from both age groups. Our results demonstrate that the aged animals had significantly reduced locomotor activity and movement speed compared with younger animals. Moreover, aged monkeys had significantly reduced ATP synthesis capacity (in substantia nigra and PUT), reduced pyruvate dehydrogenase activity (in PUT), and reduced calcium buffering capacity (in PUT) compared with younger animals. Furthermore, this age-related decline in mitochondrial function in the basal ganglia correlate...
Research Interests: Aging, Biology, Mitochondria, Medicine, Energy Metabolism, and 15 moreNeurodegenerative Diseases, Movement, Female, Animals, Respiration, Clinical Sciences, Motor speech disorders, Basal ganglia, Macaca Mulatta, Mitochondrial Permeability Transition Pore, Neurobiology of Aging, Neurosciences, Adenosine Triphosphate, Motor activity, and motor disorders
The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt... more
The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt continued degeneration of nigral dopaminergic neurons. Considerable effort has been devoted to the search for neurotrophic factors with survival-promoting activities on dopaminergic neurons that could potentially be of therapeutic value in the treatment of PD. One such candidate is glial cell line-derived neurotrophic factor (GDNF).
Research Interests:
Research Interests: Neuroscience, Aging, Mitochondria, Gene expression, Metabolic syndrome, and 15 moreSignal Transduction, Insulin Resistance, Hippocampus, Insulin, Female, Animals, The, Dentate Gyrus, Rhesus Monkey, Macaca Mulatta, Species Specificity, Glucocorticoid Receptors, Metabolic Syndrome X, Psychology and Cognitive Sciences, and Medical and Health Sciences
We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization.... more
We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.
Research Interests: Cognitive Science, Chemistry, Medicine, Subthalamic Nucleus, Dopamine, and 15 moreMice, Female, Animals, Cocaine, Male, Substantia nigra, Organophosphorus Compounds, Membrane transport proteins, Dopamine Transporter, Radioligand Assay, Basal ganglia, Macaca fascicularis, Neurosciences, Corpus striatum, and parkinsonian disorders
The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was... more
The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.