Enhancement of the response to levodopa therapy after intrastriatal transplantation of autologous sympathetic neurons in patients with Parkinson disease

2001 ◽  
Vol 95 (2) ◽  
pp. 275-284 ◽  
Author(s):  
Naoyuki Nakao ◽  
Koji Kakishita ◽  
Yuji Uematsu ◽  
Tatsuya Yoshimasu ◽  
Toshiya Bessho ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Sympathetic Ganglion ◽  
Ethical Issues ◽  
Sympathetic Neurons ◽  
Performance Status ◽  
Sympathetic Neuron ◽  
Content Type ◽  
Intracerebral Transplantation ◽  
Fine Print

Object. There is growing evidence to indicate that tissue transplantation can potentially be a restorative neurosurgical treatment for patients with Parkinson disease (PD). In this study the authors investigated the clinical effect of unilateral intrastriatal grafting of autologous sympathetic neurons in patients with PD. Methods. Four patients with PD who had been observed for 1 year after graft placement of autologous sympathetic neurons were selected for an analysis of the effect of that procedure. Sympathetic ganglion tissue was endoscopically excised from the thoracic sympathetic trunk and grafted into the unilateral caudate head and putamen of the PD patients. No changes were made in the patients' preoperative regimens of antiparkinsonian medications, and clinical evaluations were made principally according to those established by the Core Assessment Program for Intracerebral Transplantation Committee. Whereas the sympathetic neuron grafts failed to affect clinical scores reflecting the patients' motor performance, which was evaluated during either the “on” or “off” phases, the grafts significantly increased the duration of the levodopa-induced on period with consequent reduction in the percentage of time spent in the off phase. This beneficial effect may be explained by the results of the present in vitro experiment, which show that human sympathetic neurons have the ability to convert exogenous levodopa to dopamine and to store this synthesized dopamine. Conclusions. Sympathetic neuron autografts were found to improve performance status in patients with PD by reducing the time spent in the off phase. This clearly indicates that sympathetic ganglion tissue, the use of which involves few ethical issues, can be an efficacious donor source in cell transplantation therapy for PD. Further studies are needed to determine whether the grafts may provide long-lasting clinical benefits.

Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study

2002 ◽  
Vol 96 (3) ◽  
pp. 589-596 ◽  
Author(s):  
Ivar Mendez ◽  
Alain Dagher ◽  
Murray Hong ◽  
Paula Gaudet ◽  
Swarna Weerasinghe ◽  
...  
Keyword(s):  
Pilot Study ◽  
Parkinson Disease ◽  
Rating Scale ◽  
Perioperative Complications ◽  
Clinical Results ◽  
Neural Transplantation ◽  
Content Type ◽  
Intracerebral Transplantation ◽  
Positron Emission ◽  
Fine Print

✓ The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson′s Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

The mechanism and effect of chronic electrical stimulation of the globus pallidus for treatment of Parkinson disease

2004 ◽  
Vol 100 (6) ◽  
pp. 997-1001 ◽  
Author(s):  
Mitsuhiro Ogura ◽  
Naoyuki Nakao ◽  
Ekini Nakai ◽  
Yuji Uematsu ◽  
Toru Itakura
Keyword(s):  
Electrical Stimulation ◽  
Parkinson Disease ◽  
Globus Pallidus ◽  
Rating Scale ◽  
Underlying Mechanism ◽  
Clinical Effects ◽  
Content Type ◽  
Chronic Electrical Stimulation ◽  
Fine Print ◽  
Stimulation Of

Object. Although chronic electrical stimulation of the globus pallidus (GP) has been shown to ameliorate motor disabilities in Parkinson disease (PD), the underlying mechanism remains to be clarified. In this study the authors explored the mechanism for the effects of deep brain stimulation of the GP by investigating the changes in neurotransmitter levels in the cerebrospinal fluid (CSF) during the stimulation. Methods. Thirty patients received chronic electrical stimulation of the GP internus (GPi). Clinical effects were assessed using the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr Staging Scale at 1 week before surgery and at 6 and 12 months after surgery. One day after surgery, CSF samples were collected through a ventricular tube before and 1 hour after GPi stimulation. The concentration of neurotransmitters such as γ-aminobutyric acid (GABA), noradrenaline, dopamine, and homovanillic acid (HVA) in the CSF was measured using high-performance liquid chromatography. The treatment was effective for tremors, rigidity, and drug-induced dyskinesia. The concentration of GABA in the CSF increased significantly during stimulation, although there were no significant changes in the level of noradrenaline, dopamine, and HVA. A comparison between an increased rate of GABA concentration and a lower UPDRS score 6 months postimplantation revealed that the increase in the GABA level correlated with the stimulation-induced clinical effects. Conclusions. Stimulation of the GPi substantially benefits patients with PD. The underlying mechanism of the treatment may involve activation of GABAergic afferents in the GP.

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

2005 ◽  
Vol 102 (6) ◽  
pp. 1101-1107 ◽  
Author(s):  
Hartmut Vatter ◽  
Michael Zimmermann ◽  
Veronika Tesanovic ◽  
Andreas Raabe ◽  
Lothar Schilling ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Isometric Force ◽  
Inhibitory Effect ◽  
Affinity Constant ◽  
Dependent Manner ◽  
Content Type ◽  
The Right ◽  
Fine Print

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature. Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−). Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

Bilateral stimulation of the subthalamic nucleus in patients with Parkinson disease: a study of efficacy and safety

2002 ◽  
Vol 96 (4) ◽  
pp. 666-672 ◽  
Author(s):  
Tanya Simuni ◽  
Jurg L. Jaggi ◽  
Heather Mulholland ◽  
Howard I. Hurtig ◽  
Amy Colcher ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Parkinson Disease ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Bilateral Stimulation ◽  
Content Type ◽  
Preoperative Status ◽  
Fine Print ◽  
Deep Brain ◽  
Stimulation Of

Object. Palliative neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson disease (PD) that is complicated by severe motor fluctuations. Despite great enthusiasm for long-term deep brain stimulation (DBS) of the subthalamic nucleus (STN), existing reports on this treatment are limited. The present study was designed to investigate the safety and efficacy of bilateral stimulation of the STN for the treatment of PD. Methods. In 12 patients with severe PD, electrodes were stereotactically implanted into the STN with the assistance of electrophysiological conformation of the target location. All patients were evaluated preoperatively during both medication-off and -on conditions, as well as postoperatively at 3, 6, and 12 months during medication-on and -off states and stimulation-on and -off conditions. Tests included assessments based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests. The stimulation effect was significant in patients who were in the medication-off state, resulting in a 47% improvement in the UPDRS Part III (Motor Examination) score at 12 months, compared with preoperative status. The benefit was stable for the duration of the follow-up period. Stimulation produced no additional benefit during the medication-on state, however, when compared with patient preoperative status. Significant improvements were made in reducing dyskinesias, fluctuations, and duration of off periods. Conclusions. This study demonstrates that DBS of the STN is an effective treatment for patients with advanced, medication-refractory PD. Deep brain stimulation of the STN produced robust improvements in motor performance in these severely disabled patients while they were in the medication-off state. Serious adverse events were common in this cohort; however, only two patients suffered permanent sequelae.

Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo

1994 ◽  
Vol 80 (3) ◽  
pp. 527-534 ◽  
Author(s):  
Yasuhiro Matsuda ◽  
Keiichi Kawamoto ◽  
Katsuzo Kiya ◽  
Kaoru Kurisu ◽  
Kazuhiko Sugiyama ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Tumor Volume ◽  
Collagen Gel ◽  
Antitumor Effects ◽  
Histological Changes ◽  
Content Type ◽  
The Relationship ◽  
Fine Print

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

Neoplastic and pharmacological influence on the permeability of an in vitro blood-brain barrier

1995 ◽  
Vol 82 (6) ◽  
pp. 1053-1058 ◽  
Author(s):  
Paul A. Grabb ◽  
Mark R. Gilbert
Keyword(s):  
Endothelial Cell ◽  
Rat Brain ◽  
Phospholipase A ◽  
Cell Permeability ◽  
Capillary Endothelium ◽  
Brain Capillary ◽  
Content Type ◽  
Endothelial Cell Permeability ◽  
Fine Print

✓ The authors investigated the effects of glioma cells and pharmacological agents on the permeability of an in vitro blood-brain barrier (BBB) to determine the following: 1) whether malignant glia increase endothelial cell permeability; 2) how glucocorticoids affect endothelial cell permeability in the presence and absence of malignant glia; and 3) whether inhibiting phospholipase A2, the enzyme that releases arachidonic acid from membrane phospholipids, would reduce any malignant glioma—induced increase in endothelial cell permeability. Primary cultures of rat brain capillary endothelium were grown on porous membranes; below the membrane, C6, 9L rat glioma, T98G human glioblastoma, or no cells (control) were cocultured. Dexamethasone (0.1 µM), bromophenacyl bromide (1.0 µM), a phospholipase A2 inhibitor, or nothing was added to culture media 72 hours prior to assaying the rat brain capillary endothelium permeability. Permeability was measured as the flux of radiolabeled sucrose across the rat brain capillary endothelium monolayer and then calculated as an effective permeability coefficient (Pe). When neither dexamethasone nor bromophenacyl bromide was present, C6 cells reduced the Pe significantly (p < 0.05), whereas 9L and T98G cells increased Pe significantly (p < 0.05) relative to rat brain capillary endothelium only (control). Dexamethasone reduced Pe significantly for all cell preparations (p < 0.05). The 9L and T98G cell preparations coincubated with dexamethasone had the lowest Pe of all cell preparations. The Pe was not affected in any cell preparation by coincubation with bromophenacyl bromide (p > 0.45). These in vitro BBB experiments showed that: 1) malignant glia, such as 9L and T98G cells, increase Pe whereas C6 cells probably provide an astrocytic influence by reducing Pe; 2) dexamethasone provided significant BBB “tightening” effects both in the presence and absence of glioma cells; 3) the in vivo BBB is actively made more permeable by malignant glia and not simply because of a lack of astrocytic induction; 4) tumor or endothelial phospholipase A2 activity is probably not responsible for glioma-induced increased in BBB permeability; and 5) this model is useful for testing potential agents for BBB protection and for studying the pathophysiology of tumor-induced BBB disruption.

Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, short-term outcomes, and hospital charges in a nationwide sample

2003 ◽  
Vol 99 (5) ◽  
pp. 863-871 ◽  
Author(s):  
Emad N. Eskandar ◽  
Alice Flaherty ◽  
G. Rees Cosgrove ◽  
Leslie A. Shinobu ◽  
Fred G. Barker
Keyword(s):  
Surgical Treatment ◽  
Parkinson Disease ◽  
Practice Patterns ◽  
The United States ◽  
Hospital Charges ◽  
Short Term ◽  
Content Type ◽  
The Us ◽  
Fine Print ◽  
Deep Brain

Object. The surgical treatment of Parkinson disease (PD) has undergone a dramatic shift, from stereotactic ablative procedures toward deep brain stimulaion (DBS). The authors studied this process by investigating practice patterns, mortality and morbidity rates, and hospital charges as reflected in the records of a representative sample of US hospitals between 1996 and 2000. Methods. The authors conducted a retrospective cohort study by using the Nationwide Inpatient Sample database; 1761 operations at 71 hospitals were studied. Projected to the US population, there were 1650 inpatient procedures performed for PD per year (pallidotomies, thalamotomies, and DBS), with no significant change in the annual number of procedures during the study period. The in-hospital mortality rate was 0.2%, discharge other than to home was 8.1%, and the rate of neurological complications was 1.8%, with no significant differences between procedures. In multivariate analyses, hospitals with larger annual caseloads had lower mortality rates (p = 0.002) and better outcomes at hospital discharge (p = 0.007). Placement of deep brain stimulators comprised 0% of operations in 1996 and 88% in 2000. Factors predicting placement of these devices in analyses adjusted for year of surgery included younger age, Caucasian race, private insurance, residence in higher-income areas, hospital teaching status, and smaller annual hospital caseload. In multivariate analysis, total hospital charges were 2.2 times higher for DBS (median $36,000 compared with $12,000, p < 0.001), whereas charges were lower at higher-volume hospitals (p < 0.001). Conclusions. Surgical treatment of PD in the US changed significantly between 1996 and 2000. Larger-volume hospitals had superior short-term outcomes and lower charges. Future studies should address long-term functional end points, cost/benefit comparisons, and inequities in access to care.

Impairment of helper T-cell function and lymphokineactivated killer cytotoxicity following severe head injury

1991 ◽  
Vol 75 (5) ◽  
pp. 766-773 ◽  
Author(s):  
Keith B. Quattrocchi ◽  
Edmund H. Frank ◽  
Claramae H. Miller ◽  
Asim Amin ◽  
Bernardo W. Issel ◽  
...  
Keyword(s):  
T Cell ◽  
Head Injury ◽  
Severe Head Injury ◽  
Cell Cytotoxicity ◽  
Content Type ◽  
Lak Cell ◽  
Head Injured ◽  
Injured Patients ◽  
Fine Print

✓ Infection is a major complication of severe head injury, occurring in 50% to 75% of patients who survive to hospitalization. Previous investigations of immune activity following head injury have demonstrated suppression of helper T-cell activation. In this study, the in vitro production of interferon-gamma (INF-γ), interleukin-1 (IL-1), and interleukin-2 (IL-2) was determined in 25 head-injured patients following incubation of peripheral blood lymphocytes (PBL's) with the lymphocyte mitogen phytohemagglutinin (PHA). In order to elucidate the functional status of cellular cytotoxicity, lymphokine-activated killer (LAK) cell cytotoxicity assays were performed both prior to and following incubation of PBL's with IL-2 in five patients with severe head injury. The production of INF-γ and IL-2 by PHA-stimulated PBL's was maximally depressed within 24 hours of injury (p < 0.001 for INF-γ, p = 0.035 for IL-2) and partially normalized within 21 days of injury. There was no change in the production of IL-1. When comparing the in vitro LAK cell cytotoxicity of PBL's from head-injured patients and normal subjects, there was a significant depression in LAK cell cytotoxicity both prior to (p = 0.010) and following (p < 0.001) incubation of PBL's with IL-2. The results of this study indicate that IL-2 and INF-γ production, normally required for inducing cell-mediated immunity, is suppressed following severe head injury. The failure of IL-2 to enhance LAK cell cytotoxicity suggests that factors other than decreased IL-2 production, such as inhibitory soluble mediators or suppressor lymphocytes, may be responsible for the reduction in cellular immune activity following severe head injury. These findings may have significant implications in designing clinical studies aimed at reducing the incidence of infection following severe head injury.

VSM growth is stimulated in sympathetic neuron/VSM cocultures: role of TGF-β2 and endothelin

2000 ◽  
Vol 278 (2) ◽  
pp. H404-H411 ◽  
Author(s):  
Deborah H. Damon
Keyword(s):  
Transforming Growth Factor ◽  
Sympathetic Neurons ◽  
Sympathetic Nerves ◽  
Sympathetic Neuron ◽  
Vessel Growth ◽  
Coculture Model ◽  
Transforming Growth Factor Β2 ◽  
Cervical Ganglia ◽  
Stimulation Of

Sympathetic nerves are purported to stimulate blood vessel growth. The mechanism(s) underlying this stimulation has not been determined. With use of an in vitro coculture model, the present study tests the hypothesis that sympathetic neurons stimulate the growth of vascular smooth muscle (VSM) and evaluates potential mechanisms mediating this stimulation. Sympathetic neurons isolated from superior cervical ganglia (SCG) stimulated the growth of VSM. Growth of VSM in the presence of SCG (856 ± 81%) was significantly greater than that in the absence of SCG (626 ± 66%, P < 0.05). SCG did not stimulate VSM growth in transwell cocultures. An antibody that neutralized the activity of transforming growth factor-β2 (TGF-β2) inhibited SCG stimulation of VSM growth in coculture. SCG stimulation of VSM growth was also inhibited by an endothelin A receptor antagonist. These data suggest novel mechanisms for sympathetic modulation of vascular growth that may play a role in the physiological and/or pathological growth of the vasculature.

The role of σ-receptors in levodopa-induced dyskinesia in patients with advanced Parkinson disease: a positron emission tomography study

2004 ◽  
Vol 100 (4) ◽  
pp. 606-610 ◽  
Author(s):  
Taro Nimura ◽  
Tadashi Ando ◽  
Keiichiro Yamaguchi ◽  
Takeshi Nakajima ◽  
Reizo Shirane ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Severity Score ◽  
Rating Scale ◽  
Binding Potential ◽  
Strong Positive Correlation ◽  
Female Ratio ◽  
Content Type ◽  
Positron Emission ◽  
Before And After ◽  
Fine Print

Object. Levodopa-induced dyskinesia (LID) in patients with Parkinson disease (PD) mimics acute dystonic reactions induced by antipsychotic agents, possibly mediated by σ-receptors; however, there are few reports in which the relationship between σ-receptors and LID in advanced PD is investigated. The binding potential of cerebellar σ-receptors before and after a pallidal surgery for dyskinesia in patients with advanced PD is assessed. Methods. Six patients with advanced PD (male/female ratio 3:3, age 56.7 ± 9.8 years) underwent stereotactic pallidal surgery (two posteroventral pallidotomy procedures and four deep brain stimulation of the globus pallidus internus, including one bilateral case). Clinical features of patients with PD were assessed using Hoehn and Yahr (H & Y) stages, the Unified Parkinson's Disease Rating Scale (UPDRS), and the Schwab and England Activities of Daily Life Scale (S & E). The LID was evaluated by LID severity score. The binding potential of cerebellar σ-receptors was determined before and after the surgery by 11C-nemonapride positron emission tomoraphy, a specific radioligand for σ-receptors in the cerebellum. All clinical scores, especially the LID severity score, were dramatically improved after the surgery (p < 0.05). Preoperatively, contralateral cerebellar binding potential was significantly elevated (p < 0.01), and it was reduced after the surgery, but it was still higher than that of healthy volunteers (p < 0.05). The ipsilateral cerebellar binding potential remained unchanged after the surgery. The level of binding potential did not correlate with H & Y stage, UPDRS, or S & E score, but a strong positive correlation was seen between the binding potential and the preoperative LID severity score when the patients were receiving medication (r = 0.893, p < 0.05). Conclusions. Cerebellar σ-receptors may potentially involve the genesis of LID in advanced PD.

Sign in / Sign up

Export Citation Format

Share Document