Transplantation Of Mesencephalic Tissue Research Articles

Research progress of neural stem cells as a source of dopaminergic neurons for cell therapy in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease, the most characteristic pathological feature is the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compactus (SNpc) of the mesencephalon, along with reduced dopamine content in the striatum. Researchers have been searching for drugs and therapies to treat PD in decades. However, no approach could stop the progression of the disease, and even some of them caused adverse clinical side effects. PD has a well-defined lesion. Therefore, it is considered to be one of the most curable central nervous system diseases by cell replacement treatment. Fetal ventral mesencephalic tissue transplantation has been used to treat patients with PD and obtained positive treatment results. However, ethical issues, such as limited donor tissue, and side effects including graft-induced dyskinesias, limit its clinical applications. Neural stem cell (NSC) transplantation is a viable therapy choice because it possesses multipotency, self-renewal ability, and differentiation into DA neurons, which may substitute for lost DA neurons and slow down the neurodegenerative process in PD. Studies that investigated the delivery of NSCs by using animal models of PD revealed survival, migration, and even amelioration of behavioral deficits. Here, the research progress of NSCs or NSC-derived DA neurons in treating PD was reviewed, and the practicability of present manufacturing processes for clinical testing was considered. This review is expected to offer ideas for practical strategies to solve the present technical and biological problems related to the clinical application of NSCs in PD.

PET Imaging of Serotonin Transporters With 4-[(18)F]-ADAM in a Parkinsonian Rat Model With Porcine Neural Xenografts.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Apart from effective strategies to halt the underlying neuronal degeneration, cell replacement now offers novel prospects for PD therapy. Porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. This study was undertaken to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation in a PD rat model using animal positron emission tomography (PET) coupled with 4-[(18)F]-ADAM, a serotonin transporter (SERT) imaging agent. The parkinsonian rat was induced by injecting 6-hydroxydopamine into the medial forebrain bundle (MFB) of the right nigrostriatal pathway. The apomorphine-induced rotation behavioral test and 4-[(18)F]-ADAM/animal PET scanning were carried out following 6-OHDA lesioning. At the second week following 6-OHDA lesioning, the parkinsonian rat rotates substantially on apomorphine-induced contralateral turning. In addition, the mean striatal-specific uptake ratio (SUR) of 4-[(18)F]-ADAM decreased by 44%. After transplantation, the number of drug-induced rotations decreased markedly, and the mean SUR of 4-[(18)F]-ADAM and the level of SERT immunoreactivity (SERT-ir) in striatum were partially restored. The mean SUR level was restored to 71% compared to that for the contralateral intact side, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery at the fourth week postgraft. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat. The 4-[(18)F]-ADAM/animal PET can be used to detect serotonergic neuron loss in PD and monitor the efficacy of therapy.

KA-bridged transplantation of mesencephalic tissue and olfactory ensheathing cells in a Parkinsonian rat model.

The pathology of Parkinson's disease (PD) results mainly from nigrostriatal pathway damage. Unfortunately, commonly used PD therapies do not repair the disconnected circuitry. It has been reported that using kainic acid (KA, an excitatory amino acid) in bridging transplantation may be useful to generate an artificial tract and reconstruct the nigrostriatal pathway in 6-hydroxydopamine (6-OHDA) lesioned rats. In this study, we used KA bridging and a co-graft of rat olfactory ensheathing cells (OECs) and rat E14 embryonic ventral mesencephalic (VM) tissue to restore the nigrostriatal pathway of the PD model rats. The methamphetamine-induced rotational behaviour, 4-[18 F]-ADAM (a selectively serotonin transporter radioligand)/micro-PET imaging, and immunohistochemistry were used to assess the effects of the transplantation. At 9 weeks post-grafting in PD model rats, the results showed that the PD rats undergoing VM tissue and OECs co-grafts (VM-OECs) exhibited better motor recovery compared to the rats receiving VM tissue transplantation only. The striatal uptake of 4-[18 F]-ADAM and tyrosine hydroxylase immunoreactivity (TH-ir) of the grafted area in the VM-OECs group were also more improved than those of the VM alone group. These results suggested that OECs may enhance the survival of the grafted VM tissue and facilitate the recovery of motor function after VM transplantation. Moreover, OECs possibly promote the elongation of dopaminergic and serotonergic axon in the bridging graft. Copyright © 2015 John Wiley & Sons, Ltd.

PET Imaging of Serotonin Transporters with 4-[18F]-ADAM in a Parkinsonian Rat Model

This study was undertaken to address the effects of fetal mesencephalic tissue transplantation on the serotonin system in a rat model of Parkinson's disease (PD) while also investigating the usefulness of 4-[18F]-ADAM (a serotonin transporter imaging agent) coupled with micro-PET for imaging serotonin transporters (SERTs). A PD model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of the nigrostriatal pathway, while cell transplantation was performed via intrastriatal injection of mesencephalic brain tissue dissected from embryonic (E14) rats. The 4-[18F]-ADAM/micro-PET scanning was performed following both 6-OHDA lesioning and transplantation. Immunohistochemistry (IHC) studies were also performed following the final PET scan, and the results were compared to show a 17-43% decrease in the specific uptake ratio (SUR) and a 23-52% decrease in serotonin transporter immunoreactivity (SERT-ir) within various brain regions on the lesioned side. The number of methamphetamine-induced rotations also decreased significantly at the 4th week postgraft. In addition, striatal SUR and the SERT-ir levels were restored to 77% and 83% 5 weeks postgraft. These results suggest that Parkinson's disease also affects the serotonergic system, while both the dopaminergic and serotonergic systems can be partially restored in a rat model of PD after E14 mesencephalic tissue transplantation. In addition, we have also determined that 4-[18F]-ADAM/micro-PET can be used to detect serotonergic neuron loss, monitor the progress of Parkinson's disease, and oversee the effectiveness of therapy.

Parkinson's Disease: Surgical Options.

Surgical therapy for Parkinson's disease (PD) has been a treatment option for over 100 years. Advances in the knowledge of basal ganglia physiology and in techniques of stereotactic neurosurgery and neuroimaging have allowed more accurate placement of lesions or "brain pacemakers" in the sensorimotor regions of target nuclei. This, in turn, has led to improved efficacy with fewer complications than in the past. Currently, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is the preferred option (and is approved by the US Food and Drug Administration) for the surgical treatment of PD. The most important predictors for outcome for DBS for PD are patient selection and electrode location. Patients should have a documented preoperative improvement from dopaminergic medication of at least 30% in the patient's Unified Parkinson's Disease Rating Scale motor disability scores. A levodopa challenge may be needed to document the best "on" state. Dementia or active cognitive decline must be excluded. Active psychiatric disease should be treated preoperatively. Patients should be motivated, with good support systems, and committed to the postoperative management of DBS therapy. Deep brain stimulation should be considered when the patient begins to experience dyskinesia and on-off fluctuations despite optimal medical therapy. Deep brain stimulation is not a good option at the final stages of the disease because of the increased incidence of dementia and severe comorbidity. The DBS electrode should be placed in the sensorimotor region of the GPi or STN. Subthalamic nucleus and GPi DBS can improve all motor aspects of PD, as well as predictable "on" time, without dyskinesia or fluctuations. On average, STN DBS results in a greater reduction of dopaminergic medication compared with GPi DBS. Because of the smaller size of the target region, the pulse generator battery life is longer with STN then with GPi DBS. Deep brain stimulation programming is a skill that is readily learned and may be required of all neurologists in the future. Emerging surgical therapies are restorative, and they aim to replace or regenerate degenerating dopaminergic neurons. These include embryonic mesencephalic tissue transplantation, human embryonic stem cell transplantation, and gene-derived methods of intracerebral implantation of growth factors and dopamine- producing cell lines. It will be important to determine whether DBS, if performed before the onset of motor response complications to medical therapy, may prevent this stage of disease altogether or delay it for a significant period of time. The same question applies to the future with restorative therapy.

Addition of lateral ganglionic eminence to rat mesencephalic grafts affects fiber outgrowth but does not enhance function

Addition of embryonic striatal tissue, usually as a combination of the lateral and medial ganglionic eminences, to intrastriatal mesencephalic grafts has previously been reported to enhance recovery of drug-induced rotational behavior in the host and to modify axonal fiber outgrowth from the grafted dopaminergic neurons. This study investigated the effects of adding (cografting) either lateral or medial ganglionic eminence tissue to embryonic mesencephalic grafts implanted intrastriatally, in rats with unilateral 6-hydroxydopamine lesions. The cografts did not exhibit increased survival or cell size of dopaminergic neurons when compared to transplants of mesencephalic tissue alone. Neither did recipients of cografts exhibit any enhancement of graft-induced recovery of function, when tested for drug-induced rotational behavior or forelimb function in the staircase test. However, cografts containing lateral ganglionic eminence displayed patches of dense tyrosine hydroxylase-immunoreactive fibers within the graft tissue. These patches largely coincided with patches in adjacent stained sections, which were rich in immunostaining for the striatal-specific marker dopamine- and cyclic AMP-regulated phosphoprotein-32 (DARPP-32). Such patches were not present in rats receiving cografts containing medial ganglionic eminence or mesencephalic tissue alone. Thus, it seems that the grafted dopaminergic neurons preferentially grow into the areas of the transplants containing lateral ganglionic eminence tissue. In summary, the results suggest that embryonic lateral ganglionic eminence exerts trophic effects on the outgrowth of dopaminergic axons, but does not enhance the behavioral effects of grafted dopaminergic neurons.

Addition of lateral ganglionic eminence to rat mesencephalic grafts affects fiber outgrowth but does not enhance function.

Addition of embryonic striatal tissue, usually as a combination of the lateral and medial ganglionic eminences, to intrastriatal mesencephalic grafts has previously been reported to enhance recovery of drug-induced rotational behavior in the host and to modify axonal fiber outgrowth from the grafted dopaminergic neurons. This study investigated the effects of adding (cografting) either lateral or medial ganglionic eminence tissue to embryonic mesencephalic grafts implanted intrastriatally, in rats with unilateral 6-hydroxydopamine lesions. The cografts did not exhibit increased survival or cell size of dopaminergic neurons when compared to transplants of mesencephalic tissue alone. Neither did recipients of cografts exhibit any enhancement of graft-induced recovery of function, when tested for drug-induced rotational behavior or forelimb function in the staircase test. However, cografts containing lateral ganglionic eminence displayed patches of dense tyrosine hydroxylase-immunoreactive fibers within the graft tissue. These patches largely coincided with patches in adjacent stained sections, which were rich in immunostaining for the striatal-specific marker dopamine- and cyclic AMP-regulated phosphoprotein-32 (DARPP-32). Such patches were not present in rats receiving cografts containing medial ganglionic eminence or mesencephalic tissue alone. Thus, it seems that the grafted dopaminergic neurons preferentially grow into the areas of the transplants containing lateral ganglionic eminence tissue. In summary, the results suggest that embryonic lateral ganglionic eminence exerts trophic effects on the outgrowth of dopaminergic axons, but does not enhance the behavioral effects of grafted dopaminergic neurons.

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

General cognitive ability following unilateral and bilateral fetal ventral mesencephalic tissue transplantation for treatment of Parkinson's disease.

To contrast the neuropsychological profiles of Parkinsonian patients, before and after fetal ventral mesencephalic tissue transplantation. Case series of personally examined patients. Patients were evaluated by neurologists, neurosurgeons, and neuropsychologists as outpatients at a university hospital. Fetal mesencephalic tissue was implanted in the right caudate nucleus of three patients and both nuclei of one patient. These patients were evaluated prior to surgery and at 12, 24, and 26 months postoperatively. Factor analysis of the test battery identified four statistically orthogonal test clusters. No statistically significant changes were identified postoperatively for clusters assessing verbal cognitive ability, nonverbal cognitive ability, and information-processing speed. An improvement of verbal memory cluster index was observed 12 months after surgery, and the improvement reached the level of statistical significance at 24 months after surgery. However, the verbal memory of all patients declined between 24 and 36 months after surgery. Fetal tissue transplantation to one or both caudate nuclei did not permanently arrest cognitive dysfunction. Although there is some evidence of improved cognitive ability after transplantation, it is improbable that normal cognitive function can be restored by this procedure because the impairments of cognitive ability associated with Parkinson's disease do not appear to originate solely from dopamine deficiency.

Transplantation of Fetal Mesencephalic Tissue in Parkinson's Patients

Patients with idiopathic Parkinson's disease who had become refractory to medical treatment underwent unilateral stereotactic transplantation of mesencephalic tissue obtained from 7- to 9-week-old postconception fetuses. Small pieces of tissue, less than 1 mm, were deposited in 9 sites in the putamen and 3 in the caudate. Patients were 4 men and 3 women and aged from 42 to 59 years (mean 50). Symptom durations were from 9 to 21 years (mean 14). The examinations were done at 3- to 4-month intervals pre- and postoperatively. Patients were examined for a minimum of 1 year postoperatively. The examinations consisted of neurological and general physical examinations, UCLA Parkinson's Disability Scale, Hoehn and Yahr rating and United Parkinson's Disease Rating Scale (PDRS), all in both 'on' and 'off' states. Video recordings and timed tests of a number of motor tests were performed. Patients also completed 7 consecutive days of hourly self-assessments prior to each visit. Fluorodopa PET scans were obtained pre- and 6 and 15 months postoperatively. The operations took place from mid-July 1992 to January 1993. Postoperative states have been free of complications. All have been on immunosuppressants. Levodopa was transiently decreased in the postoperative period, but raised to approximately the preoperative level thereafter. In late March 1993, 3 patients appeared to show modest improvement in the UCLA and UPDRS scales and in the patients' self-assessments.

CT-Oriented Microrecording Guided Selective Thalamotomy

A further trial of CT-oriented microrecording guided stereotactic selective thalamotomy was conducted at the Centro Internacional de Restauración Neurológica, Havana City as treatment of resting tremor in 11 patients with idiopathic Parkinson's disease (PD), and in 3 other patients with intentional tremor associated with multisystemic atrophy and cerebral palsy. Three of the parkinsonian patients had undergone fetal mesencephalic tissue transplantation with significant improvement of the most debilitating symptoms of PD and stabilization of the motor state, but predominantly unilateral tremor had impaired them progressively despite increased levodopa doses. A Leksell frame was used with a novel surgical planning system and electrophysiological recordings to identify the optimal target point inside the ventralis intermedius. In all but 1 case, the tremor was totally arrested. No persistent complications were observed.