What did we learn from neural grafts in Huntington disease?

Huntington's disease is a rare, severe, and inherited neurodegenerative disorder that affects young adults. To date, there is no treatment to stop its progression. The primary atrophy of the striatum in HD, is limited in space and centrally focalised in the brain and thus constitutes a good candidate for graft. Therefore, transplantation of foetal cells from the ganglionic eminence, the germinal zone of the striatum, has the potential to restore disrupted fronto-cortical circuits and corresponding clinical functions. The international Multicentric intracerebral Grafting in Huntington's disease trial was not as successful as two pilot trials (Créteil and London) which showed promising results in the 2000s, displaying stabilisation/recovery of symptoms in some patients. A point-by-point comparison of the differences between MIG-HD and the pilot trial from Créteil in which similar data are available provides lessons on the grafting procedure and allows for strategic thinking before embarking on future trials. MIG-HD demonstrated the existence of intracerebral alloimmunisation leading to acute or chronic graft rejection into the brain and showed the limitations of surgical standardisation and immunosuppression. It has also improved the safety of the procedure and provided guidance for the follow-up of future patients. Indeed, even if disease modifiers treatments are currently the focus of intense research, they may not stop or slow the progression of the disease sufficiently, or even be administered in all patients, to prevent brain atrophy in all cases. Although disease-modifying therapies are currently the subject of intense research, they may not stop or slow disease progression sufficiently, or may not be given to all patients to prevent brain atrophy. A combination with intracerebral transplantation to repair the damaged structures may thus prove beneficial. Altogether, pursuing research in intracerebral transplantation remains necessary.

Therapeutic potentials of human microfluidic encapsulated conjunctival mesenchymal stem cells on the rat model of Parkinson's disease.

BACKGROUND AND AIM: Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the destruction of the dopaminergic neurons in the nigrostriatal pathway, leading to motor-behavioral complications. Cell therapy has been proposed as a promising approach for PD treatment using various cellular sources. Despite a few disadvantages mesenchymal stem cells (MSCs) represent, they have more auspicious effects for PD cell therapy. The present study aimed to evaluate a new source of MSCs isolated from human Conjunctiva (CJ-MSCs) impact on PD complications for the first time. MATERIALS AND METHODS: Parkinson's was induced by stereotactic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). An apomorphine-induced rotation test was used to confirm the model establishment. After PD model confirmation, green fluorescent protein (GFP) labeled CJ-MSCs and induced CJ-MSCs (microfluidic encapsulated and non-capsulated) were transplanted into the rats' right striatum. Then Rotation, Rotarod, and Open-field tests were performed to evaluate the behavioral assessment. Additionally, the immunohistochemistry technique was used for identifying tyrosine hydroxylase (TH). RESULTS: According to the obtained data, the cell transplantation caused a reduction in the rats' rotation number and improved locomotion compared to the control group. The previous results were also more pronounced in induced and microfluidic encapsulated cells compared to other cells. Rats recipient CJ-MSCs also have represented more TH-expressed GFP-labeled cell numbers in the striatum than the control group. CONCLUSION: It can be concluded that CJ-MSCs therapy can have protective effects against PD complications and nerve induction of cells due to their ability to express dopamine. On the other hand, CJ-MSCs microencapsulating leads to enhance even more protective effect of CJ-MSCs. However, confirmation of this hypothesis requires further studies and investigation of these cells' possible mechanisms of action.

Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease.

The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long-distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the nigrostriatal pathway. We are applying microtissue engineering techniques to create living, implantable constructs that mimic the architecture and function of the nigrostriatal pathway. These constructs consist of dopaminergic neurons with long axonal tracts encased within hydrogel microcolumns. Microcolumns were seeded with dopaminergic neuronal aggregates, while lumen extracellular matrix, growth factors, and end targets were varied to optimize cytoarchitecture. We found a 10-fold increase in axonal outgrowth from aggregates versus dissociated neurons, resulting in remarkable axonal lengths of over 6 mm by 14 days and 9 mm by 28 days in vitro. Axonal extension was also dependent upon lumen extracellular matrix, but did not depend on growth factor enrichment or neuronal end target presence. Evoked dopamine release was measured via fast scan cyclic voltammetry and synapse formation with striatal neurons was observed in vitro. Constructs were microinjected to span the nigrostriatal pathway in rats, revealing survival of implanted neurons while maintaining their axonal projections within the microcolumn. Lastly, these constructs were generated with dopaminergic neurons differentiated from human embryonic stem cells. This strategy may improve Parkinson's disease treatment by simultaneously replacing lost dopaminergic neurons in the substantia nigra and reconstructing their long-projecting axonal tracts to the striatum.

Intrastriatal transplantation of stem cells from human exfoliated deciduous teeth reduces motor defects in Parkinsonian rats.

BACKGROUND: This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD). METHODS: The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats to evaluate their neural differentiation and functions in vivo. RESULTS: These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED. CONCLUSION: Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA-induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.

Regulatable Lentiviral Hematopoietic Stem Cell Gene Therapy in a Mouse Model of Parkinson's Disease.

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent neuroprotective properties in preclinical models of Parkinson's disease (PD), but challenges in GDNF delivery have been reported from clinical trials. To address this barrier, we developed a hematopoietic stem cell transplantation-based macrophage-mediated GDNF therapy platform. Here, we introduced a regulatable lentiviral vector (LV-MSP-Tet-Off-hGDNF) to allow the expression of human GDNF (hGDNF) to be adjusted or stopped by oral administration of doxycycline (Dox). C57BL/6J mice were lethally irradiated with head protection and then transplanted with syngeneic bone marrow cells transduced with either the hGDNF-expressing vector or a corresponding GFP-expressing vector, LV-MSP-Tet-Off-GFP. Suppression of vector gene expression was achieved through administration of Dox in drinking water. To create a toxin-induced Parkinsonian model, mice were injected in two cycles with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to yield nigral cell/striatal dopamine loss and behavioral deficits. During the presence of Dox in the drinking water, plasma GDNF was at a basal level, whereas during the absence of Dox, plasma GDNF was significantly elevated, indicating reliable regulation of therapeutic gene expression. Midbrain GDNF levels were altered in parallel, although these did not return completely to basal levels during the periods of Dox withdrawal. Motor activities of the MPTP-Tet-off-hGDNF group were comparable to those of the Tet-off-GFP (subject to no MPTP treatment) group, but substantially better than those of the MPTP-Tet-off-GFP group. Interestingly, the improvement in motor activities was sustained during the Dox-withdrawn periods in MPTP-Tet-off-hGDNF animals. Neuroprotection by therapeutic GDNF expression was further evidenced by significant amelioration of nigral tyrosine hydroxylase loss after both the first and second MPTP treatment cycles. These data suggest that neurotrophic factor expression can be upregulated to achieve efficacy or downregulated in case of off-target effects or adverse events, a feature that may eventually increase the acceptance of this potentially neuroprotective/disease-modifying PD therapy.

Effects of Rho Kinase Inhibitors on Grafts of Dopaminergic Cell Precursors in a Rat Model of Parkinson's Disease.

UNLABELLED: In models of Parkinson's disease (PD), Rho kinase (ROCK) inhibitors have antiapoptotic and axon-stabilizing effects on damaged neurons, decrease the neuroinflammatory response, and protect against dopaminergic neuron death and axonal retraction. ROCK inhibitors have also shown protective effects against apoptosis induced by handling and dissociation of several types of stem cells. However, the effect of ROCK inhibitors on dopaminergic cell grafts has not been investigated. In the present study, treatment of dopaminergic cell suspension with ROCK inhibitors yielded significant decreases in the number of surviving dopaminergic neurons, in the density of graft-derived dopaminergic fibers, and in graft vascularization. Dopaminergic neuron death also markedly increased in primary mesencephalic cultures when the cell suspension was treated with ROCK inhibitors before plating, which suggests that decreased angiogenesis is not the only factor leading to cell death in grafts. Interestingly, treatment of the host 6-hydroxydopamine-lesioned rats with ROCK inhibitors induced a slight, nonsignificant increase in the number of surviving neurons, as well as marked increases in the density of graft-derived dopaminergic fibers and the size of the striatal reinnervated area. The study findings discourage treatment of cell suspensions before grafting. However, treatment of the host induces a marked increase in graft-derived striatal reinnervation. Because ROCK inhibitors have also exerted neuroprotective effects in several models of PD, treatment of the host with ROCK inhibitors, currently used against vascular diseases in clinical practice, before and after grafting may be a useful adjuvant to cell therapy in PD. SIGNIFICANCE: Cell-replacement therapy is one promising therapy for Parkinson's disease (PD). However, many questions must be addressed before widespread application. Rho kinase (ROCK) inhibitors have been used in a variety of applications associated with stem cell research and may be an excellent strategy for improving survival of grafted neurons and graft-derived dopaminergic innervation. The present results discourage the treatment of suspensions of dopaminergic precursors with ROCK inhibitors in the pregrafting period. However, treatment of the host (patients with PD) with ROCK inhibitors, currently used against vascular diseases, may be a useful adjuvant to cell therapy in PD.

Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms.

With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84 days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP(+) NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in our experimental model is an attractive and effective strategy for stroke therapy that deserves further proof-of-concept studies.

Donor-Specific Anti-HLA Antibodies in Huntington's Disease Recipients of Human Fetal Striatal Grafts.

Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0-49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.

Cell transplantation in the damaged adult brain.

Parkinson's disease (PD) is the most common movement disorder in Europe, affecting more than two million people between 50 and 70 years of age. The current therapeutic approaches are of symptomatic nature and fail to halt the progressive neurodegenerative course of the disease. The development of innovative and complementary approaches to promote cellular repair may pave the way for disease-modifying therapies which may lead to less suffering for the patients and their families and finally to more cost-effective therapies. To date, cell replacement trials in PD aiming at replacing lost dopamine neurons were mainly focused on placing the transplanted cells within the target site, the striatum, and not within the lesioned site, the substantia nigra (SN). This was based on the misconception that the adult brain constitutes a non-permissive barrier not allowing the outgrowth of long distance axons originating from transplanted embryonic neurons. A growing body of evidence is challenging this concept and proposing instead to place the graft within its ontogenic site. This has been performed in several lesional animal models for various traumatic or neurodegenerative pathologies of the brain. For instance, transplanted neurons within the lesioned motor cortex were shown to be able to send distant and appropriate projections to target areas including the spinal cord. Similarly, in an animal model of PD, mesencephalic embryonic cells transplanted within the lesioned SN send massive projections to the striatum and, to a lesser extent, the frontal cortex and the nucleus accumbens. This has lead to the proposal that homotopic transplantation may be an alternative in cell-based therapies as transplanted neurons can integrate within the host brain, send projections to target areas, restore the damaged circuitry, increase neurotransmitter levels and ameliorate behavior. We will discuss also the potential of replacing embryonic neuronal cells by stem cell derived neurons as the use of embryonic cells is not without an ethical and logistical burden; in this line many have thrived to derive neurons from embryonic stem cells (ESC) in order to use them for cell transplantation. These studies are already yielding important information for future approaches in the field of cell therapies in PD but also in other neurodegenerative disorders where cell transplantation therapy may be considered. While the field of cell replacement therapies has been recently called into question with contrasting results in transplanted PD patients, these new sets of findings are raising new hopes and opening new avenues in this rejuvenated field.

Clinical neurotransplantation protocol for Huntington's and Parkinson's disease.

PURPOSE: The concept of transplantation of neuronal cells to treat Huntington's and Parkinson's diseases is based on the proven principle that dopaminergic and GABA-ergic progenitor neurons (from the human developing ventral mesencephalon and whole ganglionic eminence) can survive, differentiate and functionally integrate into an allogenic host brain. However, several donor and host-specific variables play a major role in the safety and outcome of this procedure. In this paper, we seek to summarize an updated neural transplantation protocol, based on our institutional experience and many years of collaboration with other neurotransplantation centers. METHODS: We present a detailed clinical neurotransplantation protocol for Parkinson's (PD) and Huntington's (HD) diseases with special emphasis in understanding the anatomical relationships of the human fetal tissue that are relevant for selection of the desired cell populations. RESULTS: Two detailed step-wise neurotransplantation protocols are presented, outlining strategies facilitating the avoidance of possible procedure-related complications. CONCLUSIONS: In this paper we delineated some crucial technical factors enabling the execution of a safe and effective neural transplantation. The protocols presented here might contribute to further development of the experimental clinical neurotransplantation towards a routine therapeutic procedure.

Striatal allografts in patients with Huntington's disease: impact of diminished astrocytes and vascularization on graft viability.

Neuronal transplantation has been proposed as a potential therapy to replace lost neurons in Huntington's disease. Transplant vascularization and trophic support are important for graft survival. However, very few studies have specifically addressed graft vascularization in patients with neurological disorders. In the present study, we analysed the vasculature of the host putamen and solid grafts of foetal striatal tissue transplanted into patients with Huntington's disease 9 and 12 years previously. Grafts were characterized by a significantly reduced number of large calibre blood vessels in comparison with the host brain. There were also significantly fewer astrocytes and gap junctions, suggesting a lack of functional blood-brain barrier components within the grafted tissue. Additionally, grafts demonstrated a nearly complete absence of pericytes (compared with the striatum) that are considered important for vascular stabilization and angiogenesis. Finally, the host striatum had a marked increase in atrophic astrocytes in comparison with controls and grafts. The extent to which the lower number of large calibre vessels and astrocytes within the transplants contributed to suboptimal graft survival is unknown. The marked increase in atrophic astrocytes in the host brain surrounding the grafts suggests that reduced host trophic support may also contribute to poor graft survival in Huntington's disease. A better understanding of the way in which these components support allografted tissue is critical to the future development of cell-based therapies for the treatment of Huntington's disease.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Skilled motor control for the preclinical assessment of functional deficits and recovery following nigral and striatal cell transplantation.

Neural transplantation holds the promise for restoring behavioral function following brain injury. Substantial evidence indicates that fetal neurons transplanted to the adult brain survive and incorporate into remaining neural tissue and produce positive behavioral effects. A yet-unanswered question is whether the integration of new tissue can restore complex neural circuits that connect the neocortex, basal ganglia, and brainstem, and restore functions that are mediated by these circuits. This chapter describes the skilled reaching task, a task that requires transport of the arm and hand to grasp a food item and withdrawal to place the food item in the mouth for eating. It is a movement that is readily expressed in rodents and is fundamental to both nonhuman primates and humans. Methods for analyzing skilled reaching have been developed for preclinical rodent and mouse models of Parkinson's disease and Huntington's disease that are generalizable to humans with those clinical disorders. It is suggested that the task provides a motor benchmark for assessing the restoration of function produced by neural transplantation.

Role of experience, training, and plasticity in the functional efficacy of striatal transplants.

Cell-based treatments of neurodegenerative diseases have been tested clinically with partial success. In the context of Huntington's disease (HD), experimental studies show that the grafted embryonic striatal cells survive, integrate within the host brain, and reverse some functional deficits. Importantly, once transplanted, the grafted striatal neurons retain a significant level of cellular, morphological, and functional plasticity which allows the experimental modification of their character through the manipulation of environmental cues or learning protocols. Using embryonic striatal grafts in the rodent model of HD as the principal example, this chapter summarizes seminal experiments that demonstrate that environmental factors, training, and activity can tap into mechanisms that influence the development of the grafted cells and can change the profile of graft-mediated behavioral recovery. Although currently there is limited understanding of the biological rationale behind the recovery, we put forward experimental data indicating that striatal grafts can express experience-dependent physiological plasticity at the synaptic as well as at the systemic functional level.

In vivo imaging of integration and function of striatal grafts in rodent and nonhuman primate animal models.

The assessment of the therapeutic efficacy of cell transplantation in repairing dysfunctional or degenerating brain tissues is conditioned by our capacity to follow up the grafted cells longitudinally in a noninvasive fashion. In fact, to date, postmortem histological analysis remains the main method used to characterize cell survival, maturation, differentiation, and absence of adverse effects upon intracerebral grafting. However, the increasing availability of sophisticated imaging techniques such as positron emission tomography, magnetic resonance imaging, and spectroscopy offers the possibility to directly exploit anatomical and functional information coming from the grafted cells in vivo. This, in turn, opens the way to the amelioration of existing applications and the development of new methodologies capable of addressing challenges arising in the preclinical transplantation field in views of a clinical application. This review summarizes the principles of the different imaging techniques and their validation in the preclinical setting in animal models of striatal degeneration.

Derivation of striatal neurons from human stem cells.

Huntington's disease cell therapy is for the moment the only therapeutic approach for this devastating neurodegenerative disorder that has demonstrated significant and long-lasting functional benefits in patient. Logistical and biological difficulties associated with the use of human fetal tissue however dramatically reduce the number of patients eligible to this therapy. During the past decade, the exploration of alternative cellular sources, conducted in parallel to the clinical trials, has gradually put forward human pluripotent stem cells as prime candidate for Huntington's disease cell therapy. Protocols for the differentiation of such cells into therapeutically relevant striatal neuron precursors require thorough understanding of the molecular determinant that controls the development of the anterior and ventral part of the forebrain from which the striatum arises. Key secreted molecules that play pivotal roles in the development of these regions in mice have been successfully used to direct the specification of neural derivatives of human pluripotent stem cells. Assessment of the therapeutic potential of resulting striatal grafts has made significant progress in the last 4 years. The proof of principle that human embryonic stem cell derivatives can achieve some degrees of functional striatal repair in a mouse model of Huntington's disease is now established. As in other neurodegenerative diseases such as Parkinson's disease, recent developments have raised hopes for stem cell-based therapy of Huntington's disease.

Clinical trials of neural transplantation in Huntington's disease.

Clinical neural transplantation in Huntington's disease has moved forward as a series of small studies, which have provided some preliminary proof of principle that neural transplantation can provide benefit. However, to date, such benefits have not been robust, and there are a number of important issues that need to be addressed. These include defining the optimum donor tissue conditions and host characteristics in order to produce reliable benefit in transplant recipients, and whether, and for how long, immunosuppression is needed. Further clinical studies will be required to address these, and other issues, in order to better understand the processes leading to a properly functioning neural graft. Such studies will pave the way for future clinical trials of renewable donor sources, in particular, stem cell-derived neuronal progenitor grafts.

Progress in restorative neurosurgery: human fetal striatal transplantation in Huntington's disease. Review.

The purpose of this paper was to offer a review of the rationale, methods, biological and clinical results of human fetal striatal transplantation (HFST) in the treatment of Huntington's disease (HD). HD is a heritable neurodegenerative disease in which degeneration of neurons in the striatum leads to motor, psychiatric and cognitive deficits. The disease is progressive and inexorably lethal. At present there are no curative treatments for HD. A restorative therapy based on the intrastriatal transplantation of striatal neuroblasts taken from human fetus is currently being explored as potential treatment in selected HD patients. Pilot clinical trials of HFST have been started in few neurosurgery restorative centres. Results demonstrated that HFST is feasible and safe without relevant adverse effects; grafted neuroblasts survive, grow without evidence of neoplasia or teratoma, build new tissue with striatal-like imaging features, and move into the host brain towards short and long-distance cortical and sub-cortical targets. HFST delays disease progression and provides a period of improvement and stability. Even though larger-scale studies are still necessary to establish the true value of such a treatment, at this time, HFST represents a promising experimental therapy for patients with HD and one of the most interesting clinical application of restorative neurosurgery.

The effect of striatal dopaminergic grafts on the neuronal activity in the substantia nigra pars reticulata and subthalamic nucleus in hemiparkinsonian rats.

The electrophysiological correlates of parkinsonism in the basal ganglia have been well studied in patients with Parkinson's disease and animal models. Separately, striatal dopaminergic cell transplantation has shown promise in ameliorating parkinsonian motor symptoms. However, the effect of dopaminergic grafts on basal ganglia electrophysiology has not thoroughly been investigated. In this study, we transplanted murine foetal ventral mesencephalic cells into rats rendered hemiparkinsonian by 6-hydroxydopamine injection. Three months after transplantation, extracellular and local field potential recordings were taken under urethane anaesthesia from the substantia nigra pars reticulata and subthalamic nucleus along with cortical electroencephalograms and were compared to recordings from normal and hemiparkinsonian controls. Recordings from cortical slow-wave activity and global activation states were analysed separately. Rats with histologically confirmed xenografts showed behavioural improvement measured by counting apomorphine-induced rotations and with the extended body axis test. Firing rates in both nuclei were not significantly different between control and grafted groups. However, burst firing patterns in both nuclei in the slow-wave activity state were significantly reduced (P < 0.05) in rats with large surviving grafts, compared to hemiparkinsonian controls. The neuronal firing entropies and oscillations in both nuclei were restored to normal levels in the large-graft group. Electroencephalogram spike-triggered averages also showed normalization in the slow-wave activity state (P < 0.05). These results suggest that local continuous dopaminergic stimulation exerts a normalizing effect on the downstream parkinsonian basal ganglia firing patterns. This novel finding is relevant to future preclinical and clinical investigations of cell transplantation and the development of next-generation therapies for Parkinson's disease that ameliorate pathophysiological neural activity and provide optimal recovery of function.

Environmental enrichment facilitates long-term potentiation in embryonic striatal grafts.

BACKGROUND: Housing animals in an enriched environment improves motor and cognitive performance and anatomical connectivity in rodent lesion models of Huntington disease and transplantation of embryonic striatal grafts. OBJECTIVE: The authors evaluate the extent to which environmental enrichment can modify synaptic plasticity in the host-graft neuronal circuitry to try to find a physiological substrate for the observed improvements. METHODS: C57BL/6 mice, housed in enriched or standard environments, received unilateral quinolinic acid lesions of the striatum, followed by embryonic striatal grafts. Then, 3 months posttransplantation, synaptic physiology and plasticity were evaluated by extracellular recording from in vitro striatal slices. RESULTS: Environmental enrichment had no effect on the chance of long-term depression (LTD) induction or expression of LTD from either normal or grafted striatum. In contrast, enrichment increased the chance of long-term potentiation (LTP) induction and level of expression associated with increased levels of brain-derived neurotrophic factor within both the intact and grafted striatum compared with levels in the striatum of animals housed in standard environments. CONCLUSIONS: Environmental enrichment induces changes in host-graft corticostriatal LTP, thus providing a potential physiological substrate for the enrichment-induced improvement in motor and cognitive performance. The effect may be mediated by modulation of the trophic environment in which the grafted cells develop and integrate.