Priming for L-DOPA-induced abnormal involuntary movements increases the severity of amphetamine-induced dyskinesia in grafted rats

Lane, Emma Louise; Vercammen, Linda; Cenci, M. Angela; Brundin, Patrik

doi:10.1016/j.expneurol.2009.04.010

Cited by 44 publications

(36 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ventrolateral (VL) striatum is an area influencing orofacial and forelimb movements (14,15). Of importance for this study, this region receives rich fiber innervation from grafted neurons being in close proximity to the grafted core with the most traditionally used coordinates for transplantation (16)(17)(18)(19). In this study, therefore, LTP was measured in both DL region and the more ventral region of striatum (i.e., VL) that received a denser fiber innervation from the grafted neurons ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Only after some time are synapses and fiber outgrowth from the transplanted neurons formation sufficient to restore the striatal synaptic plasticity deficits associated with the parkinsonian state. Indeed, maturation of the grafts can be a slow process, continuing for many months after initial formation of DA-fiber projections (55), which is also supported by the gradual and protracted recovery of 18 F-dopa uptake in the grafted striatum (56). The clinical outcome after DA cell transplantation thus continues to improve for up to 4 y in patients (57).…”

Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 94%

“…Transplantation of dopaminergic neurons into the striatum can provide long-lasting therapeutic benefit in PD patients. A clinical study has shown a delayed recovery in motor cortical activity occurring first after 18 mo posttransplantation compared with the increase in DA storage capacity that is detected with 18 F-dopa position emission tomography already after 6 mo (53). Also, in animal models of PD, the capacity for DA synthesis and storage in the grafts is detected before a significant improvement in complex sensory motor behavior (1,54).…”

Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 99%

See 2 more Smart Citations

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Rylander

Bagetta

Pendolino

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine-and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamineenriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.onpharmacological dopamine (DA) replacement approaches to the therapy of Parkinson disease (PD) focus on the transplantation of DA-producing neurons into the striatum. Parkinson disease is indeed viewed as the disease of choice to develop intracerebral transplantation therapies, and promising results have been obtained both in experimental models and in some patients using embryonic DA neurons (1, 2). Embryonic DA neurons are able to innervate the host striatum, release DA, and reverse alterations in neuropeptide expression after a parkinsonian lesion (3). There is a continuous debate about whether these effects are sufficient for transplanted neurons to partially restore clinical symptoms or whether other underlying mechanisms also are required. In particular, a functional integration of the graft into the host microcircuits, with bidirectional synaptic contacts between the host and grafted neurons, may give superior therapeutic benefit than a mere neurochemical restoration. Transplanted DA neurons are able to form synapses with the surrounding striatal medium-sized spiny neurons (MSNs) (4) and receive innervation from the host neurons with bidirectional synaptic interactions (5-7). It is, however, unknown wh...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 94%

Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 99%

See 1 more Smart Citation

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Rylander

Bagetta

Pendolino

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Studies performed after the report by Freed et al [6] have reported similar findings, confirming that fetal mesencephalic grafts typically reduce established L-DOPA-induced dyskinesias, and do not induce any off-state dyskinesias, in 6-hydroxydopamine-lesioned rats (for more detail see Lane et al [38]). A distinct type of GID, however, has been identified in these rodent studies (i.e., dyskinesia induced by the DA-releasing agent amphetamine) [39][40][41]. This phenomenon, which is never seen in nongrafted controls, appear gradually after transplantation, and is highly correlated with the number of DA neurons in the graft.…”

Section: Adverse Effects Are Few With Dopaminergic Grafts Except Dysmentioning

confidence: 93%

“…This phenomenon, which is never seen in nongrafted controls, appear gradually after transplantation, and is highly correlated with the number of DA neurons in the graft. Interestingly, this type of GID develops only in animals that have developed L-DOPA-induced dyskinesia prior to transplantation, suggesting that animals have become dyskinetic by chronic L-DOPA treatment are particularly susceptible to develop GID [40,42].…”

Section: Adverse Effects Are Few With Dopaminergic Grafts Except Dysmentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

View full text Add to dashboard Cite

The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

show abstract

Potential for cell therapy in Parkinson's disease using genetically programmed human embryonic stem cell–derived neural progenitor cells

Ambasudhan

Dolatabadi

Nutter

et al. 2014

J of Comparative Neurology

View full text Add to dashboard Cite

Neural transplantation is a promising strategy for restoring dopaminergic dysfunction and modifying disease progression in Parkinson's disease (PD). Human embryonic stem cells (hESCs) are a potential resource in this regard because of their ability to provide a virtually limitless supply of homogenous dopaminergic progenitors and neurons of appropriate lineage. The recent advances in developing robust cell culture protocols for directed differentiation of hESCs to near pure populations of ventral mesencephalic (A9-type) dopaminergic neurons has heightened the prospects for PD cell therapy. Here, we focus our review on current state-of-the-art techniques for harnessing hESC-based strategies toward development of a stem cell therapeutic for PD. Importantly, we also briefly describe a novel genetic-programming approach that may address many of the key challenges that remain in the field and that may hasten clinical translation.

show abstract

Priming for L-DOPA-induced abnormal involuntary movements increases the severity of amphetamine-induced dyskinesia in grafted rats

Cited by 44 publications

References 28 publications

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Cell Therapeutics in Parkinson's Disease

Potential for cell therapy in Parkinson's disease using genetically programmed human embryonic stem cell–derived neural progenitor cells

Contact Info

Product

Resources

About