Abstract
ABSTRACTBackgroundThe risk of graft‐induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa‐induced dyskinesia.ObjectiveTo elucidate the mechanisms of GIDs.MethodsNeonatally desensitized, dopamine denervated rats received intrastriatal grafts of human embryonic stem cells (hESCs) differentiated into either ventral midbrain dopaminergic progenitor (vmDA) (n = 15) or ventral forebrain cells (n = 14).ResultsOf the eight rats with surviving grafts, two vmDA rats developed chronic spontaneous GIDs, which were observed at 30 weeks post‐transplantation. GIDs were inhibited by D2‐like receptor antagonists and not affected by 5‐HT1A/1B/5‐HT6 agonists/antagonists. Grafts in GID rats showed more microglial activation and lacked serotonin neurons.ConclusionsThese findings argue against current thinking that rats do not develop spontaneous GID and that serotonin neurons are causative, rather indicating that GID can be induced in rats by hESC‐derived dopamine grafts and, critically, can occur independently of both previous levodopa exposure and grafted serotonin neurons. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Highlights
Relevant conflicts of interest/financial disclosures: None to declare
To obtain long-term survival of human grafts in a rodent model without the need for daily immunosuppression, we applied a model of neonatal desensitization in rats, which required subcutaneous injection of human cells at P0-5.20,22 In adulthood, the desensitized rats received unilateral lesions and subsequently hESCderived ventral midbrain dopaminergic progenitor (vmDA) or vFB intrastriatal transplants
A subset of the transplanted rats (4/15) had surviving vmDA grafts and, of these, two displayed spontaneous contralateral rotations, a trend for L-dopa-induced rotations and reduced amphetamine-induced rotations (Fig. 1D). These two rats developed spontaneous AIMs at 30 weeks post-graft (Fig. 1C and Supporting Data). These were compared to rats with smaller surviving vmDA grafts (n = 2) and rats with non-DA, vFB grafts (n = 4/14)
Summary
Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia.
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