Embryonic mesencephalic grafts increase levodopa-induced forelimb hyperkinesia in parkinsonian rats.
Recent observations from clinical trials of neural grafting for Parkinson's disease (PD) have demonstrated that grafted dopamine neurons can worsen dyskinesias in some graft recipients. This deleterious side effect reveals a new challenge for neural transplantation, that of elucidating mechanisms underlying these postgraft dyskinesias. One problem facing this challenge is the availability of a cost-effective and reliable animal model in which to pursue initial investigations. In the current study, we investigated the interaction of an embryonic ventral mesencephalic (VM) dopamine (DA) neuron graft on levodopa (LD)-induced dyskinetic movements in unilaterally 6-hydroxydopamine-lesioned rats. Rats were administered LD (levodopa-carbidopa, 50:5 mg/kg) twice daily for 6 weeks after either a sham graft or VM DA graft. Although a single solid graft of embryonic DA neurons can prevent progression of some lesioned-induced behavioral abnormalities such as LD-induced rotation and dystonia, it significantly increases hyperkinetic movements of the contralateral forelimb. This differential effect of grafted neurons on abnormal behavioral profiles is reminiscent of that reported in grafted patients with PD. Data from this study illustrate important similarities between this model of parkinsonism and PD in human patients that make it suitable for initial preclinical investigations into possible mechanisms underlying postgraft aggravation of dyskinetic movements.
Steece-Collier
Kathy
K
Department of Neurological Science, Research Center for Brain Repair, Rush Presbyterian St Luke's Medical Center, Chicago, Illinois 60612, USA. kathy_a_steece-collier@rush.edu
Collier
Timothy J
TJ
Danielson
Paul D
PD
Kurlan
Roger
R
Yurek
David M
DM
Sladek
John R
JR
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005552:Forelimb / Q000503:physiopathology*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000503:physiopathology*; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008636:Mesencephalon / Q000196:embryology* / Q000378:metabolism / Q000637:transplantation*; D009474:Neurons / Q000378:metabolism / Q000637:transplantation; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology* / Q000601:surgery*; D011183:Postoperative Complications; D051381:Rats; D011916:Rats, Inbred F344
D000978:Antiparkinson Agents; D007980:Levodopa; D004298:Dopamine