Enhancement of sensorimotor behavioral recovery in hemiparkinsonian rats with intrastriatal, intranigral, and intrasubthalamic nucleus dopaminergic transplants

One of the critical variables that influences the efficacy of clinical neur al transplantation for Parkinson's disease (PD) is optimal graft placement. The current transplantation paradigm that focuses on ectopic placement of fetal grafts in the striatum (ST) fails to reconstruct the basal ganglia ci rcuitry or normalize neuronal activity in important basal ganglia structure s, such as the substantia nigra (SN) and the subthalamic nucleus (STN). The aim of this study was to investigate a multitarget neural transplantation strategy for PD by assessing whether simultaneous dopaminergic transplants in the ST, SN, and STN induce functional recovery in hemiparkinsonian rats. Forty- six female Wistar rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were randomly divided into eight groups and rece ived lesions only or injections of 900,000 embryonic rat ventral mesencepha lic cells in the (1) ST, (2) SN, (3) STN, (4) ST and SN, (5) ST, SN, and ST N, (6) ST and STN, or (7) SN and STN. The number of cells transplanted was equally divided among grafting sites. Animals with two grafts received 450, 000 cells in each structure, and animals with three grafts received 300,000 cells per structure. Recovery was assessed by amphetamine- induced rotatio ns and the stepping tests. Graft survival was assessed using tyrosine hydro xylase immunohistochemistry. At 8 weeks after transplantation, simultaneous dopaminergic transplants in the ST, SN, and STN induced significant improv ement in rotational behavior and stepping test scores. Intrastriatal transp lants were associated with significant recovery of rotational asymmetry, wh ereas SN and STN transplants were associated with improved forelimb functio n scores. These results suggest that restoration of dopaminergic activity t o multiple basal ganglia targets, such as the ST and SN, or the ST and STN, promotes a more complete functional recovery of complex sensorimotor behav iors. A multitarget transplant strategy aimed at optimizing dopaminergic re innervation of the basal ganglia may be crucial in improving clinical outco mes in PD patients.