Simultaneous intrastriatal and intranigral dopaminergic grafts in the Parkinsonian rat model: Role of the intranigral graft

The current transplantation strategy in experimental and clinical Parkinson 's disease (PD) has been to place nigral dopaminergic grafts not in their o ntogenic site (substantia nigra) but in their target area (striatum). Altho ugh intrastriatal dopaminergic grafts are capable of reinnervating the stri atum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patie nts. We have previously shown that simultaneous intrastriatal and intranigr al dopaminergic grafts (double grafts) may provide a more complete restorat ion of the nigrostriatal circuitry (Mendez et al. [1996] J Neurosci 16:7216 -7227; Mendez and Hong [1997] Brain Res 778:194-205). In the present study, we investigated the contribution of the intranigral graft to functional re covery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with uni lateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway wer e divided into two groups and received either double grafts (n = 10) or int rastriatal grafts alone (n = 10). Following transplantation, both intrastri atally and double-grafted animals had a significant decrease in rotational behavior. However, only animals with double grafts exhibited a significant increase in contralateral adjusting step performance. The intranigral graft was subsequently lesioned by a second 6-OHDA injection. Following the seco nd lesion, animals with double grafts exhibited a significant reversal of r otational behavior and a 51% reduction in contralateral adjusting step perf ormance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest; that the intran igral graft has an important role in the functional recovery of double-graf ted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a supe rior strategy in neural transplantation for PD. (C) 2000 Wiley-Liss, Inc.