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

Abstract

The current transplantation strategy in experimental and clinical Parkinson's disease (PD) has been to place nigral dopaminergic grafts not in their ontogenic site (substantia nigra) but in their target area (striatum). Although intrastriatal dopaminergic grafts are capable of reinnervating the striatum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patients. We have previously shown that simultaneous intrastriatal and intranigral dopaminergic grafts (double grafts) may provide a more complete restoration 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 recovery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were divided into two groups and received either double grafts (n = 10) or intrastriatal grafts alone (n = 10). Following transplantation, both intrastriatally 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 second lesion, animals with double grafts exhibited a significant reversal of rotational behavior and a 51% reduction in contralateral adjusting step performance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest that the intranigral graft has an important role in the functional recovery of double-grafted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a superior strategy in neural transplantation for PD.

Comparison of Human Primary with Human iPS Cell-Derived Dopaminergic Neuron Grafts in the Rat Model for Parkinson’s Disease

“…The increase of D2 and D3 receptors in the striatum seems to be normalized at this time point [ 42 ]. It has been suggested that the function of SN also depends on dendritic DA release in the SN [ 46 ]. Interestingly, transplantation of DA neurons in the SN can give rise to a reduction of apomorphine-induced rotation [ 44 ].…”

Better Outcomes with Intranigral versus Intrastriatal Cell Transplantation: Relevance for Parkinson’s Disease

“…Until this study, contrasting results have been previously reported concerning functional recovery following intrastriatal or intranigral VM grafts. For instance, while some investigations have reported partial restoration in drug-induced rotation behavior in rodents after intranigral transplantation [ 37 , 106 , 107 , 108 ], only very limited [ 24 , 109 , 110 ] or no [ 111 , 112 ] improvement on more complex tasks have been reported. Similarly, in the case of intrastriatal transplantations, several studies have reported significant improvements in motor performance for simple tests [ 19 , 106 , 110 , 112 , 113 , 114 ] but only limited [ 42 , 44 , 45 ] or no improvement [ 40 , 109 , 115 , 116 , 117 ] in more complex tests, such as the grasping task.…”

“…The mechanisms underlying this arise from the significant innervation of the substantia nigra pars reticulata (SNpr) from the descending striato-nigral fibers. Specifically, it is now recognized that dendritic dopamine release plays a key role in the regulation of striato-nigral input (via D1-receptors), as well as in nigral output [ 111 , 141 , 142 ].…”

Implantation of c-mycERTAMImmortalized Human Mesencephalic-Derived Clonal Cell Lines Ameliorates Behavior Dysfunction in a Rat Model of Parkinson’s Disease

“…The cell suspensions were fi ltered through a 40-μm pore cell strainer (BD Biosciences) and counted on a hemocytometer using trypan blue (0.2%; Sigma). Cells were implanted at 21 ± 3 days after lesioning in two sites, the SN and the striatum, as this has been shown to be more effective than single intrastriatal graft alone [24,25]. Coordinates from bregma (according to [23]) were as follows: AP +0.6 mm, L +2.8 mm, V -5.5 mm (from skull surface at bregma) for striatum; and AP -5.3 mm, L +2.2 mm, V -7.5 mm (from skull surface at bregma for SN).…”