Embryonic Stem Cells Derived Neuron Transplantation Recovery in Models of Parkinsonism in Relation to Severity of the Disorder in Rats

Abstract

Abstract6-Hydroxydopamine (6-OHDA)-and 1-methyl-4-phenylpyridinium (MPP + )-induced hemi-parkinsonism was investigated in relation to the severity of the disorder in terms of behavioral disability and nigral neuronal loss and recovery regarding the number of stem cell-derived neurons transplanted in the striatum. Intramedian forebrain bundle infusion of the parkinsonian neurotoxins and intra-striatal transplantation of differentiated embryonic stem cells (ESCs) were carried out by rat brain stereotaxic surgery. The severity of the disease was determined using the number of amphetamine-or apomorphine-induced rotations, striatal dopamine levels as estimated by high-performance liquid chromatography (HPLC)-electrochemistry, and the number of surviving tyrosine hydroxylase immunoreactive dopaminergic neurons in the substantia nigra pars compacta. Rats that received unilateral infusion of 6-OHDA or MPP + responded with dose-dependent, unilateral bias in turning behavior when amphetamine or apomorphine was administered. Rotational asymmetry in both models correlated significantly well with the loss in the number of nigral dopaminergic neurons and striatal dopamine depletion. Transplantation of 2 · 10 5 differentiated murine ESCs revealed remarkably similar kinds of recovery in both animal models. The survival of the grafted dopaminergic cells in the striatum was better in animals with low-severity parkinsonism, but poor in the animals with severe parkinsonism. Amphetamine-induced rotational recovery correlated positively with an increasing number of cells transplanted in animals with uniform nigral neuronal lesion. These results suggest that disease severity is an important factor for determining the number of cells to be transplanted in parkinsonian rats for desirable recovery, which may be true in clinical conditions too.

Physical exercise and human adipose‐derived mesenchymal stem cells ameliorate motor disturbances in a male rat model of Parkinson's disease

“…Moreover, some authors have established a linear relationship between the number of cells implanted and the degree of functional motor recovery. As such, despite the fact that 2 × 10 5 cells were implanted in this study, a larger quantity may have induced a better locomotor response in rats exposed to the ADSC graft alone (Haobam, Tripathy, Kaidery, & Mohanakumar, ; Park, Kim, et al, ).…”

Human Embryonic Stem Cell-Derived Dopaminergic Grafts Alleviate L-DOPA Induced Dyskinesia

“…Striatal dopamine levels are negligible following a full medial forebrain bundle 6-OHDA lesion and both LID generation and functional recovery following transplantation have been shown to be closely linked to striatal dopamine efflux. Attenuation of LID is consistent with reduced dopamine levels following L-DOPA administration [76,77] and functional recovery from grafts conversly related to the increased dopamine release from the grafted cells [78,79]. Although it is important to note that other brain regions and neurotransmitters such as 5-HT are differentially affected and also linked to LID generation in particular [80,81].…”

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRB/E2F1 pathway in a model of Parkinson’s disease

“…The rats were divided into two groups and were unilaterally infused with 6-OHDA or vehicle targeting the medial forebrain bundle (MFB) using stereotaxic coordinates (as described in the Methods section). This approach selectively lesions the nigrostriatal dopaminergic pathway, mimicking a key feature of PD (Haobam et al . 2015).…”

“…The rats were divided into two groups and were unilaterally infused with 6-OHDA or vehicle targeting the medial forebrain bundle (MFB) using stereotaxic coordinates (as described in the Methods section). This approach selectively lesions the nigrostriatal dopaminergic pathway, mimicking a key feature of PD (Haobam et al 2015). Post infusion the rats were subjected to amphetamine and apomorphine induced rotational behavior tests on day 14 th and 16 th post infusion respectively (as described in methods section) to validate the hemiparkinsonian model.…”

“…The infusion aims at reaching the MFB accurately in rats through stereotaxic coordinates of anterioposterior (AP) -0.28 from the Bregma point, dorso-ventral (DV) -0.82, and lateral (L) 0.15. (Haobam et al 2015). Contralateral sides that received vehicle served as a control.…”