Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed. This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d-amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d-amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model.
The inadequate survival of dopamine neurons following intracerebral transplantation is in part attributed to the generation of reactive oxygen species and subsequent oxidative stress. To address this, we investigated whether the antioxidant ascorbic acid (vitamin C) had any effect on the yields of dopamine neurons derived from E14 rat ventral mesencephalic cells in vitro and in grafts. Following in vitro differentiation in medium containing ascorbic acid at concentrations ranging from 20 to 100 µM, significantly more neurons were immunopositive for the marker of mesencephalic dopamine neurons, tyrosine hydroxylase (TH), when compared to standard differentiation conditions containing no ascorbic acid. Mesencephalic cell suspensions supplemented with 100 µM ascorbic acid were also transplanted into unilateral 6-OHDA-lesioned rats and behavioral rotation was assessed at 2, 4, and 6 weeks posttransplantation. Grafts pretreated with ascorbic acid contained significantly more surviving dopamine neurons compared to nontreated grafts. However, no significant difference in rotation score was observed, with both groups showing a reversal and overcompensation of rotational bias. In addition, no evidence of neurogenesis of nigral dopamine neurons was observed in transplant groups. While the increased number of dopamine neurons observed in our study following ascorbic acid treatment may reflect a selective survival effect, our in vitro results suggest that ascorbic acid may act to increase the number dopamine neurons, both in culture and following transplantation, by stimulating dopaminergic differentiation of neural precursors from the fetal ventral mesencephalon.Key words: Ascorbic acid; Dopaminergic neurons; Neuronal survival; Parkinson's disease; Transplantation; Oxidative stress INTRODUCTIONto be achieved if neuronal replacement therapies are going to succeed (10,11). In addition, the appearance of graft-induced dyskineTransplantation of embryonic mesencephalic tissue into the dopamine-depleted striatum has shown clear sias in some patients receiving ventral mesencephalic transplants partially has been attributed to poor dopafunctional improvements by ameliorating behavioral deficits in a variety of animal models (3,4,8,26,34). The mine neuron survival, and the consequent "patchiness" of dopaminergic reinnervation within the caudate and extent of functional recovery is however limited, with grafts unable to reverse all lesion-induced behavioral abputamen where the transplants are placed (21,27). Clearly, if the survival of dopamine neurons can be increased in normalities. This limited recovery may in part relate to poor graft survival because only 5-10% of dopaminervivo, then clinicians will have far more control on the transplant procedure, including the targeting of optimal gic neurons typically survive transplantation (15). This low survival of dopamine neurons following transplantasites for graft placement, and the ability to restore full and homogenous dopaminergic innervation throughout tion means that for suffici...
Epidermoid lesions can develop anywhere in the cranial cavity. Like other space occupying lesions they often present with symptoms of raised ICP and with specific neurological deficits depending on location of the tumour. Surgical outcome is excellent with low complication rates.
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