Neural progenitor cells have shown the effectiveness in the treatment of Parkinson's disease, but the therapeutic efficacy remains variable. One of important factors that determine the efficacy is the necessity of pre-differentiation of progenitor cells into dopaminergic neuronsbefore transplantation. This study therefore investigated the therapeutic efficacy of mesencephalon-derived human neural progenitor cellswith or without the pre-differentiation in alleviating a rat model of Parkinson's disease.We found that a combination of 50ng/ml fibroblastgrowth factor 8, 10ng/ml glial cell line-derived neurotrophic factor and 10M forskolin facilitated the differentiation of human fetalmesencephalic progenitor cells into dopaminergic neurons in vitro. More importantly, after transplanted into the striatum of parkinsonianrats, only pre-differentiated grafts resulted in an elevated production of dopamine in the transplanted site and the amelioration of behavioralimpairments of the parkinsonian rats. Unlike pre-differentiated progenitors, grafted intact progenitors rarely differentiated into dopaminergicneurons in vivo and emigrated actively away from the transplanted site.These data demonstrates the importance of pre-differentiation of human progenitor cells before transplantation in enhancing therapeuticpotency for Parkinson's disease.

It has been reported recently that the immunosuppressant FK506 produced neurotrophic and neuroprotective effects on dopaminergic neurons in vitro and in vivo. We investigated whether tripchlorolide, an immunosuppressive extract of Chinese herb Tripterygium wilfordii Hook F, could exert similar neurotrophic and neuroprotective effects similar to those of FK506. It was found that tripchlorolide promoted axonal elongation and protected dopaminergic neurons from a neurotoxic lesion induced by 1-methyl-4-phenylpyridinium ion (MPP+) at concentrations of as low as 10-12 to 10-8 M. In situ hybridization study revealed that tripchlorolide stimulated brain-derived neurotrophic factor (BDNF) mRNA expression. In vivo administration of tripchlorolide (1ug/kg, ip) for 28 days effectively attenuated the rotational behavior challenged by D-amphetamine in the model rats by transection of the medial forebrain bundle. In addition, tripchlorolide treatment (0.5 or 1ug/kg/day for 28 days) increased the survival of dopaminergic neurons in substantia nigra pars compacta by 50 and 67%, respectively. Moreover, tripchlorolide markedly prevented the decrease in amount of dopamine in the striatum of model rats. Taken together, our data provide the first evidence that tripchlorolide acts as a neuroprotective molecule that rescues MPP+ or axotomy-induced degeneration of dopaminergic neurons, which may imply its therapeutic potential for Parkinson’s disease. The underlying mechanism may be relevant to its neurotrophic effect and its efficacy in stimulating the expression of BDNF.

This study investigated the proliferation and differentiation of adult neural progenitor cells (aNPCs) derived from the striatum and substantianigra (SN) of parkinsonian rats. We found that aNPCs isolated from the two areas of parkinsonian rats readily formed nestin-enrichedneurospheres in vitro and exhibited an ability to differentiate into either neurons or astrocytes. Injection of epidermal growth factor (EGF)and basic fibroblast growth factor (bFGF) into the striatum of parkinsonian rats prior to the harvesting striatal aNPCs significantly increasedthe neurosphere formation rate and multiple differentiation capacity of these aNPCs when cultured in vitro. These data suggest that striataland nigral adult NPCs in parkinsonian rats retain the abilities of proliferation and differentiation in vitro. In addition, exogenously appliedgrowth factors could up-regulate the developmental potential of aNPCs. We conclude that our data supports the notion that endogenous cellreplacement therapies may be useful for the future treatment of Parkinson’s disease (PD).

Electroacupuncture (EA) has been used in China for many years to treat Parkinson’s disease (PD) with reportedly effective results. However, the physiological and biological mechanism behind its effectiveness is still unknown. In the present study, different frequencies of chronic EA stimulation (0, 2, 100 Hz) were tested in a partially lesioned rat model of PD which was induced by transection of the medial forebrain bundle (MFB). After 24 sessions of EA stimulation (28 days after MFB transection), dopaminergic neurons in the ventral midbrain were examined by immunohistochemical staining, and brain-derived neurotrophic factor (BDNF) mRNA levels in ventral midbrain were measured by in situ hybridization. The results show a marked decrease of dopaminergic neurons on the lesioned side of the substantia nigra (SN) comparing with the unlesioned side. Zero Hz and 2 Hz EA stimulation had no effect on the disappearance of dopaminergic neurons. However, after 100 Hz EA, about 60% of the tyrosine hydroxylase (TH)-positive neurons remained on the lesioned side of the SN. In addition, levels of BDNF mRNA in the SN and ventral tegmental area (VTA) of the lesioned side were significantly increased in the 100 Hz EA group, but unchanged in the 0 and 2 Hz groups. Our results suggest that long-term high-frequency EA is effective in halting the degeneration of dopaminergic neurons in the SN and up-regulating the levels of BDNF mRNA in the subfields of the ventral midbrain. Activation of endogenous neurotrophins by EA may be involved in the regeneration of the injured dopaminergic neurons, which may underlie the effectiveness of EA in the treatment of PD.

Neurotrophic factors, such as nerve growth factorand brain-derived neurotrophic factor, are members of thestructurally related neurotrophin family that play importantroles in pain modulation. Although there are also indicationsfor the involvement of glial cell line-derived neurotrophicfactor (GDNF), it is unclear whether and how GDNF is involvedin inflammatory pain. In the present study, we studiedthe expression pattern of GDNF in dorsal root ganglia (DRG)and spinal cord, using confocal microscopy. We demonstratethat GDNF is well associated with nonpeptidergic pain pathwayand that GDNF could possibly be anterogradely transportedfrom DRG neurons to superficial spinal cord dorsalhorn. We also studied the dynamic changes of GDNF expressionin rats during chronic inflammation using injection ofcomplete Freund's adjuvant as a model of chronic pain. Wefound that GDNF was down-regulated in both dorsal rootganglia and spinal cords 2 weeks after arthritis induction. Toassess the impact of this down-regulation on pain transmission,we used a function-blocking antibody against GDNFdelivered intrathecally in the same chronic-pain animal models.Injection of this antibody to GDNF produced no immediateeffect, but decreased the delayed, bilateral hyperalgesiainduced from a unilateral injection of complete Freund’s adjuvant.The effect of this antibody coincided with the downregulationof GDNF immunoreactivity in response to inflammation,suggesting that GDNF supports biochemicalchanges that contribute to hyperalgesia. © 2003 IBRO. Publishedby Elsevier Science Ltd. All rights reserved.