Mounting lines of evidence have suggested that brain inflammation participates in the pathogenesis of Parkinson's disease. Triptolide is oneof the major active components of Chinese herb Tripterygium wilfordii Hook F, which possesses potent anti-inflammatory andimmunosuppressive properties. We found that triptolide concentration-dependently attenuated the lipopolysaccharide (LPS)-induced decreasein [3H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in primary mesencephalic neuron/glia mixed culture.Triptolide also blocked LPS-induced activation of microglia and excessive production of TNFa and NO. Our data suggests that triptolide mayprotect dopaminergic neurons from LPS-induced injury and its efficiency in inhibiting microglia activation may underlie the mechanism.D 2003 Elsevier B.V. All rights reserved.

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.

Through producing a variety of cytotoxic factors upon activation, microglia are believed to participate in the mediation ofneurodegeneration. Intervention against microglial activation may therefore exert a neuroprotective effect. Our previous study has shown thatthe electro-acupuncture (EA) stimulation at 100 Hz can protect axotomized dopaminergic neurons from degeneration. To explore theunderlying mechanism, the effects of 100 Hz EA stimulation on medial forebrain bundle (MFB) axotomy-induced microglial activation wereinvestigated. Complement receptor 3 (CR3) immunohistochemical staining revealed that 24 sessions of 100 Hz EA stimulation (28 days afterMFB transection) significantly inhibited the activation of microglia in the substantia nigra pars compacta (SNpc) induced by MFBtransection. Moreover, 100 Hz EA stimulation obviously inhibited the upregulation of the levels of tumor necrosis factor (TNF)-a andinterleukin (IL)-1h mRNA in the ventral midbrains in MFB-transected rats, as revealed by reverse transcriptase polymerase chain reaction(RT-PCR). ED1 immunohistochemical staining showed that a large number of macrophages appeared in the substantia nigra (SN) 14 daysafter MFB transection. The number of macrophages decreased by 47% in the rats that received 12 sessions of EA simulation after MFBtransection. These data indicate that the neuroprotective role of 100 Hz EA stimulation on dopaminergic neurons in MFB-transected rats islikely to be mediated by suppressing axotomy-induced inflammatory responses. Taken together with our previous results, this study suggeststhat the neuroprotective effect of EA on the dopaminergic neurons may stem from the collaboration of its anti-inflammatory and neurotrophicactions.D 2004 Elsevier Inc. All rights reserved.

Through producing a variety of cytotoxic factors upon activation, microglia are believed to participate in the mediation ofneurodegeneration. Intervention against microglial activation may therefore exert a neuroprotective effect. Our previous study has shown thatthe electro-acupuncture (EA) stimulation at 100Hz can protect axotomized dopaminergic neurons from degeneration. To explore theunderlying mechanism, the effects of 100 Hz EA stimulation on medial forebrain bundle (MFB) axotomy-induced microglial activation wereinvestigated. Complement receptor 3 (CR3) immunohistochemical staining revealed that 24 sessions of 100Hz EA stimulation (28 days afterMFB transection) significantly inhibited the activation of microglia in the substantia nigra pars compacta (SNpc) induced by MFBtransection. Moreover, 100 Hz EA stimulation obviously inhibited the upregulation of the levels of tumor necrosis factor (TNF)-a andinterleukin (IL)-1h mRNA in the ventral midbrains in MFB-transected rats, as revealed by reverse transcriptase polymerase chain reaction(RT-PCR). ED1 immunohistochemical staining showed that a large number of macrophages appeared in the substantia nigra (SN) 14 daysafter MFB transection. The number of macrophages decreased by 47% in the rats that received 12 sessions of EA simulation after MFBtransection. These data indicate that the neuroprotective role of 100Hz EA stimulation on dopaminergic neurons in MFB-transected rats islikely to be mediated by suppressing axotomy-induced inflammatory responses. Taken together with our previous results, this study suggeststhat the neuroprotective effect of EA on the dopaminergic neurons may stem from the collaboration of its anti-inflammatory and neurotrophicactions.D 2004 Elsevier Inc. All rights reserved.

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.