Purpose　To summarize the current strategies for the treatment of early and late Parkinson's disease (PD).Data sources　The presented guidelines are based on the review of the literature as well as the author's extensive experience with the treatment of 7000 patients with PD over the past 25 years.Results　An analysis of reported data as well as personal experience suggest that while young patients seem to have a slower progression of the disease, they are at a higher risk for developing levodopa induced complications, such as motor fluctuations and dyskinesias. It is, therefore, prudent practice to delay levodopa therapy, particularly in younger patients, until the PD symptoms become troublesome and interfere with social or occupational functioning. Other strategies, such as the use of deprenyl, amantadine, trihexyphenidyl and dopamine agonists, should be employed before instituting levodopa therapy. Entacopone and dopamine agonists are useful in smoothing out levodopa related motor fluctuations. Surgical interventions, such as pallidotomy and pallidal or subthalamic deep brain stimulation, are effective therapeutic strategies, but should be reserved only for patients in whom optimal medical therapy fails to provide satisfactory control of symptoms.Conclusion　The medical and surgical treatment of patients with PD must be individualized and tailored to the needs of the individual patient.

Modulation by desensitized nicotinic receptors on metabolism of DA in striatum derived from the hemiparkinsonian model

Protective Effects of Procyanidins on 6-OHDA-induced PC12 Cells Injury and its Mechanism Exploration

Objective:To investigate the protective effect of procyanidins(PC)on PC12 cells injured induced by 6-hydroxydopamine(6-OHDA),and then to explore the underlying mechanism. Methods:PC12 cells were treated with 6-OHDA for 24h to establish cell injury model,PC were added in 2 h before 6-OHDA and the PI3K inhibitor LY294002 was added in 0.5 h before PC to detect the mechanism of protection. Pharmacodynamic study of PC in this model were divided into 5 groups:control group,model group(75 μmol·L-16-OHDA),PC-L,M,H group(75μmol·L-16-OHDA+12.5, 25,50 μmol/L);mechanism study of PC in this model were divided into 5 groups:control group,model group(75 μmol/L 6-OHDA),PC-H group,LY group(75 μmol·L-16-OHDA+20 μmol/L LY294002), PC-H+LY group(75μmol·L-16-OHDA+50μmol·L-1 PC +20 μmol·L-1 LY294002). MTT assay was used to detect cell viability,colorimetric method was used to detection of lactate dehydrogenase(LDH) leakage,the total superoxide dismutase(SOD)activity was measured by WST-8 method,JC-1 staining was used to detect the mitochondrial membrane potential. The expression of Akt and p-Akt(Ser473) protein was assayed by Western Blot. Results:OD570 of 1.5×105/mL PC12 cells at 0.82±0.05 was in a good linear range that for the appropriate subculturing concentration;PC12 cells were treated with 6-OHDA for 24 h and its viability decreased with the increase of 6-OHDA concentration,compared with control group,6-OHDA(75 μmol·L-1)damaged cell 49.55±5.32％(P<0.01)for the appropriate model concentration;cells were treated with PC alone for 24 hours without significant toxicity at each concentration,the cell viability was slightly increased at 50 μmol·L-1. Compared with control group, the cell viability,total SOD activity,mitochondrial membrane potential and protein of Akt Ser473 phosphorylation levels decreased in model,while the leakage rate of LDH increased. Compared with the model group,PC(12.5,25,50 μmol·L-1)treatments could improve the morphological damage of PC12 cells induced by 6-OHDA and increase the cell viability,significantly reduce the leakage rate of LDH(P<0.01),increase the activity of total SOD(P<0.01),inhibit the decrease of mitochondrial membrane potential,and increase the expression of p-Akt protein(P<0.01). All of these effects were antagonized by LY294002. Conclusion:Under the experimental conditions,PC has protective effect on 6-OHDA-induced PC12 cells injury,and its mechanism may be related to up-regulation of PI3K/Akt pathway.

Effect of Resveratrol on Motor Dysfunction in Unilateral 6-hydroxydopamine Parkinson's Model Rats and its Underlying Mechanisms

Objective:The present study was designed to investigate the effect of resveratrol (Res)on the motor function of Parkinson's model rats induced by 6-hydroxydopamine(6-OHDA)and to explore its underlying mechanism. Methods:After a week of adaptive feeding,50 male Sprague-Dawley(SD)rats were randomly divided into five groups:sham-operated group,normal group(Res, 30 mg·kg-1),model group(6-OHDA,8μg),6-OHDA+Res low-dose group(15 mg·kg-1,6-OHDA+Res high-dose group(30 mg·kg-1). 6-OHDA 8 μg(2 μg·μL-1)were injected into the substantia nigra of the rats to establish the model of dopaminergic neuronal damage,while the rats of sham group were injected with volume-matched saline with 0.2％ Vitamin C.Rats were pretreated with Res for 1 day before 6-OHDA treatment. Model and sham groups were administered with volume-matched vehicle for 36 days.Rotarod test was applied to evaluate motor function of rats on 7 th,14 th and 21 th day after surgery,open field experiment and grid-walking test applied on 33 th and 35 th day,respectively. Then the rats were sacrificed.Immunohistochemistry was used to detect the number of TH-positive cells in substantia nigra pars compacta(SNc);the protein expression of TH,Bax,Bcl-2,pro-caspase-3, active-caspase-3,p-PDK1 and p-Akt in midbrain were detected by Western blot. Results:The body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of model group were significantly decreased compared with sham group;the protein of Akt phosphorylation levels were decreased while it showed no effect on PDK1,and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly increased,pro-caspase-3 decreased. However,compared with model,the body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of Res high-dose group were markedly increased;the protein of Akt phosphorylation levels were increased while it showed no effect on PDK1, the protein level of BDNF and TrkB were significantly decreased and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly decreased,and pro-caspase-3 were increased.Conclusion:Under the experimental conditions,6-OHDA-induced motor dysfunction and apoptosis in dopaminergic neuronal cells of rats is significantly attenuated by Res,and its potential mechanism may be related to up-regulation of Akt phosphorylation at Ser473 and inhibit the expression of apoptosis-related proteins.

Protective Effects and Mechanism of Icariin on LPS-induced Dopaminergic Neuronal Damage

Objective:To observe the protective effects of Icariin(ICA)on lipopolysaccharide (LPS)-induced dopaminergic(DA)neuronal damage and explore the possible mechanisms. Methods:Thirty SD rats were randomly divided into control,ICA(20 mg·kg-1)alone,model(LPS,5μg), LPS+ICA(10 mg·kg-1)and LPS+ICA(20 mg·kg-1).The DA neuronal damage was induced by injecting LPS into one side of rat midbrain substantia nigra(SN). After seven daily intragastric administration of ICA,rat behavior changes were analyzed by the rotarod test and then brains were collected to detect the expression of tyrosine hydroxylase(TH,a marker of DA neuron)and OX-42(a marker of microglia activation)by double-labelimmunofluorescent analysis. Primary rat midbrain neuron-glia co-cultures were applied to further elucidate the ICA-exerted neuroprotection in vitro. The cultures were randomly divided into control,ICA(0.1μmol·L-1)alone,LPS(10 ng·mL-1), LPS+ICA(0.01 μmol·L-1)and LPS+ICA(0.1 μmol·L-1). LPS-induced DA neuronal damage and microglia activation were evaluated by immunofluorescent analysis and western blot analysis. The levels of NO,TNF-α and IL-1β in the culture supernatantwere measured with Griess reagent and ELISA,respectively. In addition,BV2 cell lines were prepared to investigate the effects of ICA on LPS-induced protein expressions of TLR4,MyD88,p65 and phosphorylated-p65(p-p65). Results:ICA attenuated the loss of DA neurons and microglia activation induced by LPS-injected SN in vivo.Inneuron-glia co-cultures,ICA ameliorated LPS-induced DA neuronal damage and microglia activation. Moreover,ICA reduced LPS-elevated NO,TNF-α and IL-1β production in the culture supernatant. In addition,ICA suppressed LPS-induced activation of TLR4,MyD88 and NF-κBpathways. Conclusion:ICA could afford neuroprotection against LPS-induced DA neurotoxicity both in vivo and in vitro through the inhibition of microglia activation and the subsequent production of neuroinflammatory factors.

左旋多巴试验在帕金森病外科治疗中的价值

目的介绍左旋多巴试验在PD外科治疗中的应用价值.方法对33例PD病人,在进行UPDRS评分和Webster评分后,作一次单剂量左旋多巴试验.先停药12小时以上,然后,一次性口服左旋多巴350mg,每隔30分钟对病人的状态评价一次,共计检查300分钟;后计算病人对左旋多巴的改善率.根据病人临床表现分别作Vim核或Gpi毁损术.结果左旋多巴的大改善率分为0=0%,±=12.5%,+=37.5%,++=50%,+++=75%,++++=100%.本组大改善率为:+4例,++8例,+++9例,++++12例.所有病人的手术结果均为良好.结论左旋多巴试验是PD病人术前准备过程中的一项重要检查.