The role of nerve growth factor inducible protein B in the pathogenesis of levodopa-induced dyskinesias

Objective: To study the role of the expression of nerve growth factor inducible protein B gene (NGFI-B) in striatum in the pathogenesis of levodopa-induced dyskinesias (LID). Methods: The rat model of LID was treated with SCH 23390(1 mg/kg ip,a dopamine D1 antagonist) and haloperidol (1 mg/kg ip,a dopamine D2 antagonist) respectively. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure the expression of NGFI-B mRNA in striatum and the behavior changes were observed. Results: After treatment with SCH23390, abnormal involuntary movement (AIM) in LID rats was decreased (P<0.05) and the expression of NGFI-B mRNA in striatum did not change significantly. After treatment with haloperidol, the changes of AIM in LID rats were not significant and the expression of NGFI-B mRNA was increased significantly(P<0.01). Conclusion: LID is associated with over-expression of NGFI-B in striatum. Abnormal activity in the direct pathway and the basal ganglia circuit could be involved in the occurrence of LID.

Influences of levodopa on expression of N-methyl-D-aspartate receptor-1-subunit in the visual cortex of monocular deprivation rats

AIM: Many studies have demonstrated N-methyl-D- aspartate receptor-1-subunit (NMDAR1) is associated with amblyopia. The effectiveness of levodopa in improving the visual function of the children with amblyopia has also been proved. But the mechanism is undefined. Our study was to explore the possible mechanism.METHODS: Sixty 14-day-old healthy SD rats were randomly divided into 4 groups, including normal group, monocular deprivation group, levodopa group and normal saline group, 15 rats each. We sutured all the rats' unilateral eyelids except normal group to establish the monocular deprivation animal model and raise them in normal sunlight till 45-day-old. NMDAR1 was detected in the visual cortex with immunohistochemistry methods, Western Blot and Real time PCR. LD and NS groups were gavaged with levodopa(40mg/kg) and normal saline for 28 days respectively. NMDAR1 was also detected with the methods above.RESULTS: NMDAR1 in the visual cortex of MD group was less than that of normal group. NMDAR1 in the visual cortex of LD group was more than that of NS group.CONCLUSION: NMDAR1 is associated with the plasticity of visual development. Levodopa may influence the expression of NMDAR1 and improve visual function, and its target may lie in the visual cortex.

Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias:a retrospective case-control study

Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.

Effects of levodopa on dopaminergic neurons and induced dyskinesia A radio-imaging study

BACKGROUND: Radio-imaging has been used in neurological diagnosis,in particular for extrapyramidal disease.Moreover,it has been extensively utilized for early diagnosis of Parkinson’s disease (PD) patients and in animal studies.However,it has rarely been utilized to assess drug-induced side effects in PD.OBJECTIVE: To investigate changes in dopamine transporter expression in a rat model of PD through the use of radio-imaging taking 99mTc-TRODAT-1 as an imaging agent,and to explore the effect of levodopa (L-dopa) on dopaminergic neurons and the possible mechanisms of dyskinesia induction.DESIGN,TIME AND SETTING: A randomized,controlled,animal study was performed at the Laboratory of Department of Nuclear Medicine,Soochow University from April 2006 to June 2007.MATERIALS: 6-hydroxydopamine was purchased from Sigma,USA and L-dopa was purchased from Shanghai Fuda Pharmaceutical,China.99mTcO4-fresh elutriant was provided by the Department of Nuclear Medicine,First Hospital Affiliated to Soochow University.TRODAT-1 image kit was provided by Jiangsu Atomic Energy Research Establishment,China.The SN-695B radioimmunoassay gamma counter was purchased from Shanghai Hesuo Rihuan Photoelectric Instrument,China.The AZ-CA256eZ-Scope portable γ camera was purchased from Anzai Medical,Japan.METHODS: A total of 34 healthy,male,Sprague Dawley rats were selected.Thirty were used to establish a PD model by injecting 6-hydroxydopamine into the right medial forebrain bundle,and four were injected with normal saline and served as the sham-surgery group.At the end of 4 weeks,21 successful PD models were selected and randomly assigned to the L-dopa (n = 15,20 mg/kg per day),model (n = 6,normal saline),and sham-surgery (n = 4,no treatment) groups.After 1 month of treatment,involuntary movement was evaluated twice weekly in each rat.A total of 0.2 mL 99mTc-TRODAT-1 was injected into the tail vein 2 days following drug termination,and images of dopamine transporters were acquired 2 hours later.The rats were sacrificed and the ratios of specific radioactivity uptake were calculated.MAIN OUTCOME MEASURES: Manifestations of abnormal involuntary movement (AIM) were observed and total AIM scores were calculated.Images of dopamine transporters were acquired using an eZ-Scope portable γ camera,and radioactive γ quantification of 99mTc-TRODAT-1 in the rat brains was assayed.The ratios of the left and right corpora striata were determined.The number and function of dopamine transporters was evaluated according to specific radioactivity uptake ratio (R) from the left and right corpora striata.RESULTS: Of 15 PD rats,nine exhibited AIM following L-dopa treatment: five scored > 20,i.e.,severe grade,four scored 8–16,mild grade,and the remaining exhibited normal behavior.There were no differences in specific radioactivity uptake of dopamine transporter between the left and right corpora striata in the sham-surgery rats,and the images were clear and symmetrically distributed.Specific radioactivity uptake of the normal side (left) was significantly greater than the lesioned side (right) in the model group rats (P < 0.01),and the R value was significantly increased compared with the sham-surgery group (P < 0.01).The radio-ligand accumulation in the right corpus striatum was sparse.In the L-dopa group,specific radioactivity uptake was significantly decreased in the lesioned (right) side of the AIM rats,and the R value was increased compared with the model group (P < 0.05).The amount of radio-ligand in the right corpus striatum was diminished.The R value was significantly reduced in the non-AIM rats compared with the AIM rats (P < 0.05),and specific radioactivity uptake was significantly increased in the lesioned (right) side compared with the normal side (P < 0.05).Moreover,radio-ligand accumulation was observed in the right corpus striatum,and differences in radio-ligand accumulation between the two sides were reduced.CONCLUSION: Following L-dopa treatment,the number and function of dopamine transporter in some PD rats were reduced.L-dopa was shown to be toxic to dopaminergic neurons and induced dyskinesia.

Levodopa/Carbidopa Intestinal Gel for Treatment of Advanced Parkinson’s Disease: An Update on the Effects of Cognitive Functions

Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.

Comparative study of standardized Centella asiatica and combination of levodopa and benzerazid HCl on Parkinson′s model zebrafish

OBJECTIVE To investigate the motility,dopamine,serotonin and pro-BDNF level of Centella asiatica(CA)comparable to the combination of levodopa and benzerazid HCL on zebrafish model Parkinson′s.METHODS Rotenone 5μg·L-1 induced to adult zebrafish(8months)for 28 dto made zebrafish model Parkinson′s.CA concentration were used 5 and 10μg·mL-1.The combination of levodopa 100 g and 25 mg benzerazid(L-DOPA agonist)was given at 1 μg·mL-1 at the same time to rotenone,and CA as well.Motility assessment conducted for every 7dstarted on day 0until day 28.Five fish were subjected in the 2L tank(25cm×16.5cm×12cm).Three vertical lines were drawn on the tank at equal distances,dividing the tank into four zones(the length of each zone was 6.25cm).Locomotor activity was measured for 5min by counting the number of lines that adult zebrafish crossed.Fish were sacrificed by decapitating on ice water.Dopamine level measured from whole brain by ELISA,serotonin and pro-BDNF by immunoreactivity at substantia nigra.RESULTS The locomotor activity of rotenone treated fish were significantly decrease starts at 7 dcompared to control group.Interestingly on 10μg·mL-1 group there are increasing motility start at day 7 and slightly decrease until day 28,but on L-DOPA group increasing motility at day 7 followed by decreasing motility significantly(P<0.05)until day 28.Dopamine level of rotenone group decreased compared to control group,CA 10μg·mL-1 and L-DOPA group increased significantly to rotenone group which CAμg·mL-1 higher than L-DOPA group.Serotonin and pro-BDNF level had the same profile.Its significantly increased on rotenone group compared to control group.Serotonin on group with CA administration significantly decreased compared to rotenone group,while rotenone plus CA 10μg·mL-1 had no significant differet to L-DOPA group(P>0.05).Pro-BDNF on rotenone with CA 5μg·mL-1 had no significant difference,while compare to rotenone with CA 10-1 μg·mLgroup and L-DOPA group were significantly different(P<0.05).CONCLUSION Rotenone produces reliable Parkinson′s zebrafish model by decreasing motility and dopamine level.CA was more stable,increasing motility than L-DOPA administration.CA and L-DOPA increased dopamine level,but decreasing serotonin and pro-BDNF.

Recent advances in pharmacological therapy of Parkinson’s disease: Levodopa and carbidopa protective effects against DNA oxidative damage

Parkinson’s disease is one of the most common progressive neurodegenerative disorder. It is characterized by the depletion of dopamine in the dopaminergic neurons of the striatum of the brain. Pharmacological treatment involves the administration of a dopamine precursor, levodo- pa (L-Dopa), which crosses the blood-brain barrier and replaces the loss of dopamine in the brain. One of the main drawbacks of the ad- ministration of L-Dopa is its short half-life, due to the presence of enzymes, such as the amino acid decarboxylase (AADC), able to rapidly me- tabolize L-Dopa. For this reason the intake of L-Dopa takes always place together with an AADC inhibitor such as carbidopa. The assumption of carbidopa increases L-Dopa half-life, but several patients need to increase the dosage of the pharmacological therapy during the progression of the disease. Another area of dispute is represented by the possibility that L-Dopa can exert a toxic effect on the cells, both in peripheral and in central nervous system, increasing the production of ROS following its conversion to dopamine. Past studies reported toxic effects of L-Dopa in vitro and show conflicting data in in vivo experiments. More recent studies have however shown that L-dopa may exert a protective and antioxidant effect on dopaminergic cells, and its combination with carbidopa in pharmacological treatment amplifies antioxidant capability.

Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?

Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark&reg;was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease

Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented. Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism. Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels. Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

NP-6 Rb Fraction Combined with Levodopa Prevent Parkinson Disease by Protecting Neurovascular Unit

Object:Parkinson disease(PD)is the second most common progressive neurodegenerative disorder.The available therapies for PD only treat the symptoms of the disease,without neuroprotective and disease-modifying effects.Drugs that enhance intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay of treatment for motor symptoms.Levodopa(L-DOPA)provides the greatest symptomatic benefit,but longterm using not only gradually loses its efficacy but also is associated with motor and non-motor complications,limiting function and reduce quality of life in PD patients,due to the disease progresses and medication.We previously showed that Rb fraction of ginsenosides blocks the PD progression and prevents the development and expression of L-DOPA-induced side effects.Given multiple cell types and impaired blood brain barrier(BBB)involve in the PD’S pathogenesis,this study further explores whether Rb alone or combined with L-DOPA could modify PD and protect neurovascular unit.Methods:Their anti-Parkinsonian activity was evaluated in rotenonelesioned rats.Rb and L-DOPA alone or both combination were given once a day 30 min before rotenone administration until occurrence of impaired motor function in controls,and motor deficits were surveyed at regular intervals.To determine potential persisted effect of treatments,at 3 days after stopping all the medications the last motor performances were tested and then brains were collected for assay of status of neurovascular unit and neuroinflammation.The protective effects of Rb,L-DOPA,and the combination were compared.Results:Rotenone-induced PD model rats displayed a series of motor behavior disorders,such as impaired forelimb grip,and lost balance,as well as reduced spontaneous activity and exploration behavior.Consistently,dopaminergic neuron terminals lost in dorsal-lateral striatum,while the cell bodies in the substantia nigra pars compacta largely spared,indicating dopamine nerve tip injury preceding cell body injury.This feature is highly consistent with clinical neuropathological changes in PD.Moreover,damaged astrocyte,activated microglia,and impaired BBB occurred in the striatum,with abundant infiltration of peripheral immune cells.Strikingly,Rb significantly prevented all those pathological behaviors,and morphological and cellular alterations,whereas L-DOPA only improved the motor performances of the PD rats and even exacerbated the BBB impairment.Interestingly,combination of Rb and L-DOPA showed the better protective effects than Rb alone,nearly completely blocking all the pathological manifestations.Conclusion:Rb,especially its combination with levodopa,can significantly prevent the development of PD.Direct protection of the components of neurovascular unit and consequently maintaining structural and neurochemical homeostasis may contribute to the disease-modifying effect of Rb.Our findings show a favorable application prospect of Rb,especially together with L-DOPA,in treating PD.

Mechanism of over-activation in direct pathway mediated by dopamine D_1 receptor in rats with levodopa-induced dyskinesias

Objective To study the changes of prodynorphin (PDyn) gene expression and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) phosphorylation in rats with levodopa-induced dyskinesias (LID),and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. Methods Parkinson’s disease (PD) rats were received levodopa (10 mg/kg,i.p.) for 28 d to get the LID rats. According to the behavior scale,LID rats were divided into mild (n=8) and severe (n=16) groups. On day 29,8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 (0.1 mg/kg) 15 min before levodopa treatment (MK-801 group,n=8). The normal rats received same course and dosage of levodopa as the control group (n=8). Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR,respectively. Results The levels of PDyn mRNA and phospho-Thr-34 DARPP-32 increased significantly in LID rats compared with control rats (P<0.01),and they also increased markedly in severe LID group compared with mild group (P<0.01). Conclusion Phospho-Thr-34 DARPP-32 level was increased in LID rats,which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor.

Effects of compound rehmannia formula on dopamine transporter content in the corpus striatum of Parkinson's disease rats treated with levodopa

Long-term application of levodopa (L-3,4-dihydroxyphenylalanine,L-DOPA) for Parkinson's disease can lead to adverse effects and reduce the amount of dopamine transporter (DAT) in the corpus striatum.The present study attempted to verify whether increasing the amount of DAT can reduce the adverse effects of L-DOPA.The specific radioactive uptake value of DAT in the corpus striatum of the lesioned hemisphere was significantly decreased,but was significantly increased following administration of compound rehmannia formula [Radix rehmanniae preparata (prepared rehmannia root),Concha margaritifera usta (nacre),Radix paeoniae alba (white peony alba),Radix salviae miltiorrhizae (Danshen root),Scorpio (scorpion),green tea] for 4 weeks.The changes in DAT 125I-beta-carbomethoxy-3 beta-(4-iodophenyl) tropane autoradiography were consistent with those in radioactivity.The results revealed that the compound rehmannia formula can reduce the adverse effects of L-DOPA in treating Parkinson's disease,possibly by increasing the amount of DAT.

Determination of levodopa in pharmaceutical preparations by irreversible biamperometry

在铂电极在金电极和高锰酸盐的减小基于 levodopa 的 electrocatalytic 氧化，新奇流动注射不可逆的 biamperometric 方法在在二个电极之间强加的 0 V 的潜在的差别下面为 levodopa 的决心被开发。在 H2SO4 答案，在水流和 levodopa 的集中之间的线性关系与 0.012 mg/L 的察觉限制从 0.04 mg/L 在范围被获得到 20 mg/L。建议方法在药品的准备被用于 levodopa 的决心。

Quantitative Autoradiographic Study on Receptor Regulation in the Basal Ganglia in Rat Model of Levodopa-induced Motor Complications

In order to study neurotransmitter receptor regulation in the basal ganglia involved in the functional changes underlying levodopa-induced motor complications, quantitative autoradiography was used to observe receptor bindings of dopamine D1 and D2, N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and amino butyric acid (GABA) in the basal ganglia of rats that had unilateral nigrostriatal lesions and had been chronically treated with levodopa until motor complications developed. The rats were randomly assigned to three groups: normal, denervated and treatment-complicated groups. The results showed that response duration to levodopa became progressively shorter and abnormal involuntary movement (AIM) score was progressively increased during the course of levodopa treatment. Chronic treatment augmented D1 receptors more than denervation, and reduced D2 receptors that were also increased by dopamine den- ervation. Striatal NMDA receptors were substantially up-regulated in the treatment-complicated group. Levodopa treatment did not change receptors of nigral AMPA, pallidal GABA, and subthalamic GABA, which remained the same as that in denervation group. However, chronic treatment reversed the increase of nigral GABA receptors caused by the lesion. It was concluded that a shortening of response duration and AIM mimicked levodopa-induced motor complications of Parkinson's patients. These data suggested that up-regulation of dopamine D1 and NMDA receptors in the striatum leads to an imbalance of stimulation through the striatal output pathways, which is associated with levodopa-induced motor complications.

Exogenous Levodopa Increases the Neuro-retinal Dopamine of Guinea Pig Myopic Eyes in vitro

Purpose:In our previous work,it has been shown that intraperitoneal injection of L-DOPA can inhibit the development of occlusion myopia in guinea pigs,and increase levels of retinal dopamine.The aim of this study was to investigate whether exogenous L-DOPA can be converted into dopamine in cultured retina of guinea pig eyes subjected to visual deprivation,and to evaluate whether müller cells are involved in the processing of retinal dopamine induced by L-DOPA.Methods:Fifty-eight guinea pigs were randomly divided into 2 groups at the age of 4 weeks:normal control and visual deprivation.Form deprivation was induced with translucent eye shields over the right eye,and lasted for ten days.Corneal curvature,refraction and axial length were measured in all animals.In vitro,neuro-retina and müller cell were cultured,and L-DOPA was added to the culture medium at three concentrations:1 μM,10 μMand 100 μM.Subsequently,dopamine content was evaluated by high-performance liquid chromatography,and apoptotic cells were identified by TUNEL staining.Results:Ten days of occlusion caused the affected eyes to elongate and become myopic in guinea pigs.Compared with the deprivation group,10 μML-DOPA treament significantly raised dopamine content in cultured retina and müller cells (P<0.05).However,1 μMand 100 μML-DOPA treatment caused no increase in dopamine levels(P>0.05).Apoptotic nuclei were detected in the ganglion cell layer (92.5%±8.3%) and inner nuclear layer (46.8%±9.1%)of cultured retina treated with 100 μML-DOPA.Moreover,100 μML-DOPA also caused apoptosis of retinal müller cells,at a mean rate of 59.4 ±11.3%.Conclusion:.Our results suggest that exogenous L-DOPA can cause an increase in retinal dopamine in form-deprived guinea pig eyes in vitro,and that müller cells are involved in the increase in retinal dopamine.

Capillary electrophoresis-chemiluminecence detection of levodopa and benserazide in Medopar tablet

化合光(17 号元素氯的化学符号) 被开发了的为用毛状的电气泳动(CE ) 的 benserazide 和 levodopa 的同时测定的一个新奇方法。在最佳的条件下面，检测极限(S/N = 3 ) 为 levodopa 是为 benserazide 和 0.12 μ g /mL 的 1.85 μ g /mL。这个方法成功地在 Medopar 药片被用于 benserazide 和 levodopa 的决心，结果证明检测价值根据由正式方法的那些。

Effect of Antisense FosB and CREB on the Expression of Prodynor- phin Gene in Rats with Levodopa-induced Dyskinesias

The effects of antisense FosB and CREB intra-striatum injection on the expression of prodynorphin (PDyn) gene in striatal neurons of Levodopa-induced dyskinesias (LID) rats with Parkinson disease (PD) were explored. PD model in rats was established by 6-OHDA microinjection stereotaxically. The rats were treated with chronic intermittent Levodopa celiac injection for 28 days to get the LED rats. Antisense FosB and cAMP response element-binding protein (CREB) were injected into striatum of all rats respectively. In situ hybridization was used to measure the changes in the expression of PDyn mRNA in striatum and behavior changes were observed. The results showed after administration of antisense FosB, abnormal involuntary movement (AIM) was decreased and the expression of PDyn mRNA in striatum was increased in LID rats as compared with sense FosB group (P<0.01, respectively). As compared with the control group, the expression of PDyn mRNA in striatum was decreased by antisense CREB-treated LID group (P<0.01) and compared with sense CREB treated LID group, antisense CREB-treated LID group showed no changes in AIM scores and the expressions of PDyn mRNA (both P>0.05). In conclusion, FosB protein, which replaced the CREG, could regulate the expression of PDyn mRNA and play critical role in the pathogenesis of LID.

Levodopa methyl ester increases nerve growth factor expression in visual cortex area 17 in a feline model of strabismic amblyopia

In the present study, a feline model of strabismic amblyopia was established during a sensitive developmental period, and the influence of levodopa methyl ester and levodopa on nerve growth factor expression in the visual cortex (area 17) was compared. Pattern visual-evoked potential and immunohistochemistry results showed that levodopa methyl ester and levodopa treatment shortened P100 wave latency, increased P100 amplitude, and increased the number of endogenous nerve growth factor-positive cells in visual cortex levels. In particular, the effects of levodopa methyl ester were superior to levodopa treatment.

Effect of Levodopa Chronic Administration on Behavioral Changes and Fos Expression in Basal Ganglia in Rat Model of PD

To study behavioral character and changes of neuronal activity in the basal ganglia of rat model of levodopa-induced dyskinesia, unilateral 6-hydroxydopamine lesioned rat model of Parkinson disease (PD) was treated with levodopa/benserazide twice daily for 4 weeks and the behavior observed on the 1st, 3rd, 4th, 7th, 9th, 10th, 14th, 21st and 28th day The animals were sacrificed and immunohistochemical technique was used to measure the changes of Fos expression in the caudate putamen (CPU), globus pallidus (GP) and sensorimotor area of cerebral cortex 2 h after the last treatment The results showed that pulsatile treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movement (AIM), including stereotypy (limb dyskinesia, axial dystonia and masticatory dyskinesia) towards the side contralateral to the dopamine-denervated striatum and increased contraversive rotation The motor pattern of each subtype was highly stereotypic across individual rats, and the proportion of each subtype was not consistent among individual rats Fos positive nuclei in the CPU and GP were increased by levodopa acute administration, and more remarkably in the CPU, but not in the cerebral cortex After repeated levodopa treatment, Fos positive nuclei were reduced remarkably in the CPU, but were increased in the GP and cerebral cortex It was concluded that the neural mechanisms underlying levodopa induced AIM in rat model of PD was very similar to those seen in levodopa-induced dyskinesia (LID) in PD patients and MPTP-lesioned monkeys, and increased striatopallidal neuronal activity might be involved in occurrence of

Liquid Subcutaneous Levodopa-Carbidopa ND0612 Effects on Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled “Liquid subcutaneous Levodopa-Carbidopa ND0612 effects on motor symptoms in individuals with Parkinson’s Disease: A systematic review and meta-analysis”, the objective was to conduct a systematic review with meta-analysis to investigate the effects ND0612 24-hour dosing regimen has on motor symptoms in individuals with Parkinson’s Disease (PD). Introduction: ND0612 is a novel minimally invasive continuous subcutaneous delivery system of liquid Levodopa-Carbidopa being investigated for the treatment of PD in individuals experiencing motor symptoms. Methods: A systematic literature search was conducted in PubMed, Cochrane, and EBSCO databases to identify randomized controlled trials investigating the effects of ND0612 on motor symptoms in individuals with PD. Outcomes included the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II and Part III scores. Methodological quality was assessed using the Cochrane Grading of Recommendations Assessment, Development, and Evaluation approach. Meta-analysis was performed using a random effects model with the DerSimonian and Laird method to estimate the effects of the ND0612 24-hour dosing regimen on UPDRS Part II and Part III scores. Results: Three studies were included in our review. There were statistically significant reductions in UPDRS Part II scores (mean difference (MD) −3.299;95% confidence interval (CI) −3.438, −3.159) and in UPDRS Part III scores (MD −12.695;95% CI −24.428, −0.962) in the ND0612 24-hour dosing regimen. Results were based on very low certainty of evidence. Conclusion: Based on very low certainty evidence, the ND0612 24-hour dosing regimen is effective at improving motor symptoms in individuals with PD. Our findings suggest that ND0612 is more effective at improving UPDRS Part II and Part III scores in individuals with PD than other pharmacological and non-pharmacological treatments, warranting further study.