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Objective. To explore the efficacy and safety of pramipexole sustained release (SR) versus pramipexole immediate release (IR) in treating nocturnal symptoms in levodopa-treated Chinese patients with advanced Parkinson's disease (PD) and sleep disturbances. Method. SUSTAIN was an open-label, randomised, active-controlled parallel group exploratory pilot study (NCT03521635). A total of 98 patients were randomly allocated (1 : 1) to either pramipexole SR (n = 49) or pramipexole IR (n = 49) groups. The primary endpoint was a change from baseline in PD Sleep Scale 2nd version (PDSS-2) total score at 18 weeks. A reduction in score represents improvement. Secondary endpoints included Nocturnal Hypokinesia Questionnaire, Scales for Outcomes in PD Sleep Scale, Early Morning Off (EMO), Epworth Sleepiness Scale, PD Questionnaire-8, and responder rates as measured by PDSS-2 total score (<18), EMO scores (≥1 point change), Clinical Global Impression Improvement scale, and Patient Global Impression-Improvement scale. Other endpoints included motor complications (MDS-UPDRS part IV) score. Adverse events were evaluated for each group. Results. The mean pramipexole dose for both groups was 1.5 mg/day at week 18, and the mean changes in PDSS-2 total score for pramipexole SR and IR were –13.7 (95% CI –16.0 to –11.4) and –14.4 (–16.8 to –12.0) (difference of 0.7; p = 0.688). Change from baseline for both groups achieved the minimal clinical important difference threshold (MCID = –3.44). No significant difference was observed in change from baseline for other measures of sleep-related disturbances or responder rates. For motor complications, a greater improvement in MDS-UPDRS part IV score was observed in pramipexole SR over IR (–3.4 vs –2.3; treatment group difference: –1.1; p = 0.036). Both groups had comparable safety profiles. Conclusion. In Chinese patients with advanced PD and sleep disturbances, pramipexole SR and IR have similar benefits in the treatment of nocturnal symptoms and safety, and an improvement from baseline in nocturnal symptoms was observed regardless of pramipexole formulation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To study the effects and mechanism of homocysteine(Hcy) on Parkinson''sdisease(PD) induced by 6-hydroxydopamine (6-OHDA) in vivo. Methods: Forty rats were divided into 4 groups. 6-OHDA or the solvent of 6-OHDA was focally administrated to induce PD, 2 h later Hcy or 0.9% sodium chloride was administrated in the ipsolateral substantial nigra(SN). We used behavioral testing, Immolunohistochemical techniques, biochemistry techniques to detect the injury of SN. Results: The rotary turns of PD rats induced by 6-OHDA showed significant increase after treatment with Hcy compared with the controls(P < 0.05). Also the numbers of tyrosine hydroxylase(TH)-stained neurons were decreased, and dendrites were fragmented and truncated. Free radicals were increased and antioxidant enzymes decreased. Conclusion: Focal infusion of Hcy into the SN increased the vulnerability of the dopaminergic neurons to 6-OHDA-induced degeneration, it seems that the endangering effect of Hcy is due to exacerbating oxidative stress. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the apoptosis of dopaminergic neurons and the protective effect of nicotine in 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson''s disease. Methods: The mouse model of Parkinson''s disease were formed by MPTP(30 mg/kg/d×7, i.p.); and the loss and apoptosis of dopaminergic neurons was observed by Tyrosine Hydroxylase (TH) and TUNEL stains. In “Nicotime plus MPTP” group, mice were pretreated with nicotine before MPTP injection. The putative protective effect of nicotine was analyzed. Results: The number of TH-positive cells decreased during MPTP treatment. Apoptotic neurons began to appear after three injections of MPTP and peaked on the 8 th day. In the MPTP-intoxicated mice treated with nicotine, the loss of TH-positive cells was significantly less than that of MPTP-treated group(30 mg/kg/d × 7)(P <0.05). Conclusion: The chronic treatment of MPTP can induce the apoptosis of dopaminergicneurons in substantia nigra, and nicotinemight have a neuroprotecitve effect on dopaminergic neurons against MPTP toxicity. [Copyright &y& Elsevier]

Abstract: The neuroprotective effects of erythropoietin on 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in cultured PC12 cells as well as the underlying mechanism were investigated. Treatment of PC12 cells with MPP+ caused the loss of cell viability, which was associated with the elevation in apoptotic rate, the formation of reactive oxygen species and the disruption of mitochondrial transmembrane potential. It was also shown that MPP+ significantly induced upregulation of Bax/Bcl-2 ratio and activation of caspase-3. In contrast, erythropoietin reversed these phenotypes and had its maximum protective effect at 1 U/ml. The effect of erythropoietin was mediated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway since erythropoietin failed to rescue cells from MPP+ insult in the presence of the PI3K inhibitor, LY 294002. In addition, the downstream effector of PI3K, Akt, was activated by erythropoietin, and Akt activation was inhibited by LY 294002. Furthermore, the effect of erythropoietin on reactive oxygen species levels was also blocked by LY 294002. These results show that erythropoietin may provide a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative diseases such as Parkinson disease. [Copyright &y& Elsevier]

Abstract: In the absence of a cure for Parkinson''s disease, development of preventive medications for this devastating disease is particularly encouraged. Dl-3-n-butylphthalide (NBP), an established natural antioxidant for clinical stroke treatment in China, can reportedly reduce beta-amyloid-induced neuronal toxicity in cultured neuronal cells, and attenuate neurodegenerative changes in aged rats. However, whether or not NBP confers neuroprotection in parkinsonian models is still unknown. In this study, we investigated the effects of NBP in rotenone models for Parkinson''s diseases. In a cellular model, pretreatment with NBP enhanced cell viability by decreasing nuclear fragmentation, retaining mitochondrial membrane potential, and preventing reactive oxygen species (ROS) from generation. In a rodent model, 2-week treatment with NBP was able to ameliorate apomorphine-evoked rotations by 48% and rescue dopaminergic (DA) neurons by 30% and striatal DA terminal by 49%. Furthermore, NBP upregulated the vesicular monoamine transporter 2 gene expression in vitro and in vivo. Together, NBP protects DA neurons likely by reducing oxidative stress, offering an alternative neuroprotective medication for Parkinson''s disease. [Copyright &y& Elsevier]

Several studies have shown functional improvements, neuroprotective, and neuroregenerative effects after mesenchymal stem cells transplantation to parkinsonian animal models. However, questions remain about the safety, feasibility, and long-term efficacy of this approach. In this study, we investigated migration, therapeutic, tumorigenesis, and epileptogenic effects of human umbilical cord mesenchymal stromal cells (HUMSCs) 1 year after transplantation into rotenone-induced hemiparkinsonian rats. Our data indicated that DiI-labeled HUMSCs migrated in the lesioned hemisphere, from corpus striatum (CPu) to substantia nigra. By integrating with host cells and differentiating into NSE, GFAP, Nestin, and tyrosine hydroxylase-positive cells, HUMSCs prevented 48.4% dopamine neurons from degeneration and 56.9% dopamine terminals from loss, both correlating with improvement of apomorphine-induced rotations. The CD50 and CD97 value of pentylenetetrazol and semiquantitative immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), β-catenin, C-myc, and NF-κB expression showed no significant difference between HUMSCs transplanted and untransplanted groups, whereas the expressions of Bcl-2 and P53 in the grafted CPu were upregulated by 281% and 200% compared to ungrafted CPu. The results of this long-term study suggest that HUMSCs transplantation, 1 of the most potential treatments for Parkinson''s disease, is an effective and safe approach. [Copyright &y& Elsevier]

Abstract: Dopaminergic neurons are lost mainly through apoptosis in Parkinson''s disease. Insulin like growth factor-1 (IGF-1) inhibits apoptosis in a wide variety of tissues. Here we have shown that IGF-1 protects PC12 cells from toxic effects of 1-methyl-4-phenylpyridiniumion (MPP+). Treatment of PC12 cells with recombinant human IGF-1 significantly decreased apoptosis caused by MPP+ as measured by acridine orange/ethidium bromide staining. IGF-1 treatment induced sustained phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) as shown by western blot analysis. The anti-apoptotic effect of IGF-1 was abrogated by LY294002, which indirectly inhibits phosphorylation of GSK-3beta. Lithium chloride (LiCl), a known inhibitor of GSK-3beta, also blocked MPP+-induced apoptosis. Finally, although IGF-1 enhanced phosphorylation of extracellular signal-regulated kinases ERK1 and 2 (ERK1/2), PD98059, a specific inhibitor of ERK1/2, did not alter the survival effect of IGF-1. Thus, our findings indicate that IGF-1 protects PC12 cells exposed to MPP+ from apoptosis via the GSK-3beta signaling pathway. [Copyright &y& Elsevier]

Abstract: The hallmarks of Parkinson''s disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson''s disease. [Copyright &y& Elsevier]