Progress in research on neuroprotective mechanism of glucagon-like peptide-1 receptor agonists and analogues in Parkinson's disease / 中国生物制品学杂志

@#Parkinson's disease(PD)is the second common neurodegenerative disease that mostly occurs in middle-aged and elderly people. Currently,Levodopa is the main first-line treatment drug,but the long-term efficacy of patients is not good,and even side effects such as“on-off”phenomenon and orthostatic hypotension occur. Glucagon-like peptide-1receptor agonists(GLP-1RA)and analogues are endogenous peptide hormones that can be released into the blood and enter the central nervous system to exert neuroprotection by crossing the blood-brain barrier. Numerous studies have shown that GLP-1RA can improve movement disorders and restore dopaminergic neuron activity in PD. However,the mechanism of GLP-1RA is not yet fully clear. This paper summarized the mechanism of GLP-1RA and its analogues in improving PD movement disorders and restoring dopaminergic neuron activity,and reviewed the aspects of reducing neuroinflammation,inhibiting oxidative stress,inhibiting apoptosis,regulating mitochondrial morphology,increasing neuronal protrusions,enhancing autophagy,and regulating intestinal flora homeostasis,so as to provide new ideas for research of the mechanisms of PD and development of GLP-1RA-related new drugs.

Subjective cognitive decline in idiopathic Parkinson´s disease: A systematic review.

Cognitive symptoms of Parkinson's disease (PD) have been long underestimated, but are some of the most disabling non-motor features of the disease. In order to establish signs that allow for earlier detection of cognitive decline in PD, the concept of `subjective cognitive decline´ (SCD) has gained a growing interest. SCD refers to patients who report a decline in subjective cognitive capacities, while their results on neuropsychological tests are within the normal performance range, indicating adequate cognitive functions. The aim of this review was to evaluate the concept of SCD in PD and give an overview of the current research. A systematic literature search in PubMed was performed to identify articles published before December 2020. We included 18 studies with a total of n = 2,654 patients. While there is currently no consensus on research or clinical criteria for SCD in PD, this review presents the accumulated evidence for SCD in PD patients and supports the importance of early identification of cognitive deficits, due to the relatively high prevalence for SCD in PD and the added risk of future cognitive impairment it entails. The publications included in this review indicate that SCD may be part of the PD spectrum but further research is needed. Expanding research on SCD in PD will allow for earlier detection of cognitive impairment and may foster preventive interventions.

GABA / 中国生物化学与分子生物学报

Activation and inflammation of microglial correlate with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson’ s disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system, but the mechanism is unclear. In this study, the results showed that LPS promoted the release of inflammatory factors in a dose-dependent manner compared with the control group (P<0. 01). Meanwhile, cell viability and cytotoxicity assays showed that the released inflammatory factors could induce the decline of SH-SY5Y cell viability. BV2 microglia cells were pretreated with GABA and Muscimol, a GABA

The association between TLR3 rs3775290 polymorphism and sporadic Parkinson's disease in Chinese Han population.

Accumulating evidences have pointed out that neuroinflammation is involved in Parkinson's disease (PD) pathogenesis. Toll-like receptor 3 (TLR3), as a member of pattern-recognition receptors (PRRs), is known to play a pivotal role in inflammatory responses and immune responses. It was recently suggested that TLR3 was increased in the animal models of PD. The present study aimed to evaluate whether TLR3 gene (rs3775290) polymorphism was associated with PD susceptibility. We genotyped the single-nucleotide polymorphism (SNP) of TLR3 gene (rs3775290) using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) from 380 PD patients and 380 control subjects in Chinese Han population. Our data demonstrated that rs3775290 T allele carriers were associated with a reduced risk of PD between early-onset PD(EOPD)group and its healthy-matched control subgroup (OR = 0.571, 95 %CI = 0.366-0.891, P = 0.013 for TT + TC vs CC). Moreover, there were significant differences in genotype and allele distribution between EOPD group and the late-onset PD (LOPD) group (P = 0.024 and P = 0.008, respectively). Therefore, our study suggested a possible association between TLR3 (rs3775290) gene polymorphism and PD susceptibility, indicating that T allele of rs3775290 might be a protective factor for sporadic PD in Han Chinese population.

Glucocerebrosidase genetic variants in Malays with early and late-onset Parkinson’s disease

@#Background: Mutations in glucocerebrosidase (GBA) have been associated with the risk of developing Parkinson’s disease (PD) in different ethnic populations. The prevalence of GBA mutations among Malay PD patients is unknown. Thus, the aim of this study was to determine the frequency of GBA mutations among Malay PD patients, focusing on early (EOPD) and late-onset (LOPD) patients. Methods:EOPD (n = 50) and LOPD (n = 50) patients along with 50 ethnically and age-matched control wererecruited. The GBA exons of these patients were sequenced using the Ion Torrent PGMTM System. Results: Five heterozygous mutations exclusive to EOPD patients were identified; c.-203A>G,p.S146L, p.R159Q, p.L483P and p.L483R+c.-145G>A. In LOPD patients, c.543C>T(p.(F181=)), c.28-10C>A and p.R202Q were identified in which this p.R202Q was also present in a control subject. In addition, c.259C>A(p.(R87=)) and c.-145G>A were identified in two control subjects. In summary, we observed GBA mutations in 8% and 6% of Malay PD cases and control subject, respectively. The prevalence of GBA mutations was higher in EOPD (10%) than LOPD (6%). However, these differences were not statistically significant; [PD vs. controls: OR = 1.36, 95%CI 0.35-5.38, p = 0.752] and [EOPD vs. LOPD: OR = 1.74, 95%CI 0.39-7.71, p = 0.715]. Conclusion: We identified five exclusive heterozygous GBA mutations in EOPD patients which might predict the increase susceptibility of Malays to develop PD at young age. These findings could add knowledge into the existing evidences linking genetic alterations in GBA and PD.

Intranasal Administration of chitosan-Coated Nanostructured Lipid Carriers Loaded with GDNF Improves Behavioral and Histological Recovery in a Partial Lesion Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, but current therapies are only symptomatic. A promising alternative to address the neurodegenerative process is the use of neurotrophic factors, such as the glial cell-derived neurotrophic factor (GDNF). However, its clinical use has been limited due to its short half-life and rapid degradation after in vivo administration, in addition to difficulties in crossing the blood-brain barrier (BBB). This barrier is a limiting factor in brain drug development, making the future progression of neurotherapeutics difficult. In the past few years, intranasal drug delivery has appeared as an alternative non-invasive administration route to bypass the BBB and target drugs directly to the CNS. Thus, the aim of this work was to study the in vivo neuroprotective effect of intranasally administered GDNF, encapsulated in chitosan-coated nanostructured lipid carrier (CS-NLC-GDNF), in a 6-OHDA partially lesioned rat model. The developed CS-NLC-GDNF showed a particle size of approximately 130 nm and high encapsulation efficiency. The in vitro study in PC-12 cells demonstrated the ability of the encapsulated GDNF to protect these cells against 6-OHDA toxin. After two weeks of daily intranasal administration of treatments, the administration of CS-NLC-GDNF achieved a behavioral improvement in rats, as well as a significant improvement in both the density of TH+ fibres in the striatum and the TH+ neuronal density in the SN. Thus, it can be concluded that the nose-to-brain delivery of CS-NLC-GDNF could be a promising therapy for the treatment of PD.

Single vial freeze-dried TRODAT-1 kit: preparation and demonstration of clinical efficacy of [(99m)Tc]TRODAT-1 in Indian scenario.

A single vial freeze-dried kit formulation for preparation of three patients' dose of [(99m)Tc]TRODAT-1 has been developed for early diagnosis of Parkinson's disease (PD). Kits were evaluated to ascertain the purity, stability and batch to batch variations. Preclinical evaluation was carried out in laboratory animals and clinical imaging was performed in human patients with PD. The labeling yield and purity of [(99m)Tc]TRODAT-1 was >90%. Swiss mice showed retention of [(99m)Tc]TRODAT-1 in the mid brain region. Clinical studies showed decreased striatal uptake with increasing severity of PD.

Protective Effects of Epigallocatechin Gallate in MPTP-induced Mouse Model of Parkinson's Disease / 中国康复理论与实践

@#ObjectiveTo investigate the protective effects of epigallocatechin gallate (EGCG) in a mouse model of Parkinson's disease induced by 1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP).Methods32 C57BL/ 6 male mice were randomly divided into 4 groups: Model group was administrated with 16 mg/kg MPTP (i.p., four times, 2 h interval); Sham group was treated with saline; EGCG treatment group was given EGCG (5 mg/kg) after MPTP administration; normal group was just given EGCG (5 mg/kg) as treatment group. After given EGCG for 3 weeks, behavioral tests, tyrosine hydroxylase (TH) immunohistochemistry staining and the HPLC for dopamine (DA) and its metabolites were used.ResultsThe present results indicated that oral administration of EGCG significantly improved the behavioral impairement in mice induced by MPTP (P<0.05). And in the EGCG treatment group, there were more TH-positive neurons than in model group. In addition, levels of DA and its metabolites in striatum decreased significantly in MPTP group (P<0.05). Though the concentration of DA and its metabolites in EGCG treatment group tended to increase, however, there was no significance between EGCG treatment and model group.ConclusionEGCG could improve the behavioral impairment in a mouse model of Parkinson's disease induced by MPTP and protect against the loss of the dopamine neurons in the substantia nigra (SN).

Neurobiological Characteristics of Human Histo-amniotic Mesenchymal and its Effect to Treat Parkinson's Disease Modle Mice / 中国康复理论与实践

@#ObjectiveTo evaluate the neurobiological characteristics of human histio-amniotic mesenchymal (hAMCs) and effect of hAMCs transplantation into the brain to treat Parkinson's disease(PD) modle mice.MethodsThe expressions of mesenchymal stem cells, neural stem cells, dopaminergic neurons and markers related to neurogenesis such as Vimentin, STRO-1, nestin, CD133, β-tubulin, TH, DAT, Ngn2 and mash-1 in hAMCs were evaluated through immunocytochemical stain; and the mRNA transcriptions of neural stem cell markers, Vimentin and nestin in hAMCs were detected by RT-PCR. The PD model was induced by MPTP(i.p.) in C57BL/6 mice transplanted with hAMCs into the right striatum. The therapeutical effect of hAMCs on PD mice was evaluated by spontaneous movement, rotating bar test and the immunohistochemistry of anti-human chondrosome and TH antibodies in striatum.ResultshAMCs induced by nerve cells culture medium, expressed mesenchymal stem cells, neural stem cells, dopaminergic neurons and other specific markers related to neurogenesis mentioned above. The frequency of spontaneous movement in PD mice was significantly increased(P<0-05), and the time of rotating bar was obviously prolonged(P<0-05) after transplantation with hAMCs.ConclusionhAMCs possess the characteristics of nerve cells after cultured in vitro and can significantly recover the damage of motor function induced by MPTP after transplantation into striatum in PD model mice.

Behavior and Neuronal Apoptosis in Substantia Nigra of Rats with Parkinson's Disease / 中国康复理论与实践

@#ObjectiveTo assess rat behavior, observe apoptotic morphology of neurons and measure expression of caspase-3 in substantia nigra(SN) of Parkinson's disease(PD) animal model. Methods6-OHDA was stereotacticly injected into the right striatum of the rats at two sites to produce PD models. After 5 weeks, the behavior tests including modified Morris Water Maze and narrow beam test were measured. Then tyrosine hydroxylase (TH) histochemistry, Hoechst 33258 staining, Western blotting for caspase-3 in right substantia nigra was separately conducted.ResultsEscape velocity significantly decreased and its latency was obviously enlarged in modified Morris Water Maze, and the latency and total time in narrow beam test were also markedly increased (P<0-05) in 15 successful PD rats compared with either the sham group or the normal group. Furthermore, there were obvious less TH-positive neurons in lesioned SN while more apoptotic cells appeared there. In addition, the expression of caspase-3 was highly upregulated in lesioned SN.Conclusion6-OHDA induced neuronal apoptosis in SN is associated with high levels of caspase-3, and the results of rat behavior tests are correspondent with the morphological changes including TH immunohistochemistry and Hoechst 33258 staining. Thus modified Morris Water Maze and narrow beam test are beneficial for assessments of effects of new drugs in PD animal model.

Oxidative Stress and Expression of Bax and Bcl-2 in Rat Corpus Striatum Induced by 6-Hydroxydopamine / 中国康复理论与实践

@# Objective To study the oxidative stress and apoptosis relative protein expression in rat striatum during the pathogenesis of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Methods 6-OHDA was stereotacticly injected into the right striatum of the rats at two sites to produce PD models. Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), contents of reduced glutathione (GSH) and malondialdehyde (MDA) in the injured and normal striatum were measured using assay kits; and levels of Bax and Bcl-2 were detected by Western blotting in injured striatum. Results In 10 successful PD rats, compared with either the sham group or the normal group, activities of SOD and GSH-Px and contents of GSH in the right striatum significantly decreased while contents of MDA increased obviously (P<0.05); And levels of Bax significantly increased while expression of Bcl-2 obviously decreased. Conclusion Oxidative stress plays a key role in the pathogenesis of PD. Furthermore, Bax and Bcl-2 were involved in the regulation of apoptosis under oxidative stress induced by 6-OHDA.

Preliminarily Application of Quantitive Detector for Human Tremor in Clinic / 中国康复理论与实践

@#ObjectiveTo test the effect of human tremor detector in clinic based on the principle of photoelectrical transformation.MethodsFifty-five subjects including normal youth and elderly persons, patients with Parkinson's disease (PD), hyperthyroidism and cerebellor ataxia were tested with human tremor detector. The displacement, frequency spectrograph, velocity and acceleration of both hands in four kinds of postures and action were involved.ResultsThe physiological tremor and pathological tremor in different kinds of patients were significantly different (P<0.05). Especially in PD, both quantitive and qualitative data had a significant difference.ConclusionHuman tremor detector can provide the evidence for early diagnosis of PD.