scholarly journals Systems pharmacology based approach to investigate the in-vivo therapeutic efficacy of Albizia lebbeck (L.) in experimental model of Parkinson’s disease

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Uzma Saleem ◽  
Zohaib Raza ◽  
Fareeha Anwar ◽  
Zunera Chaudary ◽  
Bashir Ahmad
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Experimental Model ◽  
Mechanism Of Action ◽  
System Level ◽  
In Vivo Studies ◽  
Substantia Nigra Pars Compacta ◽  
Systems Pharmacology ◽  
Albizia Lebbeck

Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta and clinically manifested mainly with motor dysfunctions. Plants are rich source of medicinally important bioactive compounds and inhabitants of underdeveloped countries used plants for treatment of various ailments. Albizia lebbeck has been reported to possess antioxidant and neuroprotective properties that suggest the evaluation of its traditional therapeutic potential in neurodegenerative diseases. The aim of present study was to validate the traditional use of Albizia lebbeck (L.) and delineate its mechanism of action in PD. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. Methods The haloperidol-induced catalepsy was adopted as experimental model of PD for in-vivo studies in wistar albino rats. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. Results In-vivo studies revealed that Albizia lebbeck improved the motor functions and endurance as demonstrated in behavioral studies which were further supported by the rescue of endogenous antioxidant defense and reversal of ultrastructural damages in histological studies. System pharmacology approach identified 25 drug like compounds interacting with 132 targets in a bipartite graph that revealed the synergistic mechanism of action at system level. Kaemferol, phytosterol and okanin were found to be the important compounds nodes with prominent target nodes of TDP1 and MAPT. Conclusion The therapeutic efficiency of Albizia lebbeck in PD was effectively delineated in our experimental and systems pharmacology approach. Moreover, this approach further facilitates the drug discovery from Albizia lebbeck for PD.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

scholarly journals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jialong Chen ◽  
Kanmin Mao ◽  
Honglin Yu ◽  
Yue Wen ◽  
Hua She ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Dopaminergic Neurons ◽  
Microglia Activation ◽  
Microglial Cells ◽  
Substantia Nigra Pars Compacta ◽  
Mice Model ◽  
Chaperone Mediated Autophagy

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.

scholarly journals Effect of Harmine against Parkinson’s Disease Protein (PARK7) through Molecular Docking Studies

2021 ◽  
Vol 9 (VI) ◽  
pp. 5479-5485
Author(s):  
Love Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Neurodegenerative Disorder ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Receptor Protein ◽  
Unknown Etiology

Parkinson’s disease (PD) is a common known neurodegenerative disorder with unknown etiology. It was estimated about 0.3% prevalence in the U.S population and enhance to 4 to 5% in older than 85 years. All studies were depending on the molecular docking where all ligands and protein PARK7 (PDB ID: 2RK3) were interacted by docked process. Some natural compounds was selected such as Harmine, Alloxan, Alpha spinasterol, Myrcene, and Vasicinone and PARK7 (PDB ID: 2RK3) protein. According to the PyRx and SWISS ADME result, Harmine was the only ligand which was showing minimum binding affinity. AutoDock Vina software was used for docking process between ligand (Harmine) and receptor protein PARK7 (PDB ID: 2RK3). The result was visualized under PyMol. Harmine was inhibiting the activity of PARK7 (PDB ID: 2RK3) and it may be used for the treatment of PD in future prospect after its in vitro and in vivo studies.

scholarly journals Neuroprotection in Parkinson’s disease: facts and hopes

2019 ◽  
Vol 127 (5) ◽  
pp. 821-829 ◽  
Author(s):  
András Salamon ◽  
Dénes Zádori ◽  
László Szpisjak ◽  
Péter Klivényi ◽  
László Vécsei
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Loss ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Agents ◽  
Dopaminergic Cell ◽  
Pathological Mechanism ◽  
Positive Results

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).

Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson’s disease: Synthesis, in vitro and in vivo studies

2020 ◽  
Vol 101 ◽  
pp. 103986 ◽  
Author(s):  
Fernanda Rodríguez-Enríquez ◽  
Dolores Viña ◽  
Eugenio Uriarte ◽  
José Angel Fontenla ◽  
Maria J. Matos
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Novel Agents ◽  
In Vivo Studies

scholarly journals Neuroprotective Effects of Lindleyin on Hydrogen Peroxide-Induced Cell Injury and MPTP-Induced Parkinson’s Disease in C57BL/6 Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jin-Jie Zhang ◽  
Xiao-Rong Shi ◽  
Wen-Wen Lv ◽  
Xiao-Long Zhou ◽  
Ying-Dong Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Hydrogen Peroxide ◽  
Parkinson's Disease ◽  
Cell Injury ◽  
In Vivo Studies ◽  
Antioxidant Enzyme Activities ◽  
Apoptotic Pathway ◽  
Neuroprotective Effects

Oxidative stress (OS) is a crucial factor influencing the development of Parkinson’s disease (PD). Here we first reported that Lindleyin (Lin), one of the major components of rhubarb, possessed neuroprotective effects against H2O2-induced SH-SY5Y cell injury and MPTP-induced PD of C57BL/6 mice. The results showed that Lin can decrease cell death and apoptotic rate induced by H2O2 through inhibiting mitochondrial apoptotic pathway and increasing the activities of SOD, GSH-Px, and CAT as well as decreasing the level of MDA. In addition, in vivo studies showed that oral administration of Lin (5 or 20 mg/kg) showed significant change in motor function deficits, antioxidant enzyme activities, apoptotic pathway, and tyrosine hydroxylase expression. Our results reveal that Lin might be a promising anti-PD agent by reducing OS and apoptosis.

scholarly journals Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

2020 ◽  
Vol 21 (12) ◽  
pp. 4455
Author(s):  
Rong-Tzong Tsai ◽  
Chia-Wen Tsai ◽  
Shih-Ping Liu ◽  
Jia-Xin Gao ◽  
Yun-Hua Kuo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caenorhabditis Elegans ◽  
Cell Line ◽  
Ubiquitin Proteasome System ◽  
Substantia Nigra Pars Compacta ◽  
Neuron Damage ◽  
6 Hydroxydopamine

The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease

US Neurology ◽  
2011 ◽  
Vol 07 (02) ◽  
pp. 109 ◽  
Author(s):  
Tanya Simuni ◽  
D James Surmeier ◽  
◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuroprotective Effect ◽  
Selective Vulnerability ◽  
Phase Iii ◽  
Substantia Nigra Pars Compacta ◽  
Double Blind ◽  
Finding Study

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+channels pacemakers. Continuous Ca2+influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+channels with the Cav1.3 subunit, protects these neurons inin vitroandin vivomodels of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.

scholarly journals Parkinson's disease and mitophagy: an emerging role for LRRK2

2021 ◽  
Author(s):  
Francois Singh ◽  
Ian G. Ganley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Muscle Stiffness ◽  
Substantia Nigra Pars Compacta ◽  
Common Mutation ◽  
Common Denominator

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

PTX3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via inhibiting apoptosis

2021 ◽  
Author(s):  
Changlin Lian ◽  
Qiongzhen Huang ◽  
Xiangyang Zhong ◽  
Zhenyan He ◽  
Boyang Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Brain Slices ◽  
Human Mesenchymal Stem Cells ◽  
Substantia Nigra Pars Compacta ◽  
Therapeutic Effects ◽  
Label Free

Abstract Background Adipose-derived human mesenchymal stem cells (hADSCs) transplantation has recently emerged as a promising method in the treatment of Parkinson's disease (PD), however, the mechanism underlying has not been fully illustrated. Methods In this study, the therapeutic effects of the striatum stereotaxic injected hADSCs in 6-OHDA-induced mouse model were evaluated. Furthermore, an in vitro model of PD was constructed using tissue-organized brain slices. And the therapeutic effect was evaluated by co-culture of hADSCs and 6-OHDA-constructed brain slice. Within the analysis of hADSCs' exocrine proteins through RNA-seq, Human protein cytokine arrays and label-free quantitative proteomics, key extracellular factors were identified in hADSCs secretion environment.The degeneration of DA neurons and apoptosis were measured in PD samples in vivo and vitro models, and the beneficial effects were evaluated through quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot,Fluoro-Jade C, Tunel assay and immunofluorescence analysis. Results In this study, we discovered that hADSCs protected the dopaminergic (DA) neurons in vivo and vitro models.we identified Pentraxin3 (PTX3) as a key extracellular factor in hADSCs secretion environment. Moreover, we found that human recombinant Pentraxin3 (rhPTX3) treatment could rescue the physiological behaviour of the PD mice in-vivo, as well as prevent DA neurons from death and increase the neuronal terminals in the Ventral tegmental area (VTA) + substantia nigra pars compacta (SNc) and striatum (STR) on the PD brain slices in-vitro. Furthermore, within testing on the pro-apoptotic markers of PD mice brain following the treatment of rhPTX3, we found that rhPTX3 can prevent the apoptosis and the degeneration of DA neurons. Conclusions Overall, the current study investigated that PTX3, a hADSCs secreted protein, played a potential role in protecting the DA neurons from apoptosis and degeneration in PD progression as well as improving the motor performances in PD mice to give a possible mechanism of how hADSCs works in the cell replacement therapy in PD. Importantly, our study also provided potential translational implications for the development of PTX3-based therapeutics in PD.

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