scholarly journals Neuroprotective Effect of Ropinirole Lipid Nanoparticles Enriched Hydrogel for Parkinson’s Disease: In Vitro, Ex Vivo, Pharmacokinetic and Pharmacodynamic Evaluation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 448 ◽  
Author(s):  
Narendar Dudhipala ◽  
Thirupathi Gorre
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oral Administration ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Neuroprotective Effect ◽  
Topical Delivery ◽  
Lipid Nanoparticles ◽  
Oral Dosage

Parkinson’s disease (rp) is a progressive neurodegenerative disorder. Ropinirole (RP) is a newer generation dopamine agonist used for the treatment of PD. It is prescribed as oral dosage form. However, limited oral bioavailability and frequent dosing limits the RP usage. The objective of the current investigation was to develop, optimize, evaluate pharmacokinetic (PK) and pharmacodynamic (PCD) activity of RP loaded solid lipid nanoparticles (RP-SLNs) and nanostructured lipid carriers (RP-NLCs) and containing hydrogel (RP-SLN-C and RP-NLC-C) formulations for improved oral and topical delivery. RP loaded lipid nanoparticles were optimized and converted to hydrogel using carbopol 934 as the gelling polymer. PK and PCD studies in haloperidol-induced PD were conducted in male Wistar rats. In vitro and ex vivo permeation studies showed sustained release profile and enhanced permeation compared with control formulations. Differential scanning calorimeter and X-ray diffraction studies revealed amorphous transformation; scanning electron microscope showed the spherical shape of RP in lipid nanoparticles. PK studies showed 2.1 and 2.7-folds enhancement from RP-SLN and RP-NLC from oral administration, 3.0 and 3.3-folds enhancement from RP-SLN-C and RP-NLC-C topical administration, compared with control formulations, respectively. RP-SLN-C and RP-NLC-C showed 1.4 and 1.2-folds topical bioavailability enhancement compared with RP-SLN and RP-NLC oral administration, respectively. PCD studies showed enhanced dopamine, glutathione, catalase levels and reduced lipid peroxidation levels, compared with the haloperidol-induced PD model. Overall, the results demonstrated that lipid nanoparticles and corresponding hydrogel formulations can be considered as an alternative delivery approach for the improved oral and topical delivery of RP for the effective treatment of PD.

scholarly journals Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

2015 ◽  
Vol 26 (24) ◽  
pp. 4478-4491 ◽  
Author(s):  
BK. Binukumar ◽  
Varsha Shukla ◽  
Niranjana D. Amin ◽  
Philip Grant ◽  
M. Bhaskar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Selective Inhibition ◽  
Motor Dysfunction ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 ­hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

scholarly journals The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Zinger ◽  
Carlos Barcia ◽  
Maria Trinidad Herrero ◽  
Gilles J. Guillemin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Therapeutic Strategy ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Kynurenine Pathway ◽  
Receptor Signalling

Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD bothin vivoandin vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD.

scholarly journals Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Renrong Wei ◽  
Cuiping Rong ◽  
Qingfeng Xie ◽  
Shouhai Wu ◽  
Yuchao Feng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Binding ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Mrna Levels ◽  
Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

scholarly journals Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

2020 ◽  
Author(s):  
Eiji Inoue ◽  
Takahiro Suzuki ◽  
Yasuharu Shimizu ◽  
Keiichi Sudo ◽  
Haruhisa Kawasaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Life Span ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Crocus Sativus ◽  
Motor Symptoms ◽  
Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

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 Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3455
Author(s):  
Hyuna Sim ◽  
Joo-Eun Lee ◽  
Hee Min Yoo ◽  
Sunwha Cho ◽  
Hana Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Cell Types ◽  
Motor Symptoms ◽  
Intestinal Organoids ◽  
Potential Biomarker ◽  
Homeobox Protein

The diagnosis of Parkinson’s disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.

scholarly journals A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Shankar J. Chinta ◽  
Subramanian Rajagopalan ◽  
Abirami Ganesan ◽  
Julie K. Andersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Oxidative And Nitrosative Stress ◽  
Prolyl Hydroxylases ◽  
Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

scholarly journals Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 326 ◽  
Author(s):  
Nadia Ferlazzo ◽  
Santa Cirmi ◽  
Alessandro Maugeri ◽  
Caterina Russo ◽  
Giovanni Enrico Lombardo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nuclear Translocation ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Specific Cell ◽  
Protective Effects ◽  
Human Neuroblastoma

Much evidence suggests that both oxidative stress and apoptosis play a key role in the pathogenesis of Parkinson’s disease (PD). The present study aims to evaluate the protective effect of bergamot juice (BJ) against 6-hydroxydopamine (6-OHDA)- or H2O2-induced cell death. Treatment of differentiated SH-SY5Y human neuroblastoma cells with 6-OHDA or H2O2 resulted in cell death that was significantly reduced by the pre-treatment with BJ. The protective effects of BJ seem to correlate with the reduction of intracellular reactive oxygen species and nitric oxide generation caused by 6-OHDA or H2O2. BJ also attenuated mitochondrial dysfunction, caspase-3 activation, imbalance of pro- and anti-apoptotic proteins, MAPKs activation and reduced NF-ĸB nuclear translocation evoked by neurotoxic agents. Additionally, BJ exhibited excellent antioxidant capability in cell-free assays. Collectively, our results suggest that BJ exerts neuroprotective effect through the interplay with specific cell targets and its antioxidant activity, making it worthy of consideration for the management of neurodegenerative diseases.

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