scholarly journals METABOLIC CHANGES INDUCED BY BUSHENHUOXUE GRANULES ON STRIATUM AND SUBSTANTIA NIGRA IN A RAT MODEL OF PARKINSON’S DISEASE

2017 ◽  
Vol 15 (1) ◽  
pp. 1
Author(s):  
Yunxia Guo ◽  
Junxiu Zhang ◽  
Shaodan Li ◽  
Yin Zhang ◽  
Yi Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Normal Control Group ◽  
Adenosine A2a Receptor ◽  
Rat Striatum ◽  
Control Group ◽  
Control Groups ◽  
A2a Receptor ◽  
Adenosine A2a

Background: Parkinson’s disease is a neurodegenerative disease, while its mechanism is still unclear. Long-term levodopa-based treatment leads to decreased response or loss of response, as well as severe side effects. Our previous study has proved that Bushenhuoxue Granules have effects on Parkinson’s disease, but the underlying mechanism is still need to be explored. Our research is to investigate the mechanisms of Bushenhuoxue Granules on Parkinson’s disease (PD) by examining changes in the expression of the adenosine A2A receptor、vesicular monoamine transporter 2 (VMAT2)、divalent metal transporter 1（DMT1） and nuclear factor E2 related (Nrf2) in a rat model of Parkinson’s disease (PD) . Materials and Methods: Changes in the apomorphine (APO)-induced rotational behavior of rats were observed after treatment. Immunofluorescence and immunohistochemistry were performed to investigate changes in adenosine A2A receptor 、VMAT2、DMT1 and Nrf2 expression in the rat striatum and substantia nigra. Results: Rotations after treatment were199.11 ± 27.16, which significantly decreased compared with that before treatment ( 273.0 ± 44.61, p < 0.01). Adenosine A2A receptor expression in the striatum was 3.10 ± 0.34 significantly increased in the model group and decreased in the normal control group, whereas the expression level in the Bushenhuoxue group was 1.13 ± 0.23,p < 0.05 between the two control groups. No adenosine A2A receptor expression was observed in the substantia nigra. VMAT2 expression in the rat striatum was 23.20 ± 2.68 and substantia nigra was 15.98 ± 0.70 increased in the normal control group. They were 8.99 ± 0.48 in the rat striatum and 8.45 ± 0.59 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 15.36 ± 0.89 in the rat striatum and 11.69 ± 1.17 in the rat substantia nigra (p < 0.05), also between the two control groups. DMT1 expression in the rat striatum was 3.30 ± 0.30 and substantia nigra was 6.56 ± 0.64 decreased in the normal control group. They were 7.92 ± 0.52 in the rat striatum and 12.76 ± 0.86 substantia nigra significantly increased in the model control group, whereas the expression level in the Bushenhuoxue group was 6.17 ± 0.27 in the rat striatum and 9.13 ± 0.44 in the rat substantia nigra (p < 0.05), also between the two control groups. Nrf2 expression in the rat striatum was 7.90 ± 0.29 and substantia nigra was 15.22 ± 1.22 increased in the normal control group. They were 3.09 ± 0.43 in the rat striatum and 8.57 ± 0.54 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 5.00 ± 0.34 in the rat striatum and 12.46 ± 0.62 in the rat substantia nigra (p< 0.05), also between the two control groups. Conclusion: Bushenhuoxue Granules significantly improved the rotational behavior of PD’s rats, decreased adenosine A2A receptor expression, and increased VMAT2 expression; decreased DMT1 expression, and increased Nfr2 expression.

Parkinsonism-like disease induced by rotenone in rats: Treatment role of curcumin, dopamine agonist and adenosine A2A receptor antagonist

2021 ◽  
Vol 14 ◽  
Author(s):  
Asmaa Fathy Aboul Naser ◽  
Wessam Magdi Aziz ◽  
Yomna Rashad Ahmed ◽  
Wagdy Khalil Bassaly Khalil ◽  
Manal Abdel Aziz Hamed
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Mediator ◽  
Adenosine A2a Receptor ◽  
Control Group ◽  
A2a Receptor ◽  
Adenosine A2a

Background: Parkinsonism is a neurodegenerative disorder that affects elderly people worldwide. Methods: Curcumin, adenosine A2AR antagonist (ZM241385) and Sinemet® (L-dopa) were evaluated against Parkinson’s disease (PD) induced by rotenone in rats and comparativelyrelatively compared with our previous study on mice model. Results: Rats injected with rotenone showed severe alterations in adenosine A2A receptor gene expression, oxidative stress markers, inflammatory mediator, energetic indices, apoptotic marker and DNA fragmentation levels as compare with the control group. Treatments with curcumin, ZM241385, and Sinemet® restored all the selected parameters. The brain histopathological features of cerebellum regions confirmed our results. By comparing our results with the previous results on mice, we noticed that mice respond to rotenone toxicity and treatments more than rats regarding to behavioral observation, A2AR gene expression, neurotransmitter levels, inflammatory mediator and apoptotic markers, while rats showed higher response to treatments regarding to oxidative stress and energetic indices. Conclusion: Curcumin succeeded to attenuate the severe effects of Parkinson’s disease in rat model and can be consider as a potential dietary supplement. Adenosine A2AR antagonist has almost the same pattern of improvement as Sinemet® and may be considered as a promising therapy against PD. By comparing the role of animal species in response to PD symptoms and treatments, our previous report on mice explore the response of mice to rotenone toxicity than rats, while rats showed higher response to treatments. Therefore, no animal model can perfectly recapitulate all the pathologies of PD.

scholarly journals Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson’s Disease: A Pooled Analysis of 8 Phase 2b/3 Trials

2021 ◽  
pp. 1-13
Author(s):  
Robert A. Hauser ◽  
Nobutaka Hattori ◽  
Hubert Fernandez ◽  
Stuart H. Isaacson ◽  
Hideki Mochizuki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Receptor Antagonist ◽  
Repeated Measures ◽  
Pooled Analysis ◽  
Adenosine A2a Receptor ◽  
A2a Receptor ◽  
Adenosine A2a Receptor Antagonist ◽  
Adenosine A2a ◽  
Off Time

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p <  0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

scholarly journals PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1633
Author(s):  
Susann Schröder ◽  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Mathias Kranz ◽  
Alexandra Chovsepian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Animal ◽  
Imaging Study ◽  
Adenosine A2a Receptor ◽  
Emission Tomography ◽  
One Pot ◽  
Positron Emission ◽  
A2a Receptor ◽  
Adenosine A2a

The adenosine A2A receptor (A2AR) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson’s disease (PD). An increased A2AR availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A2AR upregulation in PD. For that purpose, we selected the known A2AR-specific radiotracer [18F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [18F]FESCH in the mouse striatum. Concomitantly, metabolism studies with [18F]FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A2AR binding of [18F]FESCH was found. Nonetheless, the correlation between the increased A2AR levels within the proposed PD animal model remains to be further investigated.

scholarly journals Die adenosien A1- en A2A-reseptoraffiniteit van ’n reeks 3,4-dihidropirimidoon-analoë

2017 ◽  
Vol 36 (1) ◽  
Author(s):  
Runako M. Katsidzira ◽  
Mietha M. Van der Walt ◽  
Jacobus J. Bergh ◽  
Gisella Terre’Blanche
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Adenosine A2a Receptor ◽  
Adenosine A1 Receptor ◽  
Receptor Affinity ◽  
A2a Receptors ◽  
A2a Receptor ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Adenosine A2a

Parkinson’s disease is a complex neurodegenerative condition with current treatment only focussed on symptomatic therapy that does not slow or stop the progression of the disease. Since the discovery that adenosine A1 and A2A receptors are potential drug targets for the therapy of Parkinson’s disease, various research groups have attempted to identify adenosine antagonists. So the possibility exists that the administration of an adenosine A2A receptor antagonist may prevent further neurodegeneration. Furthermore, the antagonism of adenosine A1 receptors has the potential of treating Parkinson’s disease-associated cognitive deficits. Therefore, dual antagonism of adenosine A1 and A2A receptors would be of great benefit since this would potentially treat both the motor as well as the cognitive impairment associated with Parkinson’s disease. Based on the observation that a series of 1,4-dihydropyridine derivatives possess adenosine A1 and A2A receptor affinity, the current study investigated the potential of the structurally related 3,4-dihydropyrimidone analogues as adenosine A1 and A2A receptor antagonists. Overall, the 3,4-dihyropyrimidone analogues were found to possess weak affinity for the adenosine A2A receptor, but more promising adenosine A1 receptor affinity was found, ranging in the low micromolar range. Among the investigated compounds, the p-bromophenyl substituted dihydropyrimidone (6b) possesses the best adenosine A1 receptor affinity with a Ki value of 7.39 µM. In conclusion, this 3,4-dihydropyrimidone derivative can be used as a lead for the design of novel adenosine A1 receptor antagonists, although further structural modifications are required to enhance the adenosine A2A receptor affinity before a clinically viable candidate will be available as potential treatment of Parkinson’s disease.

scholarly journals Effect of Adenosine A2a Receptor Antagonist In Haloperidol Induced Model of Parkinson’s Disease.

2021 ◽  
Author(s):  
Syeda Najam Zehra ◽  
Ishrat Younus ◽  
Saima Mahmood Malhi ◽  
Muhammad Liaquat Raza ◽  
Azfar Athar Ishaqui ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Receptor Antagonist ◽  
Adenosine A2a Receptor ◽  
Adenosine A2a Receptor Antagonists ◽  
A2a Receptor ◽  
Parkinson’S Diseases ◽  
Adenosine A2a Receptor Antagonist ◽  
New Treatment ◽  
Adenosine A2a

Abstract One of the major causes of neurological disorders is degeneration of neurons which is commonly termed as Neurodegeneration. It is well documented that two of the neurodegenerative disorders i.e., Alzheimer’s Disease & Parkinson Disease comes in top fifteen causes of deaths in United States of America. Due to the neuroprotective property of adenosine A2a receptor antagonists (ZM241385) was evaluated in haloperidol mouse model of Parkinson’s disease. Our results reveal significant antidopaminergic effects of adenosine A2A receptor antagonist that support its utilization as a new treatment approach in Parkinson’s diseases.

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