A Critical Role of the Adenosine A2A Receptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A2A Receptor Knock-Outs

NEFA (non-esterified ‘free’ fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A2a receptor) stimulation against lipotoxicity. The effects of the A2aR agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine] were evaluated ‘in vitro’ in liver cells exposed to SA (stearic acid) and ‘in vivo’ in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt-mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A2aR stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A2aR agonists as possible new therapeutic agents in preventing fatty liver progression to NASH.

Download Full-text

The Role of Adenosine A2A Receptor Signaling in Bronchiolitis Obliterans

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2009.06.032 ◽

2009 ◽

Vol 88 (4) ◽

pp. 1071-1078 ◽

Cited By ~ 27

Author(s):

Christine L. Lau ◽

Yunge Zhao ◽

Irving L. Kron ◽

Mark H. Stoler ◽

Victor E. Laubach ◽

...

Keyword(s):

Bronchiolitis Obliterans ◽

Adenosine A2a Receptor ◽

Receptor Signaling ◽

A2a Receptor ◽

Adenosine A2a

Download Full-text

Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2011.04.014 ◽

2011 ◽

Vol 254 (3) ◽

pp. 229-237 ◽

Cited By ~ 16

Author(s):

Mahmoud M. El-Mas ◽

Sahar M. El-gowilly ◽

Mohamed A. Fouda ◽

Evan I. Saad

Keyword(s):

Adenosine A2a Receptor ◽

Receptor Signaling ◽

Sympathetic Control ◽

A2a Receptor ◽

Adenosine A2a

Download Full-text

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

Current Aging Science ◽

10.2174/1874609814666210526115740 ◽

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.

Download Full-text