Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Marco Niello; Ralph Gradisch; Claus Juul Loland; Thomas Stockner; Harald H. Sitte

doi:10.1016/j.tips.2020.04.006

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Trends in Pharmacological Sciences ◽

10.1016/j.tips.2020.04.006 ◽

2020 ◽

Vol 41 (7) ◽

pp. 446-463 ◽

Cited By ~ 3

Author(s):

Marco Niello ◽

Ralph Gradisch ◽

Claus Juul Loland ◽

Thomas Stockner ◽

Harald H. Sitte

Keyword(s):

Therapeutic Strategy ◽

Allosteric Modulation ◽

Neurotransmitter Transporters

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Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

Journal of Neuroscience ◽

10.1523/jneurosci.3377-17.2018 ◽

2018 ◽

Vol 38 (13) ◽

pp. 3218-3229 ◽

Cited By ~ 17

Author(s):

Natasha Warikoo ◽

Samuel J. Brunwasser ◽

Ann Benz ◽

Hong-Jin Shu ◽

Steven M. Paul ◽

...

Keyword(s):

Nmda Receptor ◽

Therapeutic Strategy ◽

Allosteric Modulation ◽

Nmda Receptor Encephalitis

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Positive Allosteric Modulation of CD11b as a Novel Therapeutic Strategy Against Lung Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.00748 ◽

2020 ◽

Vol 10 ◽

Author(s):

Terese Geraghty ◽

Anugraha Rajagopalan ◽

Rabail Aslam ◽

Alexander Pohlman ◽

Ishwarya Venkatesh ◽

...

Keyword(s):

Lung Cancer ◽

Therapeutic Strategy ◽

Allosteric Modulation ◽

Novel Therapeutic

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Positive allosteric modulation of A1 adenosine receptors as a novel and promising therapeutic strategy for anxiety

Neuropharmacology ◽

10.1016/j.neuropharm.2016.09.015 ◽

2016 ◽

Vol 111 ◽

pp. 283-292 ◽

Cited By ~ 22

Author(s):

Fabrizio Vincenzi ◽

Annalisa Ravani ◽

Silvia Pasquini ◽

Stefania Merighi ◽

Stefania Gessi ◽

...

Keyword(s):

Adenosine Receptors ◽

Therapeutic Strategy ◽

Allosteric Modulation ◽

A1 Adenosine Receptors

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Allosteric modulation of neurotransmitter transporters at excitatory synapses

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2004.05.006 ◽

2004 ◽

Vol 23 (1) ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Robert J. Vandenberg ◽

Pengchu Ju ◽

Karin R. Aubrey ◽

Renae M. Ryan ◽

Ann D. Mitrovic

Keyword(s):

Allosteric Modulation ◽

Excitatory Synapses ◽

Neurotransmitter Transporters

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The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through A1AR Positive Allosteric Modulation

Cells ◽

10.3390/cells9051242 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1242 ◽

Cited By ~ 2

Author(s):

Fabrizio Vincenzi ◽

Silvia Pasquini ◽

Stefania Gessi ◽

Stefania Merighi ◽

Romeo Romagnoli ◽

...

Keyword(s):

Pc12 Cells ◽

Adenosine Receptor ◽

Therapeutic Strategy ◽

Cell Injury ◽

Allosteric Modulation ◽

The Novel ◽

Positive Allosteric Modulator ◽

Endogenous Adenosine ◽

Mitochondrial Membrane Potential Loss

Glutamate cytotoxicity is implicated in neuronal death in different neurological disorders including stroke, traumatic brain injury, and neurodegenerative diseases. Adenosine is a nucleoside that plays an important role in modulating neuronal activity and its receptors have been identified as promising therapeutic targets for glutamate cytotoxicity. The purpose of this study is to elucidate the role of adenosine and its receptors on glutamate-induced injury in PC12 cells and to verify the protective effect of the novel A1 adenosine receptor positive allosteric modulator, TRR469. Flow cytometry experiments to detect apoptosis revealed that adenosine has a dual role in glutamate cytotoxicity, with A2A and A2B adenosine receptor (AR) activation exacerbating and A1 AR activation improving glutamate-induced cell injury. The overall effect of endogenous adenosine in PC12 cells resulted in a facilitating action on glutamate cytotoxicity, as demonstrated by the use of adenosine deaminase and selective antagonists. However, enhancing the action of endogenous adenosine on A1ARs by TRR469 completely abrogated glutamate-mediated cell death, caspase 3/7 activation, ROS production, and mitochondrial membrane potential loss. Our results indicate a novel potential therapeutic strategy against glutamate cytotoxicity based on the positive allosteric modulation of A1ARs.

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