scholarly journals Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1630 ◽  
Author(s):  
Débora Lanznaster ◽  
Caio M. Massari ◽  
Vendula Marková ◽  
Tereza Šimková ◽  
Romain Duroux ◽  
...  
Keyword(s):  
Hippocampal Slices ◽  
Reactive Oxygen Species Generation ◽  
Resonance Energy ◽  
Glucose Deprivation ◽  
Fine Tuning ◽  
Receptor Interaction ◽  
Neuroprotective Effects ◽  
Mediated Effects ◽  
The Impact ◽  
A2ar Agonist

Guanosine, a guanine-based purine nucleoside, has been described as a neuromodulator that exerts neuroprotective effects in animal and cellular ischemia models. However, guanosine’s exact mechanism of action and molecular targets have not yet been identified. Here, we aimed to elucidate a role of adenosine receptors (ARs) in mediating guanosine effects. We investigated the neuroprotective effects of guanosine in hippocampal slices from A2AR-deficient mice (A2AR−/−) subjected to oxygen/glucose deprivation (OGD). Next, we assessed guanosine binding at ARs taking advantage of a fluorescent-selective A2AR antagonist (MRS7396) which could engage in a bioluminescence resonance energy transfer (BRET) process with NanoLuc-tagged A2AR. Next, we evaluated functional AR activation by determining cAMP and calcium accumulation. Finally, we assessed the impact of A1R and A2AR co-expression in guanosine-mediated impedance responses in living cells. Guanosine prevented the reduction of cellular viability and increased reactive oxygen species generation induced by OGD in hippocampal slices from wild-type, but not from A2AR−/− mice. Notably, while guanosine was not able to modify MRS7396 binding to A2AR-expressing cells, a partial blockade was observed in cells co-expressing A1R and A2AR. The relevance of the A1R and A2AR interaction in guanosine effects was further substantiated by means of functional assays (i.e., cAMP and calcium determinations), since guanosine only blocked A2AR agonist-mediated effects in doubly expressing A1R and A2AR cells. Interestingly, while guanosine did not affect A1R/A2AR heteromer formation, it reduced A2AR agonist-mediated cell impedance responses. Our results indicate that guanosine-induced effects may require both A1R and A2AR co-expression, thus identifying a molecular substrate that may allow fine tuning of guanosine-mediated responses.

scholarly journals Adenosine A1 receptor-mediated protection of mouse hippocampal synaptic transmission against oxygen and/or glucose deprivation: a comparative study

2019 ◽  
Vol 122 (2) ◽  
pp. 721-728 ◽  
Author(s):  
Masahito Kawamura ◽  
David N. Ruskin ◽  
Susan A. Masino
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Acute Response ◽  
Recording Conditions ◽  
Receptor Inactivation ◽  
Acute Hippocampal Slices ◽  
Metabolic Stresses ◽  
The Impact

Adenosine receptors are widely expressed in the brain, and adenosine is a key bioactive substance for neuroprotection. In this article, we clarify systematically the role of adenosine A1 receptors during a range of timescales and conditions when a significant amount of adenosine is released. Using acute hippocampal slices obtained from mice that were wild type or null mutant for the adenosine A1 receptor, we quantified and characterized the impact of varying durations of experimental ischemia, hypoxia, and hypoglycemia on synaptic transmission in the CA1 subregion. In normal tissue, these three stressors rapidly and markedly reduced synaptic transmission, and only treatment of sufficient duration led to incomplete recovery. In contrast, inactivation of adenosine A1 receptors delayed and/or lessened the reduction in synaptic transmission during all three stressors and reduced the magnitude of the recovery significantly. We reproduced the responses to hypoxia and hypoglycemia by applying an adenosine A1 receptor antagonist, validating the clear effects of genetic receptor inactivation on synaptic transmission. We found activation of adenosine A1 receptor inhibited hippocampal synaptic transmission during the acute phase of ischemia, hypoxia, or hypoglycemia and caused the recovery from synaptic impairment after these three stressors using genetic mutant. These studies quantify the neuroprotective role of the adenosine A1 receptor during a variety of metabolic stresses within the same recording system. NEW & NOTEWORTHY Deprivation of oxygen and/or glucose causes a rapid adenosine A1 receptor-mediated decrease in synaptic transmission in mouse hippocampus. We quantified adenosine A1 receptor-mediated inhibition during and synaptic recovery after ischemia, hypoxia, and hypoglycemia of varying durations using a genetic mutant and confirmed these findings using pharmacology. Overall, using the same recording conditions, we found the acute response and the neuroprotective ability of the adenosine A1 receptor depended on the type and duration of deprivation event.

scholarly journals Enantioselective Neuroprotective Effects of Tacripyrine ITH122 Against Oxygen and Glucose Deprivation in Rat Hippocampal Slices

2013 ◽  
Vol 19 (4) ◽  
pp. 285-287 ◽  
Author(s):  
Alejandro Romero ◽  
Vanessa Gomez-Rangel ◽  
Javier Egea ◽  
Abdelouahid Samadi ◽  
José Marco-Contelles ◽  
...  
Keyword(s):  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Neuroprotective Effects ◽  
Oxygen And Glucose Deprivation

scholarly journals Neuroprotective Effects of the Sonic Hedgehog Signaling Pathway in Ischemic Injury through Promotion of Synaptic and Neuronal Health

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Sen Yin ◽  
Xuemei Bai ◽  
Danqing Xin ◽  
Tingting Li ◽  
Xili Chu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Neuronal Apoptosis ◽  
Reactive Oxygen Species Generation ◽  
Glucose Deprivation ◽  
Synaptic Proteins ◽  
Neuroprotective Effects ◽  
Shh Signaling ◽  
Gli 1

Cerebral ischemia is a common cerebrovascular condition which often induces neuronal apoptosis, leading to brain damage. The sonic hedgehog (Shh) signaling pathway has been reported to be involved in ischemic stroke, but the underlying mechanisms have not been fully elucidated. In the present study, we demonstrated that expressions of Shh, Ptch, and Gli-1 were significantly downregulated at 24 h following oxygen-glucose deprivation (OGD) injury in neurons in vitro, effects which were associated with increasing numbers of apoptotic cells and reactive oxygen species generation. In addition, expressions of synaptic proteins (neuroligin and neurexin) were significantly downregulated at 8 h following OGD, also associated with concomitant neuronal apoptosis. Treatment with purmorphamine, a Shh agonist, increased Gli-1 in the nucleus of neurons and protected against OGD injury, whereas the Shh inhibitor, cyclopamine, produced the opposite effects. Activation of Shh signals promoted CREB and Akt phosphorylation; upregulated the expressions of BDNF, neuroligin, and neurexin; and decreased NF-κB phosphorylation following OGD. Notably, this activation of Shh signals was accompanied by improved neurobehavioral responses along with attenuations in edema and apoptosis at 48 h postischemic insult in rats. Taken together, these results demonstrate that activation of the Shh signaling pathway played a neuroprotective role in response to ischemic exposure via promotion of synaptic and neuronal health.

scholarly journals Neuroprotective effects of microglial P2Y1 receptors against ischemic neuronal injury

2018 ◽  
Vol 39 (11) ◽  
pp. 2144-2156 ◽  
Author(s):  
Yuichiro Fukumoto ◽  
Kenji F Tanaka ◽  
Bijay Parajuli ◽  
Keisuke Shibata ◽  
Hideyuki Yoshioka ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
P2 Receptors ◽  
Brain Diseases ◽  
Functional Capability ◽  
Neuroprotective Effects ◽  
Dying Cells ◽  
Ischemic Neuronal Injury ◽  
Ischemic Stress

Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y1 receptors (P2Y1R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y1R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y1R to provide neuroprotective effects following ischemic stress. Cerebral ischemia resulted in increased microglial P2Y1R expression. The number of injured hippocampal neurons was significantly higher in P2Y1 R knockout (KO) mice than wildtype mice after forebrain ischemia. Propidium iodide (PI) uptake, a marker for dying cells, was significantly higher in P2Y1R KO hippocampal slices compared with wildtype hippocampal slices at 48 h after 40-min oxygen–glucose deprivation (OGD). Furthermore, increased PI uptake following OGD was rescued by ectopic overexpression of P2Y1R in microglia. In summary, these data suggest that microglial P2Y1R mediate neuroprotective effects against ischemic stress and OGD insult.

Neuroprotective effects of Ptychopetalum olacoides Bentham (Olacaceae) on oxygen and glucose deprivation induced damage in rat hippocampal slices

Life Sciences ◽  
2004 ◽  
Vol 75 (15) ◽  
pp. 1897-1906 ◽  
Author(s):  
Ionara R Siqueira ◽  
Helena Cimarosti ◽  
Cı́ntia Fochesatto ◽  
Domingos S Nunes ◽  
Christianne Salbego ◽  
...  
Keyword(s):  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Neuroprotective Effects ◽  
Oxygen And Glucose Deprivation

AMPA Induces NO-Dependent cGMP Signals in Hippocampal and Cortical Neurons via L-Type Voltage-Gated Calcium Channels

2019 ◽  
Vol 30 (4) ◽  
pp. 2128-2143 ◽  
Author(s):  
Jan Giesen ◽  
Ernst-Martin Füchtbauer ◽  
Annette Füchtbauer ◽  
Klaus Funke ◽  
Doris Koesling ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Cortical Neurons ◽  
Calcium Influx ◽  
Hippocampal Slices ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Acute Hippocampal Slices ◽  
The Impact

Abstract The nitric oxide (NO)/cGMP signaling cascade has an established role in synaptic plasticity. However, with conventional methods, the underlying cGMP signals were barely detectable. Here, we set out to confirm the well-known NMDA-induced cGMP increases, to test the impact of AMPA on those signals, and to identify the relevant phosphodiesterases (PDEs) using a more sensitive fluorescence resonance energy transfer (FRET)-based method. Therefore, a “knock-in” mouse was generated that expresses a FRET-based cGMP indicator (cGi-500) allowing detection of cGMP concentrations between 100 nM and 3 μM. Measurements were performed in cultured hippocampal and cortical neurons as well as acute hippocampal slices. In hippocampal and cortical neurons, NMDA elicited cGMP signals half as high as the ones elicited by exogenous NO. Interestingly, AMPA increased cGMP independently of NMDA receptors and dependent on NO synthase (NOS) activation. NMDA- and AMPA-induced cGMP signals were not additive indicating that both pathways converge on the level of NOS. Accordingly, the same PDEs, PDE1 and PDE2, were responsible for degradation of NMDA- as well as AMPA-induced cGMP signals. Mechanistically, AMPAR induced calcium influx through L-type voltage-gated calcium channels leading to NOS and finally NO-sensitive guanylyl cyclase activation. Our results demonstrate that in addition to NMDA also AMPA triggers endogenous NO formation and hence cGMP production.

Food Safety Security: A new Concept for Enhancing Food Safety Measures

2012 ◽  
Vol 82 (3) ◽  
pp. 216-222 ◽  
Author(s):  
Venkatesh Iyengar ◽  
Ibrahim Elmadfa
Keyword(s):  
Food Safety ◽  
Hazard Analysis ◽  
Warning System ◽  
Shared Responsibility ◽  
Fine Tuning ◽  
Strategic Action ◽  
Surveillance Network ◽  
Measurement Systems ◽  
Critical Control Points ◽  
The Impact

The food safety security (FSS) concept is perceived as an early warning system for minimizing food safety (FS) breaches, and it functions in conjunction with existing FS measures. Essentially, the function of FS and FSS measures can be visualized in two parts: (i) the FS preventive measures as actions taken at the stem level, and (ii) the FSS interventions as actions taken at the root level, to enhance the impact of the implemented safety steps. In practice, along with FS, FSS also draws its support from (i) legislative directives and regulatory measures for enforcing verifiable, timely, and effective compliance; (ii) measurement systems in place for sustained quality assurance; and (iii) shared responsibility to ensure cohesion among all the stakeholders namely, policy makers, regulators, food producers, processors and distributors, and consumers. However, the functional framework of FSS differs from that of FS by way of: (i) retooling the vulnerable segments of the preventive features of existing FS measures; (ii) fine-tuning response systems to efficiently preempt the FS breaches; (iii) building a long-term nutrient and toxicant surveillance network based on validated measurement systems functioning in real time; (iv) focusing on crisp, clear, and correct communication that resonates among all the stakeholders; and (v) developing inter-disciplinary human resources to meet ever-increasing FS challenges. Important determinants of FSS include: (i) strengthening international dialogue for refining regulatory reforms and addressing emerging risks; (ii) developing innovative and strategic action points for intervention {in addition to Hazard Analysis and Critical Control Points (HACCP) procedures]; and (iii) introducing additional science-based tools such as metrology-based measurement systems.

Monitoring the Structural Dynamics of U2 snRNA Via Single-Molecule Förster Resonance Energy Transfer

2018 ◽  
Author(s):  
Alexander Carl DeHaven
Keyword(s):  
Energy Transfer ◽  
Structural Dynamics ◽  
Single Molecule ◽  
Conformational Dynamics ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Förster Resonance Energy Transfer ◽  
U2 Snrna ◽  
Folding Dynamics ◽  
The Impact

This thesis contains four topic areas: a review of single-molecule microscropy methods and splicing, conformational dynamics of stem II of the U2 snRNA, the impact of post-transcriptional modifications on U2 snRNA folding dynamics, and preliminary findings on Mango aptamer folding dynamics.

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