Resveratrol (RSV) is a natural compound present in berries, grapes and red wine that has shown some neuroprotective properties, but the mechanism by which RSV exhibits its protective role is not very well understood yet. Little is known about the effect of RSV on adenosinergic system, a system regulated in an age-dependent manner in SAMP8 mice, widely considered as an Alzheimer's model. Therefore, the aim of the present work was to assess whether RSV intake was able to modulate the adenosine-mediated signalling in SAMP8 mice. Data showed herein clearly demonstrate the ability of RSV to modulate adenosine receptor gene expression as well as transduction pathway mediated by receptors expressed on plasma membrane. Interestingly, this polyphenol was able to reverse the age-related loss of adenosine A receptors and its corresponding signalling pathway. Moreover, adenosine A receptors were not modulated by aging or RSV, but A-mediated signalling was completely desensitized after RSV treatment compared to untreated mice. Enzymes involved on adenosine metabolism, such as 5'-nucleotidase and adenosine deaminase, were found to be reduced after RSV treatment, but adenosine levels remained unchanged. Nevertheless, an age-related decrease on 5'-nucleotidase activity and adenosine and related metabolite levels was observed. In conclusion, our data show that RSV modulates adenosine-mediated signalling, strongly suggesting that the role of RSV via adenosine receptor signalling and its modulation of neurotransmission in neurodegenerative diseases should be considered as new therapeutic target for RSV neuroprotective effect.
Rationale: Caloric restriction improves the efficacy of anti-cancer therapy. This effect is largely dependent on the increase of the extracellular ATP concentration in the tumor microenvironment (TME). Pathways for ATP release triggered by nutrient deprivation are largely unknown. Methods: The extracellular ATP (eATP) concentration was in vivo measured in the tumor microenvironment of B16F10-inoculated C57Bl/6 mice with the pmeLuc probe. Alternatively, the pmeLuc-TG-mouse was used. Caloric restriction was in vivo induced with hydroxycitrate (HC). B16F10 melanoma cells or CT26 colon carcinoma cells were in vitro exposed to serum starvation to mimic nutrient deprivation. Energy metabolism was monitored by Seahorse. Microparticle release was measured by ultracentrifugation and by Nanosight. Results: Nutrient deprivation increases eATP release despite the dramatic inhibition of intracellular energy synthesis. Under these conditions oxidative phosphorylation was dramatically impaired, mitochondria fragmented and glycolysis and lactic acid release were enhanced. Nutrient deprivation stimulated a P2X7-dependent release of ATP-loaded, mitochondria-containing, microparticles as well as of naked mitochondria. Conclusions: Nutrient deprivation promotes a striking accumulation of eATP paralleled by a large release of ATP-laden microparticles and of naked mitochondria. This is likely to be a main mechanism driving the accumulation of eATP into the TME.
Glutamate homeostasis is critical for neurotransmission as this excitatory neurotransmitter has a relevant role in cognition functions through ionotropic and metabotropic glutamate receptors in the central nervous system. During the last years, the role of the group I metabotropic glutamate receptors (mGluRs) in neurodegenerative diseases such as Alzheimer's disease has been intensely investigated. Resveratrol (RSV) is a natural polyphenolic compound that is thought to have neuroprotective properties for human health. However, little is known about the action of this compound on mGluR signaling. Therefore, the aim of this study was to investigate the possible modulation of group I mGluRs in SAMP8 mice five and seven months of age supplemented with RSV in the diet. Data reported herein show that RSV plays a different modulatory action on group I mGluRs: mGluR 5 is downregulated as age increases, independently of RSV presence, and mGluR 1 is upregulated or downregulated by RSV treatment depending on age (i.e., depending on mGluR 5 levels). In addition, a neuroprotective role can be inferred for RSV as lower glutamate levels, higher synapsin levels, and unchanged caspase-3 activity were detected after RSV treatment. In conclusion, our findings indicate that RSV treatment modifies the group I mGluR-mediated glutamatergic system in SAMP8 mice, which could contribute to the beneficial effects of this natural polyphenol.
The mode of action of trans-resveratrol, a promising lead compound for the development of neuroprotective drugs, is unknown. Data from a functional genomics study were retrieved with the aim to find differentially expressed genes that may be involved in the benefits provided by trans-resveratrol. Genes that showed a significantly different expression (p<0.05, cut-off of a two-fold change) in mice fed with a control diet or a control diet containing trans-resveratrol were different in cortex, heart and skeletal muscle. In neocortex, we identified 4 up-regulated (Strap, Pkp4, Rab2a, Cpne3) and 22 down-regulated (Actn1, Arf3, Atp6v01, Atp1a3, Atp1b2, Cacng7, Crtc1, Dbn1, Dnm1, Epn1, Gfap, Hap, Mark41, Rab5b, Nrxn2, Ogt, Palm, Ptprn2, Ptprs, Syn2, Timp2, Vamp2) genes upon trans-resveratrol consumption. Network analysis of gene products provided evidence of plakophilin 4 up-regulation as a triggering factor for down-regulation of events related to synaptic vesicle transport and neurotransmitter release via underexpression of dynamin1 and Vamp2 (synaptobrevin 2) as node-gene drivers. Analysis by RT-qPCR of some of the selected genes in a glioma cell line showed that dynamin 1 mRNA was down-regulated even in acute trans-resveratrol treatments. Taken all together, these results give insight on the glial-neuronal networks involved in the neuroprotective role of trans-resveratrol.
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