Involvement of P2Y1, P2Y6, A1 and A2A Receptors in the Purinergic Inhibition of NMDA-Evoked Noradrenaline Release in the Rat Brain Cortex.

In the cerebral cortex, glutamate activates NMDA receptors (NMDARs), localized in noradrenergic neurons, inducing noradrenaline release that may have a permissive effect on glutamatergic transmission, and therefore, on the modulation of long-term plasticity. ATP is co-released with noradrenaline, and with its metabolites (ADP and adenosine) is involved in the purinergic modulation of electrically-evoked noradrenaline release. However, it is not known if noradrenaline release evoked by activation of NMDARs is also under purinergic modulation. The present study aimed to investigate and to characterize the purinergic modulation of noradrenaline release evoked by NMDARs. Stimulation of rat cortical slices with 30 µM NMDA increased noradrenaline release, which was inhibited by ATP upon metabolization into ADP and adenosine and by the selective agonists of A1 and A2A receptors, CPA and CGS2680, respectively. It was also inhibited by UTP and UDP, which are mainly released under pathophysiological situations. Characterization of the effects mediated by these compounds indicated the involvement of P2Y1, P2Y6, A1 and A2A receptors. It is concluded that, in the rat brain cortex, NMDA-evoked noradrenaline release is modulated by several purinergic receptors that may represent a relevant mechanism to regulate the permissive effect of noradrenaline on NMDA-induced neuroplasticity.

Comparing the Effects of Ferulic Acid and Sugarcane Aqueous Extract in In Vitro and In Vivo Neurotoxic Models.

Molecules exhibiting antioxidant, neuroprotective, and regulatory properties inherent to natural products consumed by humans are gaining attention in biomedical research. Ferulic acid (FA) is a phenolic compound possessing antioxidant and cytoprotective properties. It is found in several vegetables, including sugarcane, where it serves as the main antioxidant component. Here, we compared the antioxidant and cytoprotective effects of FA with those of the total sugarcane aqueous extract (SCAE). Specifically, we assessed biochemical markers of cell dysfunction in rat cortical brain slices and markers of physiological stress in Caenorhabditis elegans upon exposure to toxins evoking different mechanisms of neurotoxicity, including direct oxidative stress and/or excitotoxicity. In rat cortical slices, FA (250 and 500 µM), but not SCAE (~ 270 µM of total polyphenols), prevented the loss of reductive capacity induced by the excitotoxin quinolinic acid (QUIN, 100 µM), the pro-oxidant agent ferrous sulfate (FeSO4, 25 µM), and the dopaminergic pro-oxidant 6-hydroxydopamine (6-OHDA, 100 µM). In wild-type (N2) C. elegans, FA (38 mM) exerted protective effects on decreased survival induced by FeSO4 (15 mM) and 6-OHDA (25 mM), and the motor alterations induced by QUIN (100 mM), FeSO4, and 6-OHDA. In contrast, SCAE (~ 13.5 mM of total polyphenols) evoked protective effects on the decreased survival induced by the three toxic agents, the motor alterations induced by FeSO4, and the reproductive deficit induced by FeSO4. In addition, FA was unable to reverse the decreased survival induced by all these toxins in the skn-1-/- strain (VC1772), which lacks the homolog of mammalian Nrf2, a master antioxidant gene. Altogether, our results suggest that (1) both FA and SCAE afford protection against toxic conditions, (2) not all the effects inherent to SCAE are due to FA, and (3) FA requires the skn-1 pathway to exert its protective effects in C. elegans.