European journal of pharmacology
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Perturbation of endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress are thought to underlie a spectrum of defects encompassing major societal diseases such as diabetes and neurodegeneration. In this report we used the NG115-401L neuronal cell line to test the hypothesis that neuroprotection against ER stress may be conferred by pharmacological stimulation of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pumps. We report that the SERCA activator gingerol stimulates SR microsomal Ca(2+)-ATPase activity and restores enzymatic function in the presence of potent SERCA blockers. ⋯ These observations suggest that gingerol is not acting as a traditional SERCA blocker as thapsigargin mediated ER Ca(2+) store depletion fails to stimulate Ca(2+) influx in the NG115-401L cell phenotype. Moreover, cell death induced by gingerol, in contrast to the classic SERCA inhibitors, is not accompanied by increases in reactive oxygen species production or enzymatic caspase activity. These results argue for a finer regulatory control on SERCA function with gingerol's actions revealing potentially novel routes of coupling altered pump regulation to the assembly of functional Ca(2+) influx units and activation of cell death pathways.
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Itch is an unpleasant sensation that evokes a desire to scratch. Although often regarded as a trivial 'alarming' sensation, itch may be debilitating and exhausting, leading to reduction in quality of life. In the current study, the question of whether caffeic acid can be used to alleviate itch sensation induced by various pruritic agents, including histamine, chloroquine, SLIGRL-NH2, and β-alanine was investigated. ⋯ However, it was found that caffeic acid is not capable of inhibiting β-alanine-induced responses via its specific receptor MRGPRD. Finally, in vivo scratching behavior tests showed that caffeic acid indeed has anti-scratching effects against histamine, chloroquine, and SLIGRL-NH2 administration but not by β-alanine. Overall, the current study demonstrated that caffeic acid has anti-itch effects by inhibition of multiple itch mechanisms induced by histamine, chloroquine and SLIGRL-NH2.
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Macranthol is a lignans natural product isolated from Illicium dunnianum Tutch. Our previous study has demonstrated that macranthol exerted an antidepressant-like effect in mice, at least in part, by increasing expression of hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the relationship between macranthol and BDNF downstream signaling pathway in the hippocampus remains unknown. ⋯ Our results found that pharmacological inhibition of tropomyosin related kinase B (TrkB) with K252a abolished the improvement of macranthol on sucrose preference and immobility time, and attenuated the stimulatory effect of macranthol on hippocampal BDNF and phospho-Akt. Furthermore, K252a also reversed the improvement of macranthol on hippocampal Bcl-2, caspase-3 expression and hippocampal neuronal cell proliferation. Therefore, our findings verify that macranthol-mediated antidepressant-like action is associated with BDNF-TrkB and downstream activation of PI3K/Akt-Bcl-2/caspase-3 signaling pathway.