Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP + ). MPP+'s mechanism of toxicity relates to its ability to inhibit complex-I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes, hence the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, while CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria.We extend these findings by characterising the drug's interactive effects at the METC level.CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+ -induced upregulated expression of Hypoxia Inducible Factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.

This study examines the reported use of three forms of address (tú, vos, usted) in Costa Rican Spanish. Previous studies indicate three phenomena of interest: (1) Usted is used with [+solidarity] interlocutors; (2) While tuteo has been historically absent, some studies suggest an increase in tuteo use among young speakers; (3) Older studies indicated that younger speakers were increasing their use of vos. Based on 209 surveys, results indicate an increase in ustedeo among younger speakers, which contradicts earlier studies. Possible explanations include the socio-political history of Costa Rica, as well as a linguistic reaction against the influx of voseo-using Nicaraguan immigrants. Finally, no clear evidence of expanding tuteo is found, at least for the survey data analyzed here.