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Mexican calea (Calea zacatechichi Schltdl.) interferes with cholinergic and dopaminergic pathways and causes neuroglial toxicity

2025-01-30Research article Embargoed access
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dc.contributor.authorGarcia, Maria Rita
dc.contributor.authorGil-Izquierdo, Ángel
dc.contributor.authorFerreres, Federico
dc.contributor.authorAndrade, Paula B.
dc.contributor.authorMineiro, Tiago
dc.contributor.authorSeabra, Vítor
dc.contributor.authorVideira, Romeu A.
dc.contributor.authorSilva, Diana Dias da
dc.contributor.authorGomes, Nelson G.M.
dc.contributor.authorDias da Silva, Diana Cristina
dc.date.accessioned2025-06-20T08:40:25Z
dc.date.available2025-06-20T08:40:25Z
dc.date.issued2025-01-30
dc.description.abstractThe use of “Mexican calea” (Calea zacatechichi Schltdl.) in ritualistic ceremonies, due to its dream-inducing effects, was until recently limited to indigenous communities in Mexico. However, the plant has recently gained popularity in Western societies being commonly used in recreational settings. Despite the traditional and recreational uses, mechanisms underlying its reported oneirogenic effects remain unknown, with no data available on its neurotoxic profile. The scarcity of toxicological data and the unknown role of major neurotransmitter systems in the dream-inducing properties of the plant prompted us to investigate which neurotransmitters might be affected upon its consumption, as well as the potential cytotoxic effects on neurons and microglial cells. Furthermore, we aimed to explore a relationship between the recorded effects and specific constituents. Effects on cholinergic and monoaminergic pathways were investigated using enzymatic assays, with the latter also being conducted in neuronal SH-SY5Y cells along with the impact on glutamate-induced excitotoxicity. Investigation of the neurotoxic profile was approached in neuronal SH-SY5Y and microglial BV-2 cells, evaluating effects on metabolic performance and membrane integrity using MTT and LDH leakage assays, respectively. Potential interference with oxidative stress was monitored by assessing free radical's levels, as well as 5-lipoxygenase mediated lipid peroxidation. Phenolic constituents were identified through HPLC-DAD-ESI(Ion Trap)MSn analysis. Based on the significant inhibition upon acetylcholinesterase (p < 0.05) and tyrosinase (IC50 = 60.87 ± 7.3 μg/mL; p < 0.05), the aqueous extract obtained from the aerial parts of C. zacatechichi interferes with the cholinergic and dopaminergic systems, but has no impact against monoamine oxidase A. Additionally, a notable cytotoxic effect was observed in SH-SY5Y and BV-2 cells at concentrations as low as 125 and 500 μg/mL (p < 0.05), respectively, LDH leakage suggesting apoptosis may occur at these concentrations, with necroptosis observed at higher ones. Despite the neurocytotoxic profile, these effects appear to be independent of radical stress, as the C. zacatechichi extract scavenged nitric oxide and superoxide radicals at concentrations as low as 62.5 μg/mL, significantly inhibiting also 5-lipoxygenase (IC50 = 72.60 ± 7.3 μg/mL; p < 0.05). Qualitative and quantitative analysis using HPLC-DAD-ESI(Ion Trap)MSn enabled the identification of 28 constituents, with 24 of them being previously unreported in this species. These include a series of dicaffeoylquinic, caffeoylpentoside, and feruloylquinic acids, along with 8 flavonols not previously known to occur in the species, mainly 3-O-monoglycosylated derivatives of quercetin, kaempferol, and isorhamnetin. Our findings regarding the neuroglial toxicity elicited by C. zacatechichi emphasize the necessity for a thorough elucidation of the plant's toxicity profile. Additionally, evidence is provided that the aerial parts of the plant inhibit both acetylcholinesterase and tyrosinase, potentially linking its psychopharmacological effects to the cholinergic and dopaminergic systems, with an apparent contribution from specific phenolic constituents previously unknown to occur in the species. Collectively, our results lay the groundwork for a regulatory framework on the consumption of C. zacatechichi in recreational settings and contribute to elucidating previous contradictory findings regarding the mechanisms underlying the dream-inducing effects of the plant.por
dc.identifier.citationGarcia, M. R., Ferreres, F., Mineiro, T., Videira, R. A., Gil-Izquierdo, Á., Andrade, P. B., Seabra, V., Dias-da-Silva, D., & Gomes, N. G. M. (2025). Mexican calea (Calea zacatechichi Schltdl.) interferes with cholinergic and dopaminergic pathways and causes neuroglial toxicity. Journal of Ethnopharmacology, 337, 118915. https://doi.org/10.1016/j.jep.2024.118915
dc.identifier.doi10.1016/j.jep.2024.118915
dc.identifier.eissn1872-7573
dc.identifier.issn0378-8741
dc.identifier.urihttp://hdl.handle.net/10400.22/30168
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relationUIDB/ 50006/2020
dc.relation.hasversionhttps://www.sciencedirect.com/science/article/pii/S0378874124012145
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectChlorogenic acid
dc.subjectEntheogen
dc.subjectNictoflorin
dc.subjectOneiromancy
dc.subjectPsychoactive
dc.subjectRutin
dc.titleMexican calea (Calea zacatechichi Schltdl.) interferes with cholinergic and dopaminergic pathways and causes neuroglial toxicitypor
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.issuePart 3
oaire.citation.titleJournal of Ethnopharmacology
oaire.citation.volume337
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameDias da Silva
person.givenNameDiana Cristina
person.identifier.ciencia-id7715-CF06-F0B5
person.identifier.orcid0000-0002-7331-9157
relation.isAuthorOfPublication1f32faf1-efa5-4ea0-982d-a755e1940abf
relation.isAuthorOfPublication.latestForDiscovery1f32faf1-efa5-4ea0-982d-a755e1940abf

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