Mariana Pazos started her academic career in the field of organic synthesis of biologically active compounds, while finishing her degree on medicinal chemistry. As she moved on to her graduate studies, she continued to work on the field of organic chemistry and started working on diverse phenotypic screening methodologies as she obtained her PhD in Chemistry from the University of the Republic in 2018, in Montevideo, Uruguay. Since 2021, she is a member of the Neurodegeneration and Neuroprotection Mechanisms Laboratory at the Clemente Estable Research Institute (IIBCE). She carries out her research studying the molecular mechanisms underlying the neuritogenic effect of various psychedelic substances using the PC12 cell line as a model.

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https://arche.ei.udelar.edu.uy/arche-grupo-interdisciplinario-de-investigacion-sobre-psicodelicos/

@arche_uruguay

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Ayahuasca’s psychedelic component DMT promotes neuritogenesis in PC12 cells

Ayahuasca, the psychedelic beverage originally from the Amazon rainforest, has been used for centuries in different shamanic settings for medicinal, spiritual, and cultural purposes. It is prepared by decoction of the vine Banisteriopsis caapi, source of β-carboline alkaloids, and Psychotria viridis, containing the classic psychedelic N,N-dimethyltryptamine (DMT). Several recent scientific reports highlight its therapeutic potential for the treatment of depression and substance use disorders, among others. The DMT present in Ayahuasca is a potent agonist of the serotoninergic receptor 5-HT2A, interacts with other serotonin receptors and the sigma-1 receptor (S1R), among others. DMT has been recently categorized as a “psychoplastogen”, able to promote structural and functional neuroplastic changes in cortical cell cultures. This property suggests that the therapeutic potential of DMT might include other pathologies where neuronal plasticity is compromised like in neurodegenerative diseases.
In this work, we studied DMT’s ability to promote neuritogenesis in the catecholaminergic cell line PC12. When cultured in the presence of nerve growth factor (NGF), PC12 cells differentiate and acquire neuronal characteristics both morphologically and functionally. We used PC12 cells as a model to characterize DMT’s neuritogenic capacity by itself and under NGF deficient conditions, as a potential treatment for neurodegeneration of catecholaminergic systems. We used pharmacological inhibitors of receptors and signaling pathways to characterize the molecular mechanisms involved.
We have found that DMT promotes neuritogenesis in PC12 cells by itself and, when in presence of low NGF concentrations, in an additive manner. Selective pharmacological inhibition suggests different neuritogenesis mechanisms for NGF and DMT, since the latter depends on S1R whereas NGF differentiation does not. On the other hand, tyrosine-kinase (Trk) receptors are key for both NGF and DMT-mediated neuritogenesis, whereas 5-HT2AR is not. Finally, we have identified the involvement of Akt and PLCγ pathaways in DMT’s neuritogenic effect.
Given the relation between S1R and mitochondrial function, we are now working to characterize DMT’s action on PC12 cells regarding mitochondrial dynamics. We are also evaluating potential interactions between NGF-receptor, TrkA, and S1R upon DMT stimulation.