Proteomic changes induced by harmine in human brain organoids reveal signaling pathways related to neuroprotection

Harmine, a β-carboline found in the ayahuasca vine Banisteriopsis caapi, upregulates proteins in human brain organoids that are involved in synaptic vesicle cycling, cytoskeleton-dependent transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling. Treatment with harmine also increased levels of Akt and phosphorylated CREB after 24 hours. These findings point to cellular and molecular pathways that may explain harmine's potential neuroprotective effects, which have been suggested by previous animal studies to include anti-inflammatory and antioxidant activities. The work advances understanding of how harmine might contribute to the antidepressant effects observed with ayahuasca.

Study at a glance

Abstract

Abstract Harmine is a β-carboline found in Banisteriopsis caapi , a constituent of ayahuasca brew. Ayahuasca is consumed as a beverage in native Americans’ sacred rituals and in religious ceremonies in Brazil. Throughout the years, the beneficial effects of ayahuasca to improve mental health and life quality have been reported, which propelled the investigation of its therapeutic potential to target neurological disorders such as depression and anxiety. Indeed, antidepressant effects of ayahuasca have been described, raising the question of which cellular mechanisms might underlie those effects. Previous animal studies describe potential neuroprotective mechanisms of harmine, including anti-inflammatory and antioxidant activities, and neurotrophin signaling activation. However, the cellular and molecular mechanisms modulated by harmine in human models remain less investigated. Here we analyzed the short-term changes in the proteome of human brain organoids treated with harmine using shotgun mass spectrometry. Harmine upregulates proteins related to synaptic vesicle cycle, cytoskeleton-dependent intracellular transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling pathway. In addition, protein expression levels of Akt and phosphorylated CREB were increased after 24 hour-treatment. Our results shed light on the potential mechanisms that may underlie harmine-induced neuroprotective effects.