Abstract
Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.
Highlights
Throughout life, specific regions in the human adult brain continuously generate neural cells from a pool of neural progenitor cells
We show that harmine increased the pool of neural progenitor cells and that inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is the possible mechanism involved in those proliferative effects
Harmine has been shown to be an inhibitor of DYRK1A (Becker & Sippl, 2011; Gockler et al, 2009), other DYRK family members (Gockler et al, 2009) and monoamine oxidase (MAO) (Santillo et al, 2014). To verify whether these two targets are involved in the harmine-dependent increase in neural proliferation, we examined the effect of two functional analogs of harmine in human neural cells: INDY (15 μM), an inhibitor of DYRK1A; and pargyline (10 μM), an irreversible selective inhibitor of MAO but not DYRK1A
Summary
Throughout life, specific regions in the human adult brain continuously generate neural cells from a pool of neural progenitor cells (hNPCs). Many physiological and pathological events are able to control neurogenesis by modulating proliferation, differentiation, maturation and integration of newborn neurons into the existing circuitry (Zhao, Deng & Gage, 2008). This balance can be disrupted by chronic stress (Egeland, Zunszain & Pariante, 2015) depression (Mahar et al, 2014), aging (DeCarolis et al, 2015), and neurodegenerative diseases (Winner & Winkler, 2015). Classical antidepressants can reverse or block stress-induced hippocampal atrophy in rodents, mostly by stimulating neuronal proliferation (Malberg et al, 2000). The demand for novel psychopharmacological agents able to revert depression remains significant
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