Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo

Abstract

The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks. Stem Cells 2017;35:458-472.

Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution

“…Animal studies suggest that Banisteriopsis caapi preparations produce antidepressant activity through hippocampal neurogenesis (Farzin and Mansouri 2006 ; Fortunato et al 2010 ). A recent study demonstrated that harmine, tetrahydroharmine, and harmaline, the three main alkaloids present in the Banisteriopsis caapi , stimulate adult neurogenesis in vitro using hippocampal progenitor cells from adult mice (Morales-Garcia et al 2017 ). Neurogenesis has also been suggested to underlie the acute and long-term antidepressant properties of other psychedelic compounds such as ketamine (Duman and Aghajanian 2012 ; Ma et al 2017 ) and psilocybin (Catlow et al 2013 ; Idell et al 2017 ).…”

Store-Operated Calcium Entries Control Neural Stem Cell Self-Renewal in the Adult Brain Subventricular Zone

“…In the brain, ablation of TRPC1 or STIM1 in knockout mice results in memory deficiencies [54,55]. Interestingly, adult neurogenesis has been implicated in learning and memory in both rodents and humans [56,57] and learning defects induced by impairment of neurogenesis could be reversed by restoring neurogenesis [58][59][60][61]. The decreases of NSC proliferation and selfrenewal induced by SOC inhibitors that we observed in vitro and in vivo after direct unilateral intracerebroventricular injection, suggest that SOCE could contribute to learning and memory not only by acting on synaptic remodeling of dendritic spines [62][63][64][65], but also by modulating NSC activities.…”

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro

“…Neural stem cells (NSCs) were isolated from the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle of adult C57BL/6 mice (3 months of age) and prepared following previously described methods 68 . A total number of 40 animals were used throughout the whole study, divided in four pools of 10 animals each.…”

“…At this point, with all NS having the same stage and size, cultures were treated daily for 7 days with vehicle or 1 μM solutions of each of the four β-carbolines tested: harmol, harmine, harmaline and tetrahydroharmine (THH). The effective dose of compounds was chosen based on our previous studies on β-carboline analogs 69 and the 7-day period was selected as a standard time frame used previously by our own and other research groups to test the neurogenic potential of drugs 37, 50, 68, 70 . The 1 μM concentrations chosen for the β-carbolines was lower than the 7.5 μM found to induce optimal proliferation in a previous in vitro study with harmine 33 but closer to the plasma concentrations of 0.52–1.52 μM reported for harmine and THH, respectively, in a recent study involving ayahuasca administration to healthy humans 71 .…”