Discovery of a Proneurogenic, Neuroprotective Chemical

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Cell (Impact Factor: 32.24). 07/2010; 142(1):39-51. DOI: 10.1016/j.cell.2010.06.018
Source: PubMed


An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:

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Available from: Noelle S Williams
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    • "Isx-9 also has therapeutic promise as it can induce terminally differentiated astrocytes to re-express neuronal genes and regain neurogenic potential in vitro (Zhang et al. 2011), revealing another way to recruit progenitor cells available for neuronal differentiation. Different small molecules also target different stages of neurogenesis; for example, KHS101 accelerates neuronal differentiation (Wurdak et al. 2010), and P7C3, prevents apoptosis of newborn neurons and improves cognition in aged rats (Pieper et al. 2010). Additional high throughput screening assays will likely lead to the discovery of additional neurogenic molecules and elucidate novel mechanisms regulating neurogenesis in healthy and pathological brain states. "
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    • "Once activated, microglia proliferate rapidly and secrete pro-inflammatory cytokines, chemokines, and neurotoxic molecules that contribute to a toxic microenvironment leading to neuronal death (Beggs and Salter, 2007; Block et al., 2007; Benarroch, 2013). P7C3 has been shown to foster stabilization of mitochondrial membrane potential in the face of otherwise overwhelming toxic insult (Pieper et al., 2010),and P7C3 may be acting directly on neurons in our model. In our model, neuronal Fig. 6. "
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    • "Interestingly, mice lacking Npas3, a genetic risk factor for schizophrenia, have SGZ proliferation deficits that accompany a thinning of the dentate gyrus and a loss of dendritic complexity in the mature neurons extending processes into the molecular layer and CA3 [29], [30]. While Disc131L/31L mutants have proliferation deficits and a degree of dentate gyrus thinning (though not reaching statistical significance) consistent with Npas3 null mice, only Disc1100P/100P mice have similar changes in neuronal morphology. "
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