Discovery of a Proneurogenic, Neuroprotective Chemical

Abstract

Summary An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1,000 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 pro-neurogenic 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.

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

“…Interestingly, a recent study reported that dimebon had remarkable effects on hippocampal neurogenesis, at doses comparable to those used in the present study (Pieper et al, 2010). One-week treatment of rats with dimebon at a dose of 0.1 mkM/kg (0.32 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus.…”

“…One-week treatment of rats with dimebon at a dose of 0.1 mkM/kg (0.32 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus. Because activation of structural plasticity and neurogenesis in the hippocampus is well demonstrated to be implicated in the mechanisms of contextual and spatial learning (Epp et al, 2007;Yang et al, 2008;Li et al, 2010;Pieper et al, 2010), we suggest that this effect might be one of the potential mechanisms which underlie the memory enhancing action of dimebon observed in the current study. Further experiments are required to address the possible link between the mnemonic effects of dimebon and its properties as a proneurogenic compound.…”

“…Dimebon prevents the opening of mitochondrial pores induced by neurotoxins, which is regarded as the major pathogenetic factor of neurodegeneration Hung, 2008), elevates extracellular levels of amyloid beta in cell culture and the hippocampus of freely moving Tg2576 mice (Steele et al, 2009), promotes neurite outgrowth in cultured hippocampal and cortical neurons Bernales et al, 2009), and enhances hippocampal neurogenesis (Pieper et al, 2010).…”

“…Recent studies provide evidence for a stimulatory effect by dimebon on neurogenesis in the dentate gyrus of the hippocampus in rats, observed after 1-week of intraperitoneal injections of the drug applied at the same range of concentrations: 0.1 MKM/kg (0.32 mg/kg; Pieper et al, 2010). Therefore, we anticipated that repeated dosing with dimebon at a dose of 0.1 mg/kg, and single administration of a dose of 0.5 mg/kg, would evoke similar neurobiological effects as described in the literature.…”

Neurogenic hypothesis and psychiatric disorders

“…Transgenic mice with NPAS3 mutation showed a behavioral phenotype with reduced memory, impaired social recognition and impaired sensorimotor gating [86], which are also characteristics of schizophrenic patients. These animals simultaneously had a reduced neurogenesis in the dentate gyrus [87]. Aminopropyl carbazole, which promotes neurogenesis by preventing apoptosis in the neurogenesis process, was able to increase neurogenesis and reversed the malformation of dentate gyrus in NPAS3 knock-out animals [86].…”