Development of Proneurogenic, Neuroprotective Small Molecules

MacMillan, Karen S.; Naidoo, Jacinth; Liang, Jue; Melito, Lisa; Williams, Noelle S.; Morlock, Lorraine; Huntington, Paula J.; Estill, Sandi Jo; Longgood, Jamie; Becker, Ginger L.; McKnight, Steven L.; Pieper, Andrew A.; Brabander, Jef K. De; Ready, Joseph M.

doi:10.1021/ja108211m

Cited by 152 publications

(126 citation statements)

References 49 publications

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“…Developing pharmacological strategies for selectively increasing adult neurogenesis remains a goal of the pharmaceutical industry; some initial success has been reported (Pieper et al 2010) and this lead compound is currently being refined (MacMillan et al 2011). , or lacking NR2B subunits in abGCs (Kheirbek et al 2012a) all perform worse than controls.…”

Section: Abgcs and Pattern Separationmentioning

confidence: 99%

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

2013

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In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity after the perinatal period suggests that unique aspects of the structure and function of DG and olfactory bulb circuits allow them to benefit from the adult generation of neurons. In this review, we consider the distinctive features of the DG that may account for it being able to profit from this singular form of neural plasticity. Approaches to the problem of neurogenesis are grouped as “bottom-up,” where the phenotype of adult-born granule cells is contrasted to that of mature developmentally born granule cells, and “top-down,” where the impact of altering the amount of neurogenesis on behavior is examined. We end by considering the primary implications of these two approaches and future directions.

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Section: Abgcs and Pattern Separationmentioning

confidence: 99%

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

2013

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“…1). This analog displays a more favorable toxicity profile than P7C3, with no hERG channel binding, histamine receptor binding, or toxicity to HeLa cells (2,4,5). We have also found that Dimebon, an antihistaminergic drug long deployed in Russia that is claimed to have anti-apoptotic and mitochondrial protective properties (6, 7), displays modest efficacy in the same biologic assays used to discover and characterize P7C3 and P7C3A20 (2).…”

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confidence: 99%

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease

Jesús-Cortés¹,

Xu²,

Drawbridge³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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117

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We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the dentate gyrus. Here, we provide evidence that P7C3 also protects mature neurons in brain regions outside of the hippocampus. P7C3 blocks 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated cell death of dopaminergic neurons in the substantia nigra of adult mice, a model of Parkinson disease (PD). Dose-response studies show that the P7C3 analog P7C3A20 blocks cell death with even greater potency and efficacy, which parallels the relative potency and efficacy of these agents in blocking apoptosis of newborn neural precursor cells of the dentate gyrus. P7C3 and P7C3A20 display similar relative effects in blocking 1-methyl-4-phenylpyridinium (MPP + )-mediated death of dopaminergic neurons in Caenorhabditis elegans, as well as in preserving C. elegans mobility following MPP + exposure. Dimebon, an antihistaminergic drug that is weakly proneurogenic and neuroprotective in the dentate gyrus, confers no protection in either the mouse or the worm models of PD. We further demonstrate that the hippocampal proneurogenic efficacy of eight additional analogs of P7C3 correlates with their protective efficacy in MPTP-mediated neurotoxicity. In vivo screening of P7C3 analogs for proneurogenic efficacy in the hippocampus may thus provide a reliable means of predicting neuroprotective efficacy. We propose that the chemical scaffold represented by P7C3 and P7C3A20 provides a basis for optimizing and advancing pharmacologic agents for the treatment of patients with PD.

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“…edu, joseph.ready@utsouthwestern.edu, or andrew-pieper@uiowa.edu. receptor binding, or toxicity to HeLa cells (13,15,16). We have also found that Dimebon, an antihistaminergic drug that is reported to have anti-apoptotic and mitochondrial protective properties (17,18), displays modest efficacy in the same biologic assays used to discover and characterize P7C3 and P7C3A20.…”

mentioning

confidence: 99%

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis

Tesla

Wolf

Xu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

115

101

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We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.

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Development of Proneurogenic, Neuroprotective Small Molecules

Cited by 152 publications

References 49 publications

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis

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