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

Rachel Tesla, HamiltonParker Wolf, Pin Xu, Jordan Drawbridge, SandiJo Estill, Paula Huntington, LaTisha McDaniel, Whitney Knobbe, Aaron Burket, Stephanie Tran, Ruth Starwalt, Lorraine Morlock, Jacinth Naidoo, Noelle S. Williams, Joseph M. Ready, Steven L. McKnight, Andrew A. Pieper

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17016-17021
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number42
DOIs
StatePublished - Oct 16 2012

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Carbazoles
Amyotrophic Lateral Sclerosis
Cell Death
Rotarod Performance Test
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parahippocampal Gyrus
Dopaminergic Neurons
Dentate Gyrus
Neurotoxins
Motor Neurons
Substantia Nigra
Gait
Walking
Parkinson Disease
Disease Progression
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

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Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis. / Tesla, Rachel; Wolf, HamiltonParker; Xu, Pin; Drawbridge, Jordan; Estill, SandiJo; Huntington, Paula; McDaniel, LaTisha; Knobbe, Whitney; Burket, Aaron; Tran, Stephanie; Starwalt, Ruth; Morlock, Lorraine; Naidoo, Jacinth; Williams, Noelle S.; Ready, Joseph M.; McKnight, Steven L.; Pieper, Andrew A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 42, 16.10.2012, p. 17016-17021.

Research output: Contribution to journalArticle

Tesla, R, Wolf, H, Xu, P, Drawbridge, J, Estill, S, Huntington, P, McDaniel, L, Knobbe, W, Burket, A, Tran, S, Starwalt, R, Morlock, L, Naidoo, J, Williams, NS, Ready, JM, McKnight, SL & Pieper, AA 2012, 'Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 42, pp. 17016-17021. https://doi.org/10.1073/pnas.1213960109
Tesla, Rachel ; Wolf, HamiltonParker ; Xu, Pin ; Drawbridge, Jordan ; Estill, SandiJo ; Huntington, Paula ; McDaniel, LaTisha ; Knobbe, Whitney ; Burket, Aaron ; Tran, Stephanie ; Starwalt, Ruth ; Morlock, Lorraine ; Naidoo, Jacinth ; Williams, Noelle S. ; Ready, Joseph M. ; McKnight, Steven L. ; Pieper, Andrew A. / Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 42. pp. 17016-17021.
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AU - Tran, Stephanie

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AU - Naidoo, Jacinth

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