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

Héctor De Jesús-Cort́es, Pin Xu, Jordan Drawbridge, Sandi Jo Estill, Paula Huntington, Stephanie Tran, Jeremiah Britt, Rachel Tesla, Lorraine Morlock, Jacinth Naidoo, Lisa M. Melito, Gelin Wang, Noelle S. Williams, Joseph M. Ready, Steven L. McKnight, Andrew A. Pieper

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)17010-17015
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
Dentate Gyrus
Parkinson Disease
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopaminergic Neurons
Caenorhabditis elegans
Hippocampus
Cell Death
Newborn Infant
1-Methyl-4-phenylpyridinium
Proxy
Substantia Nigra
Apoptosis
Neurons
Brain
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • General

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De Jesús-Cort́es, H., Xu, P., Drawbridge, J., Estill, S. J., Huntington, P., Tran, S., ... Pieper, A. A. (2012). Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America, 109(42), 17010-17015. https://doi.org/10.1073/pnas.1213956109

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. / De Jesús-Cort́es, Héctor; Xu, Pin; Drawbridge, Jordan; Estill, Sandi Jo; Huntington, Paula; Tran, Stephanie; Britt, Jeremiah; Tesla, Rachel; Morlock, Lorraine; Naidoo, Jacinth; Melito, Lisa M.; Wang, Gelin; 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. 17010-17015.

Research output: Contribution to journalArticle

De Jesús-Cort́es, H, Xu, P, Drawbridge, J, Estill, SJ, Huntington, P, Tran, S, Britt, J, Tesla, R, Morlock, L, Naidoo, J, Melito, LM, Wang, G, Williams, NS, Ready, JM, McKnight, SL & Pieper, AA 2012, 'Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 42, pp. 17010-17015. https://doi.org/10.1073/pnas.1213956109
De Jesús-Cort́es, Héctor ; Xu, Pin ; Drawbridge, Jordan ; Estill, Sandi Jo ; Huntington, Paula ; Tran, Stephanie ; Britt, Jeremiah ; Tesla, Rachel ; Morlock, Lorraine ; Naidoo, Jacinth ; Melito, Lisa M. ; Wang, Gelin ; Williams, Noelle S. ; Ready, Joseph M. ; McKnight, Steven L. ; Pieper, Andrew A. / Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 42. pp. 17010-17015.
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AU - De Jesús-Cort́es, Héctor

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AU - Huntington, Paula

AU - Tran, Stephanie

AU - Britt, Jeremiah

AU - Tesla, Rachel

AU - Morlock, Lorraine

AU - Naidoo, Jacinth

AU - Melito, Lisa M.

AU - Wang, Gelin

AU - Williams, Noelle S.

AU - Ready, Joseph M.

AU - McKnight, Steven L.

AU - Pieper, Andrew A.

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