Cited by 130Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsNeurogenetic and Muscular Disorders Research

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

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Tesla, Rachel, Wolf, Hamilton Parker, Xu, Pin, Drawbridge, Jordan, Estill, Sandi Jo, 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.·2012·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1213960109PMC PMC3479516

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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 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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Authors: Tesla, R., Wolf, H. P., Xu, P., Drawbridge, J., Estill, S. J., Huntington, P., McDaniel, L., Knobbe, W., Burket, A., Tran, S., Starwalt, R., Morlock, L., Naidoo, J., Williams, N. S., Ready, J. M., McKnight, S. L., & Pieper, A. A.
Affiliations: The University of Texas Southwestern Medical Center (US)
Departments of bPsychiatry and
ORCID: Xu, Pin
Estill, Sandi Jo
Tran, Stephanie
Starwalt, Ruth
Naidoo, Jacinth
Williams, Noelle S.
Ready, Joseph M.
McKnight, Steven L.
Pieper, Andrew A.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2012-10
Volume: 109
Issue: 42
Pages: 17016-17021
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1213960109
PMC: PMC3479516
OpenAlex: W2158315174
Cited by: 129
References: 31
Citations by year: 2026: 3 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 3 · 2021: 8 · 2020: 12 · 2019: 8 · 2018: 15 · 2017: 15 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 7 · 2012: 2
FWCI: 6.88
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p01ca095471-10)
National Institute of Mental Health (R01MH087986)
National Cancer Institute (P01-CA095471)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
Keywords: amyotrophic lateral sclerosis, neuroprotection, SOD1 G93A mice, motor neuron survival, spinal motoneurons, disease-modifying therapy, early treatment initiation, dimebon, Parkinson's disease, MPTP, dopaminergic neurons, substantia nigra
MeSH terms: Amyotrophic Lateral Sclerosis, Animals, Carbazoles, Indoles, Motor Activity, Motor Neurons, Spinal Cord, Polymerase Chain Reaction, Neuroprotective Agents, Rotarod Performance Test, Mice

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

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