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GEN News Highlights : Oct 2, 2012

Protecting Neurons in Parkinson’s Disease and ALS

A recently identified class of chemical compounds has been shown to block nerve cell death in animal models of both Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The original compound in this series, an amino propyl carbazole (designated P7C3), was originally discovered by a University of Texas Southwestern Medical Center through an in vivo screen for small molecules that enhanced postnatal hippocampal neurogenesis. P7C3 was shown to improve hippocampal functioning, and help slow neuronal death and preserve cognitive functioning in aging rodents.

Through their latest work, reported in two papers in PNAS, Andrew A. Pieper, M.D., and colleagues have demonstrated that P7C3 and an even more potent variant, P7C3 A20, protect mature neurons in other regions of the brain, and may serve as scaffolds for the development of drugs against both Parkinson’s disease and ALS. Their studies showed that P7C3 A20 and, to a lesser extent its predecessor P73, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated cell death of dopaminergic neurons in the substantia nigra of a adult mice (a recognized model of Parkinson’s disease), and also protected dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+, the active product of MPTP)-toxicity in a Caenorhabditis elegans model of neurodegeneration. Notably, preservation of dopaminergic neurons following P7C A20 treatment in the worm model was associated with improvements in the animals swimming motion, when compared with untreated animals.

P7C3 A20 in addition protected ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of ALS. In this model, P7C3 was effective when administration was initiated at disease onset, and its neuroprotective effects correlated with the treated animals retaining motor functions such as walking gate and coordination.

“We conclude that P7C3 A20 and P7C3 display a hierarchy of activities analogous to their abilities to protect newborn hippocampal neurons from cell death, to block MPTP-mediated killing of mature dopaminergic neurons in the substantia nigra (19), and to protect spinal motor neurons from dying in G93A-SOD1 mutant mice,” the investigators write. Given that the original compound was identified through a relatively rapid screen for small molecules that stimulate neurogenesis, they hope that this same screening approach may yield even more potent compounds that protect against neuronal cell death. “On the basis of the observations reported herein, we propose that a properly optimized variant of the P7C3 class of proneurogenic, neuroprotective chemicals may offer promise for the future treatment of neurodegenerative disease.”

The UT Southwestern team’s findings are published in two PNAS papers, titled “Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease” and “Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis.”