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

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.

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

“…22). In this model, using mice expressing a high level of a human transgene encoding a mutated variant of the gene encoding human Cu,Zn superoxide dismutase (23)(24)(25)(26)(27), we have observed the same hierarchy of activities wherein P7C3A20 is active, P7C3 is intermediately active, and Dimebon is inactive (22).…”

“…22). In this model, using mice expressing a high level of a human transgene encoding a mutated variant of the gene encoding human Cu,Zn superoxide dismutase (23)(24)(25)(26)(27), we have observed the same hierarchy of activities wherein P7C3A20 is active, P7C3 is intermediately active, and Dimebon is inactive (22). If the more active variants of this class of compounds indeed possess neuroprotective properties, and if we can rely on the relatively rapid in vivo assay of enhanced neurogenesis to rank order compounds for SAR scoring, it should be possible to optimize variants with the goal of selecting an appropriately qualified chemical to advance for human testing.…”

Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1)

“…Regardless, our findings demonstrate that it is possible to modify astrocytemotor neuron interaction by enhancing NAD ϩ salvage pathway in the astrocytes. Interestingly, aminopropyl carbazole derivatives previously shown to preserve motor function in hSOD1 G93A mice have been recently identified as NAMPT activators (71,72). In summary, because we have shown that therapeutic targets identified in this co-culture system may have a beneficial effect when translated into animal models of ALS (45), our data suggest that further investigation regarding the therapeutic potential of increasing NAD ϩ availability to prevent astrocyte-mediated motor neuron death in ALS is deserved.…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…A potent P7C3 analogue (P7C3A20, 1.11b, Figure 1.2) is characterized in mice models of PD [137] and ALS [138]. It prevents 1-methyl-4-phenylpyridinium (MPP + )-mediated death of dopaminergic neurons in C. elegans and preserves worm mobility (≈80% protection and mobility preservation at 10 mM), with P7C3 being less active (≈50% protection and ≈60% mobility preservation at 10 mM) [137].…”