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A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates.

Injury to the central nervous system (CNS) can result in lifelong loss of function due in part to the regenerative failure of CNS neurons. Inhibitory proteins derived from myelin and the astroglial scar are major barriers for the successful regeneration of injured CNS neurons. Previously, we described the identification of a novel compound, F05, which promotes neurite growth from neurons challenged with inhibitory substrates in vitro, and promotes axonal regeneration in vivo (Usher et al., 2010). To identify additional regeneration-promoting compounds, we used F05-induced gene expression profiles to query the Broad Institute Connectivity Map, a gene expression database of cells treated with >1300 compounds. Despite no shared chemical similarity, F05-induced changes in gene expression were remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). In contrast to antipsychotics of other structural classes, PhAPs promoted neurite growth of CNS neurons challenged with two different glial derived inhibitory substrates. Our pharmacological studies suggest a mechanism whereby PhAPs promote growth through antagonism of calmodulin signaling, independent of dopamine receptor antagonism. These findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest that clinically approved antipsychotic compounds may be repurposed for use in CNS injured patients.

Pubmed ID: 22561309 RIS Download

Mesh terms: Animals | Antipsychotic Agents | Brain | CHO Cells | Calcium Signaling | Cell Line, Tumor | Cells, Cultured | Chondroitin Sulfate Proteoglycans | Cricetinae | Cricetulus | Gene Expression Profiling | Humans | Neurites | Neurons | Oligonucleotide Array Sequence Analysis | Phenothiazines | Piperazines | Rats | Regeneration

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Associated grants

  • Agency: NEI NIH HHS, Id: P30 EY014801
  • Agency: NINDS NIH HHS, Id: U01NS074490
  • Agency: NICHD NIH HHS, Id: R01 HD057632
  • Agency: NICHD NIH HHS, Id: R01HD057632
  • Agency: NINDS NIH HHS, Id: F31 NS063593
  • Agency: NEI NIH HHS, Id: R01 EY020913
  • Agency: NINDS NIH HHS, Id: R01 NS059866
  • Agency: NINDS NIH HHS, Id: F31NS063593
  • Agency: NINDS NIH HHS, Id: U01 NS074490
  • Agency: NINDS NIH HHS, Id: R01NS059866
  • Agency: NEI NIH HHS, Id: P30EY014801

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