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

ABSTRACT: Injury to the central nervous system (CNS) may result in lifelong loss of function due, in part, to the regenerative failure of CNS neurons. Major barriers to regeneration faced by injured CNS neurons include inhibitory proteins derived from myelin and the astroglial scar. 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 the microarray derived gene expression signature of F05 to query the Broad Institute Connectivity Map, a database of gene expression profiles for cells treated with >1,300 compounds. Unexpectedly, F05 induced changes in gene expression remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). We found that, in contrast to antipsychotics of other structural classes, PhAPs were able to promote neurite growth of CNS neurons cultured on two different glial-derived inhibitory substrates, but did not promote growth on a permissive substrate. Pharmacological studies suggest that the ability of PhAPs to promote growth depends on antagonism of calmodulin signaling, but not on dopamine receptor antagonism. Our findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest a potential pathway for development of novel treatments for CNS injury. 3 Biological Replicates of Vehicle Treated (0.05% DMSO) + 3 Biological Replicates of F05 Treated (5 μM)

ORGANISM(S): Homo sapiens

SUBMITTER: Andrea Johnstone 

PROVIDER: E-GEOD-34331 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress