TY - JOUR
T1 - A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates
AU - Johnstone, Andrea L.
AU - Reierson, Gillian W.
AU - Smith, Robin P.
AU - Goldberg, Jeffrey L.
AU - Lemmon, Vance P.
AU - Bixby, John L.
N1 - Funding Information:
We thank Dr. Stan Hoffman for generously donating CSPGs, and Dr. Roman Giger for the gift of MAG-expressing CHO cells. We also thank Dr. Justin Lamb (Broad Institute) for helping to determine the experimental conditions for optimizing the microarray experiments. We acknowledge the support of the NINDS/NIMH Microarray Consortium in performing the microarray experiments. We thank Tania Slepak, Dr. Anthony Oliva, Guerline Lambert, Dr. Hassan Al-Ali, Dr. Michael Steketee, and Ephraim Trakhtenberg for help with neuronal cultures. This work was supported by grants from the National Institutes of Health ( R01NS059866 , F31NS063593 , R01HD057632 , P30EY014801 and U01NS074490 ), from the Buoniconti Foundation , and from an unrestricted grant from Research to Prevent Blindness . VPL and JLG are supported by the Walter G. Ross Foundation .
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Antipsychotics
KW - Chondroitin sulfate proteoglycans
KW - Myelin
KW - Phenothiazine
KW - Piperazine
KW - Prochlorperazine
KW - Regeneration
KW - Trifluoperazine
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U2 - 10.1016/j.mcn.2012.04.008
DO - 10.1016/j.mcn.2012.04.008
M3 - Article
C2 - 22561309
AN - SCOPUS:84861388460
VL - 50
SP - 125
EP - 135
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
SN - 1044-7431
IS - 2
ER -