Raloxifene induces neurite outgrowth in estrogen receptor positive PC12 cells.
OBJECTIVE
It is well established that gonadal steroids have direct in vivo and in vitro effects on neurons. To further study these effects, we used rat PC 12 cells to examine the effects of estrogen receptor (ER) ligands on neuronal morphology.


METHODS
PC 12 cells constitutively express ER beta, but only strongly express ER alpha after long-term priming with nerve growth factor (NGF). We therefore primed PC12 cells with NGF for 14 days before testing them for estradiol (10(-9)M)- and/or raloxifene (10(-7) M)-induced neurite growth. Neurite growth was assessed by quantitative light microscopy. As control, ER status of the PC12 cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
In this study, both estradiol and raloxifene induced the outgrowth of neurites in NGF-treated PC 12 cells (p < 0.05). The combination of estradiol- and raloxifene-induced neurite growth was statistically greater than the effects of either agent alone. RT-PCR confirms that NGF-treated PC 12 cells express both ERalpha and ERbeta.


CONCLUSIONS
This report is the first on the neurotrophic effect of raloxifene. At 10(-7) M, raloxifene's effect equaled that of estradiol; moreover, raloxifene did not block the neurite growth of simultaneously estradiol-treated PC 12 cells, despite its functional antiestrogenic effects in vivo. We conclude that raloxifene is estrogen agonistic in this animal model and therefore studies are warranted to delineate the relationship between steroidal estrogen and raloxifene.
Nilsen
J
J
Department of Obstetrics and Gynecology and Center for Reproductive Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Mor
G
G
Naftolin
F
F
D000818:Animals; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology*; D016716:PC12 Cells / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004965:Estrogen Antagonists; D009414:Nerve Growth Factors; D010880:Piperidines; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride; D004958:Estradiol