Marilyn Magazin

Evidence for nerve growth factor-potentiating activities of the nonpeptidic compound SR 57746A in PC12 cells

Abstract: SR 57746A {1‐[2‐(naphth‐2‐yl)ethyl]‐4‐(3‐trifluoromethylphenyl)‐1,2,5,6‐tetrahydropyridine hydrochloride} exhibits neurotrophic activities in vivo and in vitro. We used the rat pheochromocytoma PC12 cell line to investigate in vitro cellular changes induced by SR 57746A. A significant increase in the percentage of cells bearing neurite‐like processes was obtained in cells treated by SR 57746A and nerve growth factor (NGF) compared with NGF treatment alone. SR 57746A added alone, however, had no effect on morphogenesis or on survival of cells in serum‐free medium. In contrast, SR 57746A induced a “priming” effect on PC12 cells for neurite outgrowth within 6 h of addition of the protein tyrosine kinase inhibitor genistein. An increase in α‐actinin content resulted from treatment with SR 57746A. Expression of NGF‐mediated acetylcholinesterase and choline acetyltransferase was enhanced within 5 days by SR 57746A. The molecule also induced rapid F‐actin redistribution. Within 2 min of incubation, outgrowth of F‐actin‐containing filopodia was clearly visible at the cell periphery, as previously shown with NGF. It is interesting that this effect of SR 57746A could be mimicked by protein tyrosine kinase inhibitors and abolished by preincubation with sodium orthovanadate, a protein tyrosine phosphatase inhibitor.

Inhibition of lysophosphatidic acid-induced neurite retraction and cell rounding by SR 57746A.

Rapid neurite retraction and transient rounding of serum-starved NG108-15 and PC12 cells by lysophosphatidic acid (LPA) is retarded and reduced by pre-incubation of the cells with the small non-peptidic molecule, SR 57746A, which exhibits neurotrophic properties. The compound also antagonizes the redistribution of filamentous actin by LPA in both cell types. We hypothesize that the SR 57746A attenuation of LPA-induced effects may account for at least some of the neuroprotective properties of this molecule.