| First Author | Burkhardt U | Year | 2014 |
| Journal | Neuropharmacology | Volume | 79 |
| Pages | 1-9 | PubMed ID | 24262632 |
| Mgi Jnum | J:215283 | Mgi Id | MGI:5604990 |
| Doi | 10.1016/j.neuropharm.2013.11.002 | Citation | Burkhardt U, et al. (2014) Phospholipase D is a target for inhibition of astroglial proliferation by ethanol. Neuropharmacology 79:1-9 |
| abstractText | The proliferation of astrocytes during early brain development is driven by growth factors and is accompanied by the activation of phospholipase D (PLD). Ethanol disrupts PLD signaling in astrocytes, a process which may contribute to delayed brain growth of fetuses exposed to alcohol during pregnancy. We here report that insulin-like growth factor 1 (IGF-1) is a strong mitogen for rat astrocytes (EC50 0.2 mug/ml) and a strong stimulator of astroglial PLD activity; both effects are inhibited by ethanol and 1-butanol, but not t-butanol, suggesting participation of PLD. Downregulation of PLD1 and exposure to the PLD1 inhibitor VU0359595 attenuated PLD activity and strongly reduced the mitogenic activity of serum and IGF-1. The PLD2 inhibitor VU0285655-1 also reduced PLD activity but had lesser effects on IGF-1-driven proliferation. PLD2 down-regulation affected serum - but not IGF-1-induced proliferation. In separate experiments, alcohol treatment of murine astrocytes taken from PLD-deficient animals revealed an insensitivity of PLD1(-/-) cells to 1-butanol whereas PLD2(-/-) cells were not affected. We conclude that astroglial proliferation induced by IGF-1 is critically dependent on the PLD signaling pathway, with a stronger contribution from PLD1 than PLD2. The teratogenic effects of ethanol may be explained, at least in part, by disruption of the IGF1-PLD signaling pathway. |
