PAF analogues capable of inhibiting PAF acetylhydrolase activity suppress migration of isolated rat cerebellar granule cells.
Intracellular platelet-activating factor (PAF) acetylhydrolase in the bovine brain is a heterotrimeric enzyme composed of alpha1, alpha2 and beta subunits. The trimeric enzyme may be involved in neural cell migration, since the human homolog of the non-catalytic beta subunit is a product of the LIS-1 gene which is a causative gene for Miller-Dieker syndrome. Miller-Dieker syndrome is a form of lissencephaly that is characterized by widespread agyria of the brain and defects of neuronal cell migration. In the present study, we attempted to determine whether the catalytic activity of either the alpha1 or alpha2 subunit is required for the regulation of granule cell migration. Granule cells prepared from rat cerebellum at postnatal day 0 express all three subunit proteins (alpha1, alpha2 and beta) as determined by western blotting. Granule cell migration, which was observed in vitro on a layer coated with laminin, was effectively blocked by PAF analogs which showed PAF receptor-antagonistic activity (CV-6209 and CV-3988) and PAF receptor-agonistic activity (carbamoyl PAF). These PAF analogs also inhibited the activity of bovine brain PAF acetylhydrolase. Cell migration was restored when the inhibitors were removed by washing the treated cells with buffer, indicating that the inhibitory effect of PAF analogs is reversible. Structurally-unrelated PAF antagonists (SM-12502, TCV-309 and YM-264), none of which showed any appreciable inhibitory activity against PAF acetylhydrolase, did not block granule cell migration under the same conditions. It is suggested that the catalytic activity of PAF acetylhydrolase may play a crucial role in neural cell migration.
Adachi
T
T
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Aoki
J
J
Manya
H
H
Asou
H
H
Arai
H
H
Inoue
K
K
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats
D004791:Enzyme Inhibitors; D010972:Platelet Activating Factor; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase