Gabapentin-lactam induces dendritic filopodia and motility in cultured hippocampal neurons.
Gabapentin is currently used as a therapeutic agent against epilepsy as well as neuropathic pain. In contrast to gabapentin, its derivative gabapentin-lactam has a pronounced neuroprotective activity. We have studied in cultured hippocampal neurons whether gabapentin-lactam has also neurotrophic effects. Gabapentin-lactam enhanced the formation of dendritic filopodia, which are necessary for synapse formation. It also induced a network of F-actin-containing neurites. In studies with time lapse microscopy, gabapentin-lactam increased the addition but also the elimination of new branches. Affinity precipitation assays showed that gabapentin-lactam increased the GTP binding of the small GTPases Rac and Cdc42, which facilitate branch addition. Gabapentin-lactam also activated RhoA and phosphatidylinositol 3-kinases. In neurons transfected with dominant-negative RhoA or treated with the RhoA-inactivating C3 toxin, gabapentin-lactam increased the number of dendrites and branches. In the presence of Y-27632, which inhibits Rho kinase, newly added branches induced by gabapentin-lactam were no longer eliminated so that gabapentin-lactam increased the number of branches. Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide] also prevented the gabapentin-lactam induced activation of phosphatidylinositol 3-kinases. The phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] reduced the elimination of newly added branches caused by gabapentin-lactam and thus facilitated branch formation. In contrast to gabapentin-lactam, gabapentin had no effect on dendritic filopodia or motility. The effects exerted by gabapentin-lactam on dendritic arborization may be of potential therapeutic interest.
Henle
Frank
F
Zentrum für Neurowissenschaften, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albert-Strasse 25, D-79104 Freiburg, Germany.
Leemhuis
Jost
J
Fischer
Catharina
C
Bock
Hans H
HH
Lindemeyer
Kerstin
K
Feuerstein
Thomas J
TJ
Meyer
Dieter K
DK
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000577:Amides; D001372:Aza Compounds; D011725:Pyridines; D013141:Spiro Compounds; C404763:gabapentin-lactam; C108830:Y 27632; D019869:Phosphatidylinositol 3-Kinases; D020741:rho GTP-Binding Proteins