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NEUROPHARMACOLOGY

Gabapentin-Lactam Induces Dendritic Filopodia and Motility in Cultured Hippocampal Neurons

Zentrum für Neurowissenschaften, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie (F.H., J.L., C.F., K.L., D.K.M.), Zentrum für Neurowissenschaften, Abteilung Innere Medizin II (H.H.B.), and Sektion Klinische Neuropharmakologie der Neurochirurgischen Universitätsklinik (T.J.F.), Albert-Ludwigs-Universität, Freiburg, Germany

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.

Address correspondence to: Dr. Dieter K. Meyer, Zentrum für Neurowissenschaften, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albert-Strasse 25, D-79104 Freiburg, Germany. E-mail: dieter.meyer{at}pharmakol.uni-freiburg.de