Received for publication April 13, 2006.
Revised July 13, 2006.
Accepted for publication July 13, 2006.

Gabapentin-lactam induces dendritic filopodia and motility in cultured hippocampal neurons

Abstract

Gabapentin is currently used as a therapeutic agent against epilepsy as well as neuropathic pain. In contrast to gabapentin, its derivate 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 phosphatidylinositide 3-kinases. In neurons transfected with dominant negative RhoA or treated with the RhoA inactivating C3 toxin, GBP-L 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 also prevented the gabapentin-lactam induced activation of phosphatidylinositide 3-kinases. The phosphatidylinositide 3-kinase inhibitor LY294002 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 GBP-L on dendritic arborisation may be of potential therapeutic interest.

Key words: Gabapentin-lactam, PI3-Ks, Rho-GTPases, dendrite motility, dendritogenesis, neurotrophic