Abstracts

Rationale: Gabapentin (GBP) is an anticonvulsant that acts at the α2δ1 subunit of the L-type calcium channel. GBP is a potent inhibitor of excitatory synapse formation in vitro and in vivo (Egalo et al., 2008, unpublished) and thus it might affect posttraumatic synaptogenesis. We studied potential prophylactic effects of acute and chronic GBP administration on epileptogenesis in the partial cortical isolation (“undercut”) model of posttraumatic epilepsy, in which abnormal axonal sprouting and aberrant synaptogenesis contribute to occurrence of epileptiform discharges. Methods: Partial isolations of sensorimotor cortex (“undercuts”) were made in 30 ±1 day (d) old male rats and animals randomly assigned postoperatively to 3 groups. One group received a chronic continuous subcutaneous infusion of gabapentin 8-10 mg per day or saline for 14 days via Alzet pumps. Acute neocortical slices were then obtained from areas of injury to assess for epileptiform activity. A second group was treated identically, but slices instead obtained 7 -14 d after discontinuing the infusions. A third group received 10-30mg GBP i.p. or saline three times per day for 1-2 days and slices also assessed for epileptogenesis 14d later. Fluoro-Jade C (FJC) and 200 kD neurofilament immunoreactivity were accessed in some isolations, to evaluate cell death and axonal sprouting. Results: The incidence of evoked epileptiform discharges in undercut cortical slices was reduced with 14d of GBP infusion, studied immediately following treatment (3/17 slices from 4 GBP treated rats were hyperexcitable vs. 11/27 slices from 8 saline-treated animals; p < 0.04). However, when slices were assessed 7-14d after discontinuing GBP, the incidence of evoked epileptiform discharges was increased vs control (24/36 epileptogenic slices from 8 GBP rats vs 11/27 slices from 8 controls, p = 0.05). A reduction of evoked epileptogenic discharges was also observed in the third group of rats studied 14d after the 1-2 day GBP i.p. injections (11/42 epileptogenic slices from 10 GBP rats vs. 11/21 slices from 5 saline controls, p < 0.05). The number of FJC positive neurons 7d after injury was reduced by 34% (19.1±2.1 FJC positive neurons/350 μm