Gabapentin-lactam (8-aza-spiro[5,4]decan-9-on;: GBP-L) inhibits oxygen glucose deprivation-induced [3H]glutamate release and is a neuroprotective agent in a model of acute retinal ischemia

The modulation of the enhanced release of [H-3]glutamate following ischemia-like conditions was studied in rat hippocampal slices using a superfusion system. Ischemia was simulated by a glucose-free medium equilibrated with 95% N-2 and 5% CO2. In this model the potential neuroprotective effects of several substances on [H-3]glutamate release induced by ischemia-like conditions were investigated. Gabapentin-lactam (8-aza-spiro-5,4-decan-9-on; GBP-L) was synthesised and patented in our laboratory GBP-L (100 mu M) reduced the oxygen glucose deprivation-induced [H-3]glutamate release by 42.5%, CI95=[33.4%, 51.5%]. The K-ATP channel antagonist glibenclamide (1 mu M) blocked this effect completely. The high antagonist potency was reflected by an apparent pA(2)-value of glibenelamide of 8.3, CI95=[6.8, 9.4]. Minoxidil sulfate (10 mu M), a K-ATP channel opener, mimicked the effect of GBP-L (inhibition by 22.8%. CI95=[13.2%, 32.5%]). Similarly to its lactam, also gabapentin (100 mu M) reduced the oxygen glucose deprivation-induced [H-3]glutamate release by 30.6%, CI95=[15.5%, 45.7%], whereas the "antiglutamatergic" drug riluzole was ineffective. GBP-L and gabapentin were also tested in an in vivo model of acute retinal ischemia in rats. The intraocular pressure was elevated for 1 h above the systolic blood pressure. In the control group, 17.5%, CI95=[13%, 22%], of retinal ganglion cells had survived after 2 weeks. GBP-L doubled the number of surviving ganglion cells up to 35%, CI95=[27%, 43%], while gabapentin had no effect.