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Abstract #10163 Published in IGR 6-1
Retinal ganglion cell survival is enhanced by gabapentin-lactam in vitro: evidence for involvement of mitochondrial K(ATP) channels
Pielen A; Kirsch M; Hofmann HD; Feuerstein TJ; Lagreze WAGraefe's Archive for Clinical and Experimental Ophthalmology 2004; 242: 240-244
BACKGROUND: Recently, gabapentin-lactam (GBP-L) was shown to be neuroprotective in vivo. It has been suggested that GBP-L may act by opening mitochondrial ATP-sensitive potassium (K(ATP)) channels. The authors tested this hypothesis by quantifying the effect of GBP-L on the survival of purified retinal ganglion cells (RGCs). METHODS: RGCs were purified from early postnatal rat retinae by immunopanning with antibodies against Thy1.1 and cultured in serum-free medium for two days. Cell survival was quantified by counting vital cells under phase-contrast optics. Results were normalized to controls. RGCs were treated with various concentrations (3.2-320 μm) of GBP-L with and without 1 μm glibenclamide, blocking both plasmalemmal and mitochondrial K(ATP) channels, or 100 μm 5-hydroxydecanoate (5-HD), antagonizing selectively mitochondrial K(ATP) channels. For comparison, additional cultures were treated with 32 μm gabapentin, the parent drug of GBP-L. A combination of the neurotrophic factors BDNF and CNTF (50 ng/ml each) served as a positive control. RESULTS: GBP-L increased RGC survival to a maximum of 145 ± 5% (mean ± SEM) in a concentration-dependent manner. The pEC50 was 5.0, CI95 (4.7, 5.3). Preincubation with glibenclamide changed the dose-response of GBP-L, indicating that it acted as a competitive antagonist with a pA2 value of 6.8, CI95 (5.9, 7.5). 5-HD completely blocked the survival-promoting effect of GBP-L. Gabapentin had no effect, whereas the combination of CNTF and BDNF enhanced survival to 177 ± 9%. CONCLUSIONS: GBP-L, but not gabapentin, can promote the survival of cultured central nervous system neurons, possibly by opening mitochondrial K(ATP) channels. These results suggest further testing of GBP-L as a potentially neuroprotective drug.
Dr. A. Pielen, Department of Neuroophthalmology, Albert-Ludwig University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
Classification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
