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A. Pielen, M. Kirsch, H.D. Hofmann, T.J. Feuerstein, W.A. Lagrèze; Retinal Ganglion Cell Survival Is Enhanced by Gabapentin-Lactam In Vitro: Evidence for Involvement of Mitochondrial KATP Channels . Invest. Ophthalmol. Vis. Sci. 2003;44(13):5230.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Recently, Gabapentin-Laktam (GBP-L) was shown to be neuroprotective in vivo. It has been suggested that it may act by opening ATP-sensitive mitochondrial potassium channels. We tested this hypothesis by quantifying the effect of GBP-L on survival of purified retinal ganglion cells (RGCs) under different conditions. Methods: RGCs were purified from rat retina by immunopanning with antibodies against Thy1.1 and cultured in serumfree N2 medium for 2 days. RGCs were treated with various concentrations (3,2 - 320 µM) of GBP-L with and without glibenclamide (1 µM) or 5-hydroxydecanoate (5-HD, 100 µM). Additional cultures were treated with ciliary neurotrophic factor (CNTF, 50 ng/ml) plus brain derived neurotrophic factor (BDNF, 50 ng/ml) or gabapentin (32 µM). Cell survival was quantified by cell counts under phase-contrast microscopy. Results were normalized to controls. Results: GBP-L increased RGC survival to 145%, CI95 [134, 155] in a dose-dependent manner reaching the maximum effect at 32 µM. Preincubation with the KATP channel antagonists glibenclamide (1 µM, blocking both plasmalemmal and mitochondrial KATP channels) or 5-HD (100 µM, blocking selectively mitochondrial KATP channels) blocked this effect: Glibenclamide shifted the dose-response curve of GBP-L to the right, indicating that it acted as a competitive antagonist. The antagonist potency was reflected by a pA2 value of glibenclamide of 6.80, CI95 [5.88, 7.46]. 5-HD completely blocked the survival promoting effect of 32 µM GBP-L (98%, CI95 [84, 113]). In comparison, CNTF plus BDNF enhanced survival to 177%, CI95 [158, 196]. Gabapentin, the parent drug of GBP-L, had no effect on survival (95%, CI95 [82, 108]). Conclusions: GBP-L, but not gabapentin, increased survival of RGCs in vitro, possibly by opening mitochondrial KATP channels. These results suggest further testing of GBP-L as a potentially neuroprotective drug.
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