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M. S. Ola, Y. Xu, A. J. Barber, K. F. LaNoue; Gabapentin Ameliorates Apoptosis of the Diabetic Rat Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):632.
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Glutamate is a major neurotransmitter in both retina and brain. Glutamate released from neurons during neurotransmission is taken-up by retinal Müller cells. The glutamate has two fates, amidation to glutamine or transamination by pyruvate or branched chain keto acids (BCKA) producing α-ketoglutarate (α -KG). Conversely, branched chain amino acids (BCAA) promote synthesis of glutamate from α -KG. Diabetes disrupts the normal system by inactivating glutamine synthetase and slowing transamination of glutamate by BCKA, probably due to excess BCAA. The likely accumulation of intracellular glutamate may lead to an increase in extracellular glutamate causing glutamate excitotoxicity. Gabapentin is an inhibitor of cytosolic branched chain aminotransferase (BCATc) expressed specifically in neurons. It is a leucine analogue which inhibits BCAA transport into Müller cells as well as generation of BCAA in neurons. Therefore, effect of gabapentin on glutamate excitotoxicity and the influence of BCKA and hydrocortisone (HC) on glutamate oxidation specific to Müller cells were investigated.
Apoptosis was analyzed in control and 3 months diabetic rats treated with gabapentin. Studies were carried out in two different ways. Following treatment with 300 mg/kg gabapentin given twice daily, apoptotic retinal cells were counted by TUNEL staining. Alternatively, a dose of 150 mg/kg was given twice daily and active caspase-3 in the excised retina was measured enzymatically. In independent studies, glutamate metabolism was monitored by incubating cultured rat Müller cells (TR-MUL) in 20 mM HEPES buffer, containing 100 µM [U-14C]glutamate ± 0.6 mM BCKAs. At the end of the incubation 14C-labeled glutamine, glutamate, aspartate and lactate in the extracts were separated by anion exchange chromatography and quantitated. The rate of oxidation of glutamate was measured as release of 14CO2 and as a production of 14C-lactate.
Gabapentin (300 mg/kg/12 hours) significantly reduced the number of apoptotic cells as evaluated by TUNEL staining. Gabapentin at a lower dose (150 mg/kg/12 hours) also reduced the amount of active caspase-3, a marker of apoptosis. In Müller cells, BCKA increased the oxidation of glutamate, to form lactate (0.16 ± 0.27 to 0.27 ± 0.09 nmoles/mg), and to produce CO2 (0.33 ± 0.012 to 0.41 ± 0.01 nmoles/mg).
Gabapentin by stimulating glutamate disposal ameliorates apoptosis of the diabetic rat retina. The influence of gabapentin may be due to its capacity to increase the ratio of BCKA to BCAA which would in turn accelerate glutamate oxidation.
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