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Spring Farrell, Allison Sargoy, Jill King, Nicholas Brecha, Steven Barnes; Acute Administration Of Gabapentin Reduces Voltage-gated Calcium Channel Current In Mammalian Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4574.
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Gabapentinoids, such as gabapentin, interact with α2Δ auxiliary subunits of voltage-gated calcium channels (VGCCs), leading to decreased cell surface expression of VGCCs and reduced Ca2+ channel current (ICa). It is possible that administration of gabapentin may prevent the deleterious effects of elevated Ca2+ levels in retinal ganglion cells (RGCs) in ocular trauma and retinal disease. The aim of the present study was to establish the expression pattern of α2Δ1 subunits in the retina and to determine the effects of gabapentin on ICa and light evoked spiking in RGCs.
Sodium citrate heat-induced antigen retrieval immunohistochemistry was performed on rat retinal sections to reveal the antigenic sites for the binding of an α2Δ1 antibody (Sigma C5105). Spiking of RGCs in response to light stimulation, in the absence and presence of gabapentin (10 µM), was measured in whole mount guinea pig retina using a multielectrode array. ICa was measured in isolated rat RGCs using standard whole cell patch-clamp protocols (Axopatch 1B, pClamp) and reagents under acute and chronic gabapentin application (10 µM).
Retinal sections exhibited pronounced α2Δ1 immunoreactivity in RGC cell bodies and their primary dendrites, which extended into the IPL. Application of gabapentin (10 min) reduced ON RGC spike rates during illumination compared to control (4.8 ± 0.5 vs. 3.6 ± 0.4 spikes/sec, absence vs. presence of drug; p<0.05). In isolated RGCs, acute gabapentin administration (2 min) reduced ICa compared to control (-179.7 ± 32.6 vs. -96.7 ± 24.9 pA, absence vs. presence of drug, -10 mV; p<0.05). Also, pretreatment of RGCs with gabapentin (2-4 hr) reduced ICa compared to non-pretreated cells (-179.7 ± 32.6 vs. -109.5 ± 39.7 pA, non-pretreated vs. pretreated, -10 mV; p<0.05). Acute administration of gabapentin to RGCs after they had been pretreated further reduced ICa (-109.5 ± 39.7 vs. -67.1 ± 19.7 pA, absence vs. presence of acute gabapentin, -10 mV; p<0.05).
α2Δ1 VGCC subunits are expressed in RGC cell bodies and their primary dendrites. Acute application of gabapentin reduced ICa in isolated RGCs and reduced spiking in ON RGCs in the intact retina. Thus, gabapentin may be neuroprotective as it decreases Ca2+ influx and reduces excitability of RGCs. Further research is warranted to determine whether gabapentinoids may improve RGC survival in the setting of ocular trauma and retinal disease.
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