Contribution of glial metabolism to neuronal damage caused by partial inhibition of energy metabolism in retina.

Glial cells are relatively resistant to energy impairment, although little is known of the extent to which glial metabolism is affected during partial energy impairment and how this influences neurons. Fluorocitrate has been shown to be a glial specific metabolic inhibitor. Its selective effect on chick retinal Müller cells was verified by measuring incorporation of radiolabel from 3H-acetate and U-14C-glucose into glutamate and glutamine following exposure of isolated embryonic day 15-18 chick retina to 20 microm fluorocitrate. Fluorocitrate significantly reduced the incorporation of radiolabel from acetate and glucose into glutamine, with less effect on incorporation of label from acetate into glutamate and no reduction of label from glucose into glutamate. The relative specific activity (RSA; ratio of glutamine to glutamate) increased between embryonic day 15 and 18 consistent with the increase in glutamine synthetase activity that occurs in Müller cells at this time in chick retinal development. As with previous findings, mild energy stress produced by inhibiting glycolysis with the general inhibitor iodoacetate (IOA) for up to 45 min, caused acute neuronal damage that was predominately NMDA receptor mediated and occurred in the absence of a net efflux of excitatory amino acids. Acute NMDA-mediated toxicity in this preparation is characterized by the selective damage to amacrine and ganglion cells and quantitatively, by GABA release into the medium. When IOA was combined with fluorocitrate, acute toxicity was potentiated and temporally accelerated. Acute damage was first noted at 15 min, occurred throughout all retinal layers and was accompanied by an overflow of excitatory amino acids at 30 and 45 min. Blocking NMDA receptors with MK-801 during IOA plus fluorocitrate exposure attenuated the rise in excitatory amino acids and prevented the swelling in neuronal, but not Müller cells. Following incorporation of radiolabel from acetate and glucose into glutamate and glutamine after different times of exposure to IOA showed that while the effects of incorporation of label from glucose were immediate, glutamine synthesis from acetate was preserved for a longer period of time. These findings suggest that during a partial energy impairment, neuronal metabolism is affected to a greater extent than is glial metabolism. Glial cells may play a protective role in this situation, and can delay the onset of acute neuronal damage.