WE determined whether exogenous Mg2+and/or mexiletine (Mex), which are reported to be neuroprotective agents, reduced neuronal energy requirements and protected against ischemia, using isolated rabbit retinas. Under non-ischemic conditions, Mex (30 μM) and the combination of Mg2+(1 mM) plus Mex (30 μM) significantly reduced glucose utilization, by 19% and 31%, respectively. The combination of Mg2+plus Mex, but not either agent alone, significantly reduced lactate production (by 18%p< 0.05). When added during 2 h of ischemia (simulated by the reduction of oxygen from 95% to 15% and of glucose from mM to 1 mM), Mg2+plus Mex improved the recovery of glucose utilization (p< 0.01), lactate production (p< 0.05) and neuronal function (p< 0.05) for 3 h following return to control (post-ischemia/recovery) conditions. Thus reducing energy demands by blocking functions during temporary ischemia, protects neurons from irreversible functional damage