The brain is particularly vulnerable to ischemia. Complete interruption of blood flow to the brain for only 5 minutes triggers the death of vulnerable neurons in several brain regions, whereas 20–40 minutes of ischemia is required to kill cardiac myocytes or kidney cells. In part, the prominent vulnerability of brain tissue to ischemic damage reflects its high metabolic rate. Although the human brain represents only about 2.5% of body weight, it accounts for 25% of basal metabolism, a metabolic rate 3.5 times higher even than that of the brains of other primate species. In addition, central neurons have a near-exclusive dependence on glucose as an energy substrate, and brain stores of glucose or glycogen are limited. However, over the last 15 years, evidence has emerged indicating that energetics considerations and energy substrate limitations are not solely responsible for the brain’s heightened vulnerability to ischemia. Rather, it appears that the brain’s intrinsic cell-cell and intracellular signaling mechanisms, normally responsible for information processing, become harmful under ischemic conditions, hastening energy failure and enhancing the final pathways underlying ischemic cell death in all tissues, including free radical production, activation of catabolic enzymes, membrane failure, apoptosis, and inflammation. Since these common pathways are explored in other accompanying JCI Perspectives, we will emphasize the role of injury-enhancing signaling mechanisms specific to the central nervous system (CNS) and discuss potential therapeutic approaches to interrupting these mechanisms. Refinement of glutamate receptor antagonist approaches. A major limitation in past clinical trials of glutamate receptor antagonists has been dose ceilings imposed by drug side effects. Not unexpectedly, interfering with the brain’s major excitatory transmitter system can lead to alterations in motor or cognitive function (prominent with NMDA antagonists), or sedation (prominent with AMPA antagonists). It seems plausible that the therapeutic index of NMDA antagonist therapy might be improved by the utilization of subtype-selective agents, such as ifenprodil, an antagonist selective for the NR2B subtype of NMDA receptors. NR2B receptors are preferentially expressed in forebrain relative to hindbrain, so blocking these receptors may produce greater neuroprotection in forebrain with less interference with motor function than subtype-unselective NMDA antagonists. In addition, ifenprodil inhibition of NR2B receptors increases with increasing agonist stimulation, a “use dependency” that might increase drug effect at overactivated synapses relative to normal synapses (46). The neuroprotective efficacy of NMDA antagonist therapy might also be enhanced by combination with AMPA or kainate receptor antagonists, both to increase overall antiexcitotoxic efficacy on ischemic neurons, as well as specifically to extend protection to GABAergic neurons expressing Ca2+-permeable AMPA receptors, and oligodendrocytes. Indeed, failure to rescue GABAergic neurons while successfully rescuing nearby excitatory neurons might lead to an increase in local circuit excitation and seizure activity in stroke survivors. High-level pan-blockade of both NMDA and AMPA receptors could have problematic side effects, for example, respiratory depression, but these difficulties might be surmountable through the use of subtype-selective drugs. An alternative approach to blocking NMDA and AMPA receptors concurrently might be to reduce glutamate release, for example, through hypothermia or reduction of circuit excitability with GABA agonists or blockers of voltage-gated Na+ channels. Zinc-directed therapies. While current putative antiexcitotoxic therapies have focused on glutamate receptor activation and resultant Ca2+ overload, the pathological role of neuronal Zn2+ overload suggests additional targets for therapeutic intervention. Indeed, variable reduction of toxic Zn2+ influx may underlie some of the inconsistent beneficial effects of voltage-gated Ca2+-channel antagonists observed in animal models of transient global ischemia (47). Further delineation of the precise routes responsible for toxic Zn2+ may permit greater reduction in this toxic Zn2+ overload. Another possible approach would be to reduce Zn2+ release from nerve terminals. In settings where ischemia is anticipated, it may even prove possible to accomplish this via acute dietary zinc reduction, as anecdotal evidence in humans has suggested that such reduction profoundly disturbs brain function, likely due to reduction of transmitter Zn2+ release (48). Further off, one can envision strategies for modifying neuronal Zn2+ transporters to improve the extrusion or sequestration of intracellular Zn2+, or for upregulating intracellular Zn2+-binding proteins such as metallothioneins. Combination therapies. Recent implication of apoptosis in the pathogenesis of ischemic neuronal death raises an unsettling possibility that current efforts to block NMDA receptor-mediated Ca2+ influx may go too far, achieving the desired reduction of toxic calcium overload and excitotoxicity in some neurons, but then promoting apoptosis in other neurons through Ca2+ starvation (4). It is plausible that different neurons might sustain different levels of [Ca2+]i at different times, with neurons further from the ischemic core or at later time points after ischemia onset sustaining less calcium influx than counterparts in the acute ischemic core. These neurons may be damaged badly enough to trigger apoptosis, but their [Ca2+]i levels may fall below the “set point” optimal for promoting survival (49), such that broad and sustained NMDA receptor blockade promotes apoptosis, reducing the benefits to be had by attenuating calcium overload in other neurons. If this scenario proves valid, it may be possible to enhance the benefits and reduce the dangers of NMDA antagonists by concurrently administering antiapoptotic treatments. Dual inhibition of excitotoxic necrosis and ischemic apoptosis has shown promise in two experimental studies to date. Coadministration of the NMDA antagonist dextrophan with cycloheximide produced greater than 80% reduction in infarct volume following transient focal ischemia in rats, better than either agent alone (50); and Ma et al. (51) observed neuroprotective synergy between MK-801 and the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.FMK) on both infarct size and therapeutic window. The combination of antiexcitotoxic strategies with thrombolysis has also been shown to provide additive protection in a rodent model of embolic stroke (52). On theoretical grounds, antioxidant drugs might be especially valuable in reducing reperfusion-induced injury, for example in association with thrombolytic therapy, or the deleterious component of certain growth factor actions.