Although the management of stroke has improved remarkably over the last decade due mainly to the advent of thrombolysis, most neuroprotective agents, although successful in animal studies, have failed in humans. Our increasing knowledge concerning the ischemic cascade is leading to a considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cytoprotection.

The brain requires a continuous supply of oxygen and glucose to maintain normal function and viability. When this supply is interrupted, a cascade of events takes place: 1) the reduction of ATP and failure of the Na⁺/K⁺ ATPase causing an increase in extracellular K⁺ as well as an influx of Na⁺, Cl^- and Ca²⁺ into the cells. 2) Glutamate, an excitatory amino acid which has been implicated in the pathogenesis of brain injury, results in excitotoxicity in which excessive extracellular glutamate kills neurones. Regarding the inhibition of glutamate release as a possible target for cytoprotection, it might be afforded either by decreasing glutamate efflux or by increasing glutamate uptake. 3) the generation of free radicals provoking damage to lipids, DNA and proteins due to their high reactivity 4) inflammatory response in which several mediators are released or activated, such as inflammatory cytokines and adhesion molecules. Other important inflammatory mediators being expressed and/or activated in this setting are several proteolytic enzymes belonging to the family of the metalloproteases, including matrix metalloproteases, implicated in damage to extracellular matrix.

We will discuss the effect of different neuroprotective tools (Na⁺/Ca²⁺ exchangers –NCXs-; metabotropic glutamate receptor agonists or antagonists; drugs acting on glutamate transporters; nuclear receptor agonists –PPARgamma, LXR-; membrane stabilizers, etc...) affecting different steps of this cascade as targets of cytoprotection.