Ischemic neuronal damage.
Knowledge of the molecular mechanisms that underlie neuron death following stroke is important to allow the development of effective neuroprotective strategies. Since studies in human stroke are extremely limited due to the inability of collecting post mortem tissue at time points after the onset of stroke where neuronal death occurs, brain ischemia research focuses on information derived from animal models of ischemic injury. The two principal models for human stroke are induced in rodents either by global or focal ischemia. In both cases, blood flow disruptions limit the delivery of oxygen and glucose to neurons causing ATP reduction and energy depletion, initiating excitotoxic mechanisms that are deleterious for neurons. These include activation of glutamate receptors and release of excess glutamate in the extracellular space inducing neuron depolarisation and dramatic increase of intracellular calcium that in turn activates multiple intracellular death pathways. The notion that excitotoxicity leads only to neuron necrosis has been abandoned, as ultrastructural and biochemical analysis have shown signs of apoptotic and autophagic cell death in ischemic neurons and this has been further confirmed in neurons subjected to in vitro ischemia models. Both in vitro and in vivo studies, targeting a single death mechanism either by the inhibition of death-inducing molecules or the overexpression of antiapoptotic components in neurons, have shown tremendous neuroprotective potential. Despite their effectiveness in preclinical studies, a large number of neuroprotectants have failed in clinical trials for stroke suggesting that we still lack essential knowledge on the triggers and mediators of ischemic neuron death. In this review evidence will be presented on how ischemic injury occurs, what death mechanisms are activated and how these can be manipulated to induce neuroprotection.
Taoufik
Era
E
Department of Molecular Genetics, Hellenic Pasteur Institute, 127 Vas. Sofias Avenue, 11521 Athens, Greece. etaoufik@pasteur.gr
Probert
Lesley
L
D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000473:pathology*