Cerebrovascular diseases are a major health problem and account for more than 15% of all deaths in elderly cohorts. Acute therapeutic interventions in ischemic stroke can only be successful as long as tissue in the area of the ischemic compromise is still viable.
The mode of neuronal death caused by cerebral ischemia and reperfusion appears on the continuum between the poles of catastrophic necrosis and apoptosis: ischemic neurons exhibit many biochemical hallmarks of apoptosis but remain cytologically necrotic. The ischemia-induced neuronal death is an energy dependent process related to the activation of cascades of detrimental biochemical events that include altered calcium homeostasis leading to increased excitotoxicity, mitochondrial dysfunction, elevation of oxidative stress causing DNA damage, alteration in proapoptotic gene expression, and activation of the effector cysteine proteases (caspases) and endonucleases leading to the final degradation of the genome. Various pharmacological approaches for neuroprotection are based on the current knowledge of molecular events in the pathophysiology of cerebral ischaemia. Candidate agents include free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, metal ion chelators, and ion channel modulatory, antisense oligonucleotides. Clinical effectiveness of some of the strategies has not be proven in clinical trials, some of which had to be abandoned due to adverse effects outweighing the beneficial effects.
It is becoming clear that targeting a single gene or factor is not sufficient for stroke therapeutics. An effective neuroprotective therapy is likely to be a cocktail aimed at all of the above detrimental events evoked by cerebral ischemia and the success of such therapeutic intervention relies upon the complete elucidation of pathways and mechanisms of the cerebral ischemia-induced active neuronal death.
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