Reperfusion after ischemia is followed by multiple mechanisms that lead to cell death, and the need is crucial for neuroprotective agents to reduce tissue damage. Naturally occurring substances, such as caffeinol, have been purported to both prevent and reverse neuronal and vascular cell injury in animal models of AIS and are currently being evaluated in trials with thrombolysis (28 ).

TIAs can represent a form of clinical hypoxic preconditioning and are partly associated with increased plasma levels of tumor necrosis factor-a in the presence of reduced concentrations of interleukin-6 (29).

Human albumin has been shown to reduce swelling and infarct volumes in animal models of focal ischemia by 60% to 65%, with a therapeutic window extending to 4 hr. Modulating thrombin and its inhibitors might establish novel therapeutic strategies for ischemia.

Erythropoietin (EPO) is thought to rescue neurons from nitric oxide-induced death. A recent development has been the engineering of hematopoietic growth factor EPO to have neuroprotective, but not hematopoietic, activity, implying that it might soon be possible to treat AIS patients with short-term, high-dose recombinant human EPO (30 ).

Estrogen has been implicated as a neuroprotectant, but despite promising laboratory results, data from randomized clinical trials, including the Women's Estrogen for Stroke Trial, has shown that hormone replacement therapy offers no benefit for either primary or secondary prevention of stroke. However, nonfeminizing estrogen analogs exhibit enhanced neuroprotective activity in in vitro models.

Novel strategies employing single interfering RNA duplexes have been proposed to prevent Ca2+ overload through the transient receptor potential cation channel superfamily (31).

Statins increase expression of neurotrophic factors (e.g., vascular endothelial growth factor, and brain-derived neurotrophic factor), amplify endogenous brain plasticity, and reduce neurologic deficits. However, in other studies, statins did not decrease the risk of recurrent stroke but did decrease the risk of myocardial infarction (32).

Apoptosis, which is mediated by caspases, is more extensive after transient focal cerebral ischemia than that following permanent focal brain ischemia and might contribute to delayed neuronal death in the penumbra. Novel approaches might utilize protein transduction technology to deliver antiapoptotic molecules to protect neuronal cells following ischemia (33 ).

As many neuroprotective agents that target apoptotic pathways have been failures, alternative strategies that involve neuronal survival signaling pathway, such as the phosphatidylinositol 3-kinase/Akt (protein kinase B) pathway, are being investigated (34). To avoid repeating past failures, neuroprotective agents must be tested on multiple animal models and in conjunction with thrombolytics before the launch of clinical trials. Biomarkers that allow monitoring the effects of therapy would be desirable.

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