Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

Abstract

The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.

Neuroprotection Induced In Vitro by Ischemic Preconditioning and Postconditioning: Modulation of Apoptosis and PI3K–Akt Pathways

“…Distinctly identified in the heart by Murry et al in 1986, preconditioning-induced ischemic tolerance was also demonstrated in the brain (Kitagawa et al 1990) and rapidly attracted the interest of clinical and basic neuroscientists (Wang et al 1997;Blondeau et al 2002;O'Duffy et al 2007). In all studies, preconditioning was used to induce a state of tolerance prior to subsequent, potentially injurious ischemia that would be equivalent to neuroprotective pretreatment.…”

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…Second, retrospective case-control studies showed a clinical correlate of the phenomenon discovered experimentally. Patients with a history of transient ischemic attack (TIA) have a decreased morbidity after stroke (284,432). Finally, other findings suggested that brain tolerance may be induced, or mimicked pharmacologically (39).…”

Effect of Antioxidant Treatment in Global Ischemia and Ischemic Postconditioning in the Rat Hippocampus

“…The first mechanism appearing 4 h after ischemia involves prevention of protein synthesis inhibition (Burda et al 2003). The other one is characterized by the second wave of synthesis of protective proteins (Burda et al 2003;Abe and Nowak 2004;O'Duffy et al 2007) Those facts were used in our experiment to select the time intervals for administration of EGb 761 as follows: 30 min before 10 min of ischemia and 5 h, 1 day or 2 days after 10 min of ischemia following ischemic postconditioning. According to our results, the beneficial effect of ischemia/postconditioning was fully suppressed by administration of EGb 761 pronounced by increased number of degenerated neurons in CA1 region.…”