Nrf2 Activation, an Innovative Therapeutic Alternative in Cerebral Ischemia

Abstract

Cerebrovascular disease is the second cause of death and the most frequent cause of nontraumatic disability in adults worldwide, according to the World Health Organization (WHO, 2005). Noteworthy, acute ischemic stroke accounts for about 85% of all cases (DiezTejedor et al., 2001). The most common cause of stroke is a sudden occlusion of a blood vessel, resulting in activation of a series of biochemical events eventually leading to neuronal death (Dirgnal et al., 1999). Although return of blood flow (reperfusion) in ischemic brain tissue is essential for restoring normal function, paradoxically it can result in a secondary damage, where oxidative stress mediators play a critical role (Wong & Crack, 2008). Antioxidant therapies have been used to determine whether oxidative stress may constitute a valuable therapeutic target in cerebral ischemia. Indeed, free radical scavengers (direct antioxidants) and agents that decrease free radicals production reduce damage in experimental models of cerebral ischemia. Despite experimental evidence supports the concept that free radicals production represents a valuable therapeutic target in stroke, negative results have been obtained in a number of clinical trials when some direct antioxidant agents have been evaluated (Aguilera et al., 2007). At present, this discrepancy is unclear; however, administration of treatment outside the temporal window of efficacy and difficulties in the establishment of the onset of ischemia and reperfusion in humans (Hsu et al., 2000) are factors that likely contributing to these differences. Clearly, development of preclinical testing must consider these factors in order to improve successful transition to clinical studies. NF-E2-Related Factor-2 (Nrf2) is a transcription factor that play a crucial role in the cellular protection against oxidative stress. Nrf2 is referred to as the "master regulator" of the antioxidant response due to the fact that it modulates the expression of several genes including phase 2 and antioxidant enzymes playing an important role in detoxification of reactive oxygen species (ROS) and electrophilic species, including heme oxygenase-1, NAD(P)H:quinone oxidoreductase, glutathione-S-transferase, gamma-glutamyl cysteine ligase, glutathione reductase, etc. Recent studies demonstrate that dysfunction of Nrf2driven pathways impairs cellular redox state thus oxidative stress.