Neuroprotection in stroke: slowing down AMPK activation

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Lack of blood and oxygen after ischemic stroke causes disruption of cell ion homeostasis and lead to neuronal cell death. To repair the damage and return neurons to homeostasis, a number of energy-consuming processes are activated. Overactivation of these pathways during ischemia can lead to complete energy failure and cell death. Activation of AMPK was initially considered to be an adaptive response due to altered AMP/ATP ratio in response to ischemia, hypoxia, or glucose deprivation (Culmsee et al., 2001; Gadalla et al., 2004; McCullough et al., 2005) but there has been some discordance about the outcome on cell survival and neuroprotection. Some groups proposed that AMPK represents an endogenous neuroprotective pathway conserving cellular energy levels under conditions of intense metabolic stress (Culmsee et al., 2001) or ischemic injury in addition to limiting neuronal injury via excitotoxicity (Kuramoto et al., 2007). Conversely, McCullough and coworkers suggested that AMPK over-activation is detrimental in models of ischemia reperfusion (McCullough et al., 2005). Pharmacological and genetic approaches were used to clarify the role of AMPK in stroke outcome. AMPK inhibition with Compound C or with the fatty acid synthase inhibitor C75 (which reduces AMPK activation indirectly) provided sustained neuroprotection after stroke (Li et al., 2007). Similarly, AMPKa2 knockout mice were protected from stroke damage (Li et al., 2007). Furthermore, the beneficial effect of Compound C was lost in AMPKa2 knockout mice implying that targeting neuronal energy balance during cerebral ischemia may be therapeutic (Li et al., 2007). However, the physiological consequences of AMPK activation after hypoxic stress on cerebral vasculature has been poorly investigated and it is not known if AMPK activation exacerbates or ameliorates cerebral blood flow. In contrast, regarding peripheral vasculartue, many studies confirmed the beneficial effects of pharmacological AMPK activation (Bradley et al., 2010; Davis et al., 2006; Evans et al., 2005; Rubin et al., 2005; Wang et al., 2009), thereby favoring blood flow. Some of the protective actions of AMPK have been related to the activation of endothelial NO synthase (eNOS) and formation of NO, which is a central signaling molecule in the vasculature (Zou and Wu, 2008). AMPK has been shown to enhance eNOS activity by direct phosphorylation of Ser1177 (Chen et al., 2000; Chen et al., 1999), Ser633 (Chen et al., 2009b) and by promoting its association with heat shock protein 90 (Davis et al., 2006) leading to endothelial NO production. In addition, AMPK also produces its regulatory effects in the peripheral vasculature through vascular endothelial growth factor (VEGF)-mediated endothelial angiogenesis (Nagata et al., 2003; Ouchi et al., 2005; Stahmann et al., 2010). Interestingly, a recent study has shown increased phosphorylation of AMPK and eNOS in endothelial cells of cerebral arteries following severe subarachnoid hemorrhage (Osuka et al., 2009).  Thus, it is likely that AMPK causes beneficial effects in the brain vasculature through eNOS-mediated acute vasodilatation (Osuka et al., 2009) or VEGF-induced angiogenesis (Lopez-Lopez et al., 2007).