A Pharmacological Activator of AMP-Activated Protein Kinase Protects Hypoxic Neurons in a Concentration-Dependent Manner

Abstract

5'adenosine monophosphate-dependent protein kinase (AMPK) is a member of metabolite-sensing kinase family which plays an important role in intracellular energy metabolism, particularly in the hypoxic neurons process. However, the effect of AMPK activation on hypoxic neurons remains controversial. In the present study, we report that the effect of AMPK activation induced by pretreatment with 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR) in neurons using the hypoxic model in vitro. The level of AMPK activation, the neuronal viability, and the levels of two important cytoskeleton proteins were analyzed during the oxygen deprivation. The AMPK activation was increased with the elevation of the AICAR concentration in hypoxic neurons. Moreover, the AMPK activation induced by AICAR protected neurons against death from hypoxic deprivation and that strongly depended on the extent of the AMPK activation. The AMPK activation at specific range protects hypoxic neurons, but the protective effect of AMPK activation disappeared when the AMPK was over-activated by AICAR. The result from an AMPK inhibitor, Compound C, in hypoxic neurons further proves the neuroprotective effect of AICAR.

Carbimazole Is an Inhibitor of Protein Synthesis and Protects from Neuronal Hypoxic Damage In Vitro

“…Furthermore, we could establish the molecular mechanism responsible for carbimazole-mediated eEF2 phosphorylation, which includes AMPK-dependent activation of eEF2K. Interestingly, both kinases are associated with cytoprotective molecular mechanisms, including reduced hypoxic injury, stress resistance, autophagy, inhibition of plaque formation in Alzheimer's disease, regulation of energy homeostasis, and endothelial nitric oxide synthesis that improves blood flow in ischemic brain tissue (Hardie, 2004;Terai et al, 2005;Greco et al, 2009;Py et al, 2009;Li and McCullough, 2010;Zhang et al, 2010). However, whether carbimazole exerts all of these protective mechanisms remains to be established.…”

“…Activation of eEF2K promotes cell survival, reduces hypoxic injury, and regulates autophagy in response to nutrient deprivation (Terai et al, 2005;Py et al, 2009). AMPK preserves energy homeostasis (Hardie, 2004) and attenuates ischemic cell damage (Zhang et al, 2010), inflammation (Salminen et al, 2011), arrhythmias (Wong et al, 2009), hypertrophy (Chan et al, 2004), structural remodeling (Du et al, 2008), and plaque formation in Alzheimer's disease (Greco et al, 2009). Additionally, it promotes neurogenesis, angiogenesis, and vascular function (Li and McCullough, 2010).…”

AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain

“…Furthermore, it was shown that the AMPK inhibitor compound C was able protect neurons from tributyltin toxicity. Studies from another group showed that AICAR could protect rat primary cortical neurons from hypoxic death in a concentration-dependent manner [49]. Interestingly, whereas low doses were neuroprotective, higher doses lost their efficacy.…”

Selective kinase inhibitors as tools for neuroscience research

“…These included the kinases AuroraA, Pim and AMPK. Of these AMPK has been shown to have an important role in the neural response to ischemia, hypoxia and glucose deprivation (Cheung and Hart, 2008;McCullough et al, 2005;Zhang et al, 2010). BMS-SHN753 was the most selective for tyrosine kinases e of the13 kinases that were inhibited either more strongly or to a similar degree as TrkA, 6 were tyrosine kinases e however it did inhibit several Ser/Thr kinases, including CDC like kinase 2, AuroraA and ERK8, as strongly as it inhibited Trk.…”