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Protein kinases Akt1 and Akt3 are considered to be more crucial to brain function than Akt2. We investigated the roles of Akt1 and Akt3 in stroke-induced brain injury and examined their interactions with the Akt/mTOR pathways. Focal ischemia was induced in rats. Lentiviral vectors expressing constitutively active Akt1 and Akt3 (cAkt1 and cAkt3) were injected into the ischemic cortex. Infarct sizes and gene and protein expressions in the Akt/mTOR pathways were evaluated. The results show that Akt1 and Akt3 proteins were degraded as early as 1 hour after stroke, whereas Akt2 proteins remained unchanged until 24 hours after stroke. Lentiviral-mediated overexpression of cAkt1 or cAkt3 reduced neuronal death after in vitro and in vivo ischemia. Interestingly, cAkt3 overexpression resulted in stronger protection than cAkt1 overexpression. Western blot analyses further showed that cAkt3 promoted significantly higher levels of phosphorylated Akt and phosphorylated mTOR than cAkt1. The mTOR inhibitor rapamycin blocked the protective effects of both cAkt1 and cAkt3. In conclusion, Akt isoforms are differentially regulated after stroke and Akt3 offers stronger protection than cAkt1 by maintaining Akt levels and promoting mTOR activity. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) and estrogen can modulate neuron death and dysfunction during neurological insults. Glucocorticoids are adrenal steroids secreted during stress, and hypersecretion of GCs during cerebral ischemia compromises the ability of hippocampal and cortical neurons to survive. In contrast, estrogen can be neuroprotective after cerebral ischemia. Here we evaluate the protective potential of a herpes viral vector expressing a chimeric receptor (ER/GR), which is composed of the ligand-binding domain of the GC receptor (GR) and the DNA-binding domain of the estrogen receptor-α (ER). This novel receptor can transduce an endangering GC signal into a protective estrogenic one. Using an in vitro oxygen glucose deprivation model (OGD), GCs exacerbated neuron death in primary cortical cultures, and this worsening effect was completely blocked by ER/GR expression. Moreover, blocking GC actions with a vector expressing a dominant negative GC receptor promoted neuron survival during postischemia, but not preischemia. Thus, gene therapeutic strategies to modulate GC and estrogen signaling can be beneficial during an ischemic insult.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 130–136; doi:10.1038/jcbfm.2008.105; published online 17 September 2008 [ABSTRACT FROM AUTHOR]