Akt1 gene deletion and stroke

Abstract

Activation of Akt has been implicated as a major contributor to neuronal survival after an ischemic insult. Numerous neuroprotective agents have been shown to augment Akt activity, suggesting that this protein represents a major mechanism of cellular salvage after injury. Estrogen is known to augment Akt, but the possibility that Akt plays a differential role in the male and female brain has yet to be evaluated. In this study, we employed both pharmacological and genetic approaches to investigate the role of Akt in stroke. Utilizing a focal stroke model we show that deletion of the Akt1 isoform does not affect stroke outcome in either male or female mice. Akt1 deficient mice had equivalent levels of phosphorylated Akt (p-Akt) when compared to their WT controls following stroke suggesting that alternative isoforms can compensate for Akt1 loss. Secondly, estrogen's neuroprotective effect is maintained in Akt1 −/− mice and estrogen exposure did not enhance p-Akt levels in WT female mice. Thirdly, we show that inhibiting Akt using the direct pan-Akt inhibitor triciribine has no effect on stroke outcome despite dramatic reductions in p-Akt. Our study demonstrates the limitations of genetic mouse models and suggests that the importance of Akt to ischemic outcome remains unclear.

miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia

“…No differences were seen in physiological parameters (Table S4) or blood flow (Table S5) in female mice treated with vehicle or embelin. We have previously shown that no sex differences exist in physiological parameters or blood flow in our model (39).…”

Preconditioning induces sustained neuroprotection by downregulation of adenosine 5′-monophosphate-activated protein kinase

“…In this study, mice treated with compound C demonstrated no additional neuroprotective effects with IPC, suggesting that AMPK inhibition is the common neuroprotective pathway. Although a floor effect is possible, this is less likely as mice treated with combination therapy still had substantial infarcts (30%), and we have shown previously that infarct volumes can be reduced to as low as 16% with other neuroprotective agents in earlier studies using this MCAO model (Li et al, 2008). However, it does remain possible that the smaller infarcts are masking an additive effect of AMPK and IPC.…”

PHLPP1 Gene Deletion Protects the Brain from Ischemic Injury

“…Neuronal-specific transgenic mice overexpressing an activated form of Akt after injury showed reduced infarct area after middle cerebral artery occlusion (MCAO), 6 but it is not clear whether these levels of expression and activity of Akt are physiologic. Indeed mice deficient in Akt1, a major contributor to neuronal survival, do not show differences in stroke outcome 8 but the observation that Akt1-deficient mice and control mice have equivalent levels of phosphorylated Akt suggests that alternate isoforms of Akt compensate for germline loss of Akt1. 8 Recent studies revealed that increasing Akt activity by removal of its endogenous inhibitor, carboxyl terminal modulator protein (CTMP), protects neurons from ischemia-induced death.…”

“…Indeed mice deficient in Akt1, a major contributor to neuronal survival, do not show differences in stroke outcome 8 but the observation that Akt1-deficient mice and control mice have equivalent levels of phosphorylated Akt suggests that alternate isoforms of Akt compensate for germline loss of Akt1. 8 Recent studies revealed that increasing Akt activity by removal of its endogenous inhibitor, carboxyl terminal modulator protein (CTMP), protects neurons from ischemia-induced death. 9 This provides encouraging evidence that increasing endogenous activation of all Akt isoforms are protective, although how CTMP affects Akt activity has not been clearly defined.…”