Akt1 gene deletion and stroke.
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.
Li
Jun
J
Department of Neurology, University of Connecticut Health Center, Farmington CT, 06030, United States.
Lang
Jesse
J
Zeng
Zhiyuan
Z
McCullough
Louise D
LD
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D020520:Brain Infarction / Q000175:diagnosis / Q000517:prevention & control; D004195:Disease Models, Animal; D004958:Estradiol / Q000627:therapeutic use; D004967:Estrogens / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency*; D012720:Severity of Illness Index; D013997:Time Factors
D004967:Estrogens; D004958:Estradiol; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt