Turn Me On--Insulin and eIF2

As it happens, results from your lab at the turn of the century demonstrated that rescuing protein synthesis in vulnerable neurons was possible--and that it happened in the presence of a known neuroprotectant.

That neurprotectant was insulin. Insulin was first suggested for stroke in the mid-80s on the basis of its ability to reduce hyperglycemia, which correlates with poorer outcome. However, soon after the initial studies by LeMay, Voll and Auer, it was shown (by Voll and Auer again) that insulin's neuroprotective effect was independent of its hypoglycemic effect. Insulin protected neurons by a different mechanism.

In the late 90s, we hypothesized, for reasons we needn't dwell on here, that insulin could restore protein synthesis in the injured neuron, by inducing dephosphorylation of eIF2α(P). And in fact, this turned out to be true. It took 20U/kg to achieve the desired effect, but our data showed that insulin, a known neuroprotective agent, dephosphorylated eIF2α(P) and restored protein synthesis in vulnerable neurons after global brain ischemia. Not only was this a neat way to underscore the role of phosphorylation in protein synthesis inhibition, it gave us new insight on a potential therapy.

Figure. Insulin to the rescue! The images above are autoradiographs of protein synthesis in CA1 paired with immunohistochemistry of the same areas for eIF2α(P) . On the left, the autoradiographs show protein synthesis as little black dots overlying the cells like so much pepper. These are silver grains "developed" by radiation from S-35 methionine given to the animals at 1 hour of reperfusion. The radioactive methionine was incorporated into protein only in those cells that had intact translation. Note that in control (nonischemic) animals, the neurons are busily making protein and are clear of eIF2α(P). After ischemic injury, the neurons are full of eIF2α(P) and protein synthesis is offline. But if the animals receive 20U/kg of insulin at onset of reperfusion, by 90 minutes the neurons are clear of eIF2α(P) and protein synthesis is back online.