Target: Protein Synthesis

Unlike excitoxicity, calpain, apoptosis and oxidative stress, reversing the inhibition of protein synthesis has received relatively little attention as a therapeutic target. There are, I think, a couple of reasons for this. First of all, the exact nature of this phenomenon is still being worked out. The discovery that PERK is the guilty kinase is relatively recent, and the mechanism of exactly how PERK is activated is still under investigation.

A second and, I think, more important reason is that not everybody is convinced that protein synthesis inhibition during early reperfusion is a bad thing. This may strike you as a bit odd (I know it strikes me that way). But the thinking seems to go a bit like this: (a) during reperfusion, the ER is messed up and proteins don't fold properly, so making them is a waste of time and perhaps even harmful. (b) The cell's ATP stores are still on the low side and it has better things to do than make protein anyway. (c) Meanwhile, transcripts for pro-apoptotic proteins are waiting in the wings. You don't want to be making those. (d) The UPR is activated for a reason, dammit. Nature knows what She's doing. (e) Finally, there is evidence that protein synthesis inhibitors like cyclohexamide improve outcome after ischemia.

I'm not convinced. (a) Yes, it's true that the ER is messed up--but some of the mRNA transcripts induced by ischemia are for heat-shock proteins and chaperones that could help in that department. In fact, the neuron responds to ischemia with a whole smorgasbord of transcripts for anti-ROS, anti-apoptotic, and other proteins that migh well rescue the neuron...if only they got made. (b) Better things to do than make protein? Like what? (c) Yes, some anti-apoptotic message is transcribed--but we've already seen that the apoptosis cat is let out of the bag even without new protein synthesis after reperfusion. And I've just pointed out that salutary messages are also produced. (d) If Nature knows what She's doing, then how come the UPR never actually materializes after activation of PERK? (e) Yes, and there is also some indication that cyclohexamide by neuroprotective apart from its PS inhibiting properties--like the fact that it's damn near impossible to keep the animal normothermic after administration of the drug. Moreover, I suspect that the cyclohexamide effect may be just another manifestation of Krause's Law.

But for me it really boils down to this: if the cell never recovers its ability to synthesize protein, it will die. Period. So we can talk about when to restore protein synthesis, but talking about whether to do it makes no sense to me at all.