We now turn to the last Horseman, although certainly not the last potential target for brain ischemia. Remember, brain ischemia is hideously complex, and the Four Horsemen concept is a gross simplification. Certainly, though, apoptosis is a huge target. How do we hit it?
Well, there are lots of ways you could do it. Maybe you could try to influence the outcome of the Showdown at the Mito Corral by getting more White-Hat Bcl2 guys into the vulnerable neurons. That's a huge technical challenge, though, because you're talking about getting big proteins through the blood-brain barrier and across the neuronal membrane. Not impossible, but currently out of reach.
What about caspase inhibitors? Hey, there's a great idea. And as it happens, there are such things, and they certainly seem to work in animal models. Of course, we all know that story now--no proof that they'll work in humans. And the human data is, right now, virtually nonexistent. Moreover, there are reasons to suspect that caspase inhibitors aren't the answer. The most important of these is what we know about intrinsic apoptosis, in which most of the caspase activation seems to happen after the release of cytochrome c. The release of cytochrome c is a relatively delayed event (it doesn't happen until about 4-6 hours in our model). A lot of damage gets done up to that point. Moreover, the release of cytochrome c is indicative a mitochondrial catastrophe. Even if you could block the subsequent activation of caspases, you still have a cellular 3 Mile-Island catastrophe on your hands: leaky power plants full of toxic crap. Not good. Still, caspase inhibitors are an approach to watch.
But there's another way to go after apoptosis: growth factors.