Nip It in the Bud

Like a lot of smart people, you may have elected to go right to the roots of the illness. Of course, the real root is the ischemia itself, and the immediate dump of calcium. There are two ways to go after this very early part of the problem. The first is to invent a time machine and go back to prevent it from happening. The second is to practice good preventative medicine. Those two approaches speak for themselves and we won't dwell on them further. In the acute situation, there's just nothing you can do about it. You can open the artery or start the heart, but there's no way to do it fast enough to prevent the depolarization of the membranes and the initial calcium dump.

Figure. Potential targets during ischemia.

So the first available targets at this level are the glutamate surge, the ongoing calcium flux, the initial activation of calpain, and the activation of phospholipases. We'll talk about calpain later. Let's take each of the others in turn.

Glutamate Antagonists seem like a natural, don't they? Blocking the glutamate cascade has, in theory, a number of salutary effects. It would dampen the ongoing calcium fluxes, suppress excitotoxicity, and might effect some other harmful effects we haven't had the time to talk about.

Here's the problem with glutamate antagonists: they don't work. Although animal studies have demonstrated that glutamate antogonists ameliorate excitotoxicity and calcium flux, and although glutamate shows neuroprotection in rats and gerbils, clinical trials with glutamate antagonists have been uniformly disappointing.

Calcium Channel Blockers also seem like a no-brainer. By limiting calcium flux into the neuron, you might limit the activation of phospholipases and calpain, limit the secondary surges of glutamate, decrease the stress on the mitochondria, and block the generation of reactive oxygen species. Moreover, calcium-channel blockers are off-the-shelf technology, familiar to any physician who's ever treated hypertension, atrial fibrillaiton or svt.

Here's the problem with calcium channel blockers: they don't work. The animal evidence is equivocal, and clinical trials have failed miserably. I think this is because there's simply no way to stop those calcium surges that occur in the first few moments of ischemia. You might block later waves of calcium, but not enough to limit the damage done by that first spike. Moreover, a lot of the calcium that floods the cytosol in ischemia comes from inside the cell--from the endoplasmic reticulum, very early on. A slug of nifedipine, no matter how well-intentioned, just isn't going to stop that.

Phospholipase Antagonists and Cycloxygenase/Lipoxygenase Inhibitors are another natural. By blocking the enzymes that split free fatty acids out of the membrane, we could suppress the generation of superoxide, and thereby dial down the generation of all the secondary ROS, including the evil peroxynitrite. Alternatively, we could block the metabolism of free fatty acids.

Here's the problem with this approach: it doesn't  work. At least, not yet, although efforts are ongoing to bring such agents to clinical trial.