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.
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
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.
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