During ischemia, brain tissue is unable to continue aerobic metabolism due to the loss of oxygen and substrate. Since the brain cannot switch to anaerobic metabolism and has no long-term energy stores, ATP levels fall rapidly. Without biochemical energy, cells quickly lose their ability to maintain electrochemical gradients. This loss of bioenergy and the ability to partition ions leads to several untoward developments during ischemia:
1. A massive influx of calcium into the cytosol. This is only natural, as the gradient between extracellular and intracellular calcium is about 10,000/1. Calcium also spills from the endoplasmic reticulum into the cytosol during ischemia (again, the ratio is about 10,000/1).
2. A massive release of glutamate from synaptic vesicles. This massive depolarization is both caused by, and causes, calcium release. This surge of glutamate and other excitatory neurotransmitters results in so much subsequent evildoing that it is called excitotoxicity.
3. Lipolysis. The glutamate and calcium surges activate phospholipases, enzymes that begin the breakdown of membrane lipids. In particular, this process results in the generation of free arachidonic acid. During reperfusion, the metabolism of arachidonate and other lipid products will lead to the generation of free radicals--although arachidonate appears to have toxic effects independent of free radical generation.
4. Calpain activation. Calpain is a calcium-activated protease responsible for the ongoing remodeling of the cytoskeleton, particularly in the area of the synapse. During ischemia, huge calcium fluxes result in overhwelming activation of calpain, which then proceeds to eat the cytoskeleton on a grand scale.
5. Arrest of protein synthesis. Without ATP, translation of mRNA into protein stops dead in its tracks, and in cells that go on to die, this translation inhibition is permanent, even when circulation is restored and ATP levels normalize. Vulnerable neurons never regain their ability to incorporate amino acids into protein. This is bad news for any cell, but for neurons, which have an extraordinarily high protein synthetic requirment (50% of the neuronal plasma membrane is protein), it really sucks.
Badness during ischemia. Highly simplified representation of events during ischemia. Loss of ATP results in an immediate arrest of protein synthesis, depolarization, release of glutamate, and flooding of the cytosol with calcium ion. The calcium surge triggers additional glutamate release, lipolysis, and activation of calpain, as well as mitochondrial stress (not shown).