Ischaemic cascade · Grey Matter

The ischaemic cascade is the chain of events that follows when blood stops reaching part of the brain, from the loss of oxygen and glucose through the failure of the ion pumps to glutamate release and cell death, and it explains why brain tissue tolerates only minutes without circulation.

Ischaemic cascade. The ischaemic cascade is the chain of events that follows when blood stops reaching part of the brain, from the loss of oxygen and glucose through the failure of the ion pumps to glutamate release and cell death, and it explains why brain tissue tolerates only minutes without circulation.

The brain has no fuel reserve to speak of, so the sequence starts at once. Within about 10 seconds of a complete stop in blood flow consciousness is lost, and the EEG goes flat within about 20 to 40 seconds, as neurons fall silent to save energy. Over the next minutes oxidative phosphorylation stops, ATP runs out and the sodium-potassium pump fails. The ion gradients then collapse: potassium leaks out, sodium, chloride, calcium and water flow in and cells swell, and the tissue undergoes a sudden, near-complete depolarisation (anoxic depolarisation) that can spread through the cortex. Terminals release glutamate and transporters stop clearing it, and the calcium that floods in starts excitotoxicity.

Time decides the outcome. Neurons that stay depolarised for more than about half an hour are unlikely to survive even if blood returns, while a shorter interruption may be survived.

In a stroke there is a gradient. The core with no flow dies quickly; the surrounding penumbra, with reduced flow, can be saved if circulation returns, and repeated waves of spreading depolarisation through it worsen its energy deficit.

Reperfusion has its own cost. Restoring blood flow brings oxygen back but also a burst of reactive oxygen species and inflammation, a second hit after the first.

Ischaemia is the pump losing its power source, and everything else follows from the gradients running down.

Silence comes first, swelling and glutamate next, death last, and each stage is a window for treatment.

Questions: What happens, step by step, when blood stops reaching the brain? Within about 10 seconds consciousness is lost, and within about 20 to 40 seconds the EEG goes flat, because neurons stop firing to conserve energy before ATP has fallen much. Over the next minutes ATP runs out and the sodium-potassium pump stops, so potassium leaks out, sodium, chloride, calcium and water flow in, and the tissue undergoes a sudden, near-total depolarisation (anoxic depolarisation). Terminals then release glutamate that transporters can no longer clear, and calcium overload starts excitotoxic damage. Neurons kept depolarised for more than about half an hour are unlikely to recover even if the circulation returns. What does oxygen actually do in a neuron, and why does losing it stop the brain within seconds? Oxygen accepts the electrons at the end of the mitochondrial transport chain and becomes water; that last step keeps the chain moving, the chain pumps protons, and the proton flow drives ATP synthase. Without oxygen the chain jams within moments, and the brain has almost no stored oxygen and little stored fuel to fall back on. When blood flow stops completely, consciousness is lost in about 10 seconds and the EEG flattens within about 20 to 40 seconds, as neurons go quiet to save energy. Over the following minutes ATP runs out, the pumps fail and the ion gradients collapse, which starts the damage. Why does a lack of energy turn into a flood of glutamate? Glutamate is cleared by transporters that use the sodium gradient, and that gradient is kept by the ATP-driven pump. When ATP fails, the gradient runs down and the transporters slow, stop, and can even run in reverse, releasing glutamate from astrocytes and neurons. At the same time depolarised terminals open their calcium channels and release vesicles, adding more. The glutamate depolarises the neighbouring cells, which worsens their own energy deficit, so energy failure and excitation feed each other in a loop that spreads through tissue short of blood.