The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the
brain and other aerobic tissues after seconds to minutes of
ischemia (inadequate blood supply).[1] This is typically secondary to
stroke, injury, or
cardiac arrest due to
heart attack. Most ischemic
neurons that die do so due to the activation of chemicals produced during and after ischemia.[2] The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.[3]
Mechanism
A
cascade is a series of events in which one event triggers the next, in a linear fashion. Thus "ischemic cascade" is actually a misnomer, since the events are not always linear: in some cases they are circular, and sometimes one event can cause or be caused by multiple events.[4] In addition, cells receiving different amounts of blood may go through different chemical processes. Despite these facts, the ischemic cascade can be generally characterized as follows:[citation needed]
Low blood supply decreases amount of oxygen that reaches tissues, leading to
hypoxia
Deficiency of oxygen causes the neuron's normal process for making
ATP for energy to fail.
The
caspase-dependent
apoptosis cascade is initiated, causing cells to "commit suicide."
If the cell dies through
necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby
neurons, and glutamate can overexcite them.
If and when the brain is reperfused, a number of factors lead to
reperfusion injury.
An
inflammatory response is mounted, and
phagocytic cells engulf damaged but still viable tissue.
Cerebral edema (swelling of the brain) occurs due to leakage of large
molecules like
albumins from blood vessels through the damaged
blood brain barrier. These large molecules pull water into the brain tissue after them by
osmosis. This "
vasogenic edema" causes compression of and damage to brain tissue (Freye 2011; Acquired Mitochondropathy-A New Paradigm in Western Medicine Explaining Chronic Diseases).
Mitigation of effects
The fact that the ischemic cascade involves a number of steps has led doctors to suspect that
cerebroprotectants could be produced to interrupt the cascade at a single one of the steps, blocking the downstream effects. Over 150 cerebroprotectants have been tested in clinical trials, leading to the approval of
tissue plasminogen activator (also known as tPA, t-PA, rtPA, Activase, or Alteplase or Actilyse)[7] in the US and other countries, and
edaravone (Radicut) in Japan.[8]