Ischemic cascade

The ischemic cascade is a series of biochemical reactions that take place in the brainafter seconds to minutes of ischemia(inadequate blood supply) (Arnold, 2003). Most ischemic neuronsthat die do so due to the activation of chemicals produced during and after ischemia (Internet Stroke Center, 2003). The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns (NINDS, 1999; Panacea Pharmaceuticals, 2004).

A cascadeis a series of events in which one event triggers the next, in a linear fashion. Thus "ischemic cascade" is actually a misnomer, since in it, events are not always linear: in some cases, they are circular, and sometimes one event can cause or be caused by multiple other events (Hinkle and Bowman, 2003). 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:

• Lack of oxygen causes the neuron's normal process for making ATPfor energy to fail.
• The cell switches to anaerobic metabolism, producing lactic acid.
• ATP-reliant ion transport pumpsfail, causing the cell to become depolarized, allowing ions, including calcium(Ca⁺⁺), to flow into the cell.
• The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high.
• The presence of calcium triggers the release of the excitatory amino acidneurotransmitterglutamate.
• Glutamate stimulates NMDA receptorsand Ca⁺⁺-permeable AMPA receptors, which open to allow more calcium into cells.
• Excess calcium overexcitescells and causes the generation of harmful chemicals like free radicals, phospholipases, and calcium-dependent enzymessuch as calpain, endonucleases, ATPases, and phospholipases(Jauch, 2003; National Stroke Association, 2002; Conway, 2000). Calcium can also cause the release of more glutamate.
• As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.
• Mitochondriabreak down, releasing toxins and apoptoticfactors into the cell.
• The caspase-dependent apoptosiscascade 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 inflammatoryresponse is mounted, and phagocyticcells engulfe damaged but still viable tissue.
• Harmful chemicals damage the blood brain barrier.
• Cerebral edema(swelling of the brain) occurs due to leakage of large moleculeslike albuminfrom 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.

The fact that the ischemic cascade involves a number of steps has led doctors to suspect that neuroprotectantssuch as calcium channel blockerscould be produced to interrupt the cascade at a single one of the steps, blocking the downstream effects. Though initial trials for such neuroprotective drugs led many to be hopeful, human clinical trialswith neuroprotectants were unsuccesful and had to be cancelled.

References

• Conway, Jill. 2000. "Diseases at the Cellular Level Lecture Handout" and Inflammation and Repair Lecture Handout" University of Illinois College of Medicine.

• Jauch, Edward C MD. 2003. ?Acute Stroke Management.? eMedicine.com, Inc.

• National Institute of Neurological Disorders and Stroke (NINDS). 1999. Stroke: Hope Through Research. Bethesda, Maryland: National Institutes of Health.

• National Stroke Association. 2002. "Classes of Acute Treatment."

• Panacea Pharmaceuticals. 2004. "Panacea Pharmaceuticals, Inc. Awarded SBIR from National Institute of Neurological Disorders and Stroke to Develop Neuroprotectants for Stroke and other Ischemia-Related Conditions."

• Stroke Centerof the Washington University School of Medicine.

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It uses material from the http://en.wikipedia.org/wiki/Ischemic+cascade Wikipedia article Ischemic cascade.