Ischemic cascade 2865101 223827929 2008-07-06T00:46:40Z RDBrown 539176 => Cite Journal with Wikipedia template filling, add reflist The '''ischemic (ischaemic) cascade''' is a series of biochemical reactions that take place in the [[brain]] and other aerobic tissues after seconds to minutes of [[ischemia]] (inadequate blood supply).<ref name="Becker ">{{cite web |url=http://www.emedicine.com/EMERG/topic558.htm |title=eMedicine - Stroke, Ischemic : Article by Joseph U Becker |format= |work= |accessdate=}}</ref> This is typically secondary to [[stroke]], injury, or [[cardiac arrest]] due to [[myocardial infarction|heart attack]]. Most ischemic [[neuron]]s that die do so due to the activation of chemicals produced during and after ischemia.<ref name="Internet Stroke Center">[http://www.strokecenter.org/ Stroke Center] of the Washington University School of Medicine.</ref> The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.<ref name="NINDS, 1999">{{cite web |url=http://www.ninds.nih.gov/disorders/stroke/detail_stroke.htm |title=Stroke: Hope Through Research: National Institute of Neurological Disorders and Stroke (NINDS) |format= |work= |accessdate=}}</ref> A [[biochemical cascade|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 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.<ref name="Hinkle and Bowman, 2003">{{cite journal |author=Hinkle JL, Bowman L |title=Neuroprotection for ischemic stroke |journal=J Neurosci Nurs |volume=35 |issue=2 |pages=114–8 |year=2003 |month=April |pmid=12795039 |doi= |url=}}</ref> 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 [[Adenosine triphosphate|ATP]] for energy to fail. # The cell switches to [[Fermentation (biochemistry)|anaerobic metabolism]], producing [[lactic acid]]. # ATP-reliant [[Ion pump (biology)|ion transport pumps]] fail, causing the cell to become [[action potential|depolarized]], allowing [[ion]]s, including [[calcium]] (Ca<sup>++</sup>), to flow into the [[cell (biology)|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 acid]] [[neurotransmitter]] [[glutamate]]. # Glutamate stimulates [[AMPA receptor]]s and Ca<sup>++</sup>-permeable [[NMDA receptor]]s, which open to allow more calcium into cells. # Excess calcium entry overexcites cells and causes the generation of harmful chemicals like [[free radical]]s, [[reactive oxygen species]] and calcium-dependent [[enzyme]]s such as [[calpain]], [[endonuclease]]s, [[ATPase]]s, and [[phospholipase]]s in a process called [[excitotoxicity]].<ref name="conway">Jill Conway. 2000. "[http://www.med.uiuc.edu/m2/Pathology/DCL.htm Diseases at the Cellular Level Lecture Handout]" and [http://www.med.uiuc.edu/m2/Pathology/Inflammation%20and%20Repair%20Lecture%20Handout.htm Inflammation and Repair Lecture Handout]" University of Illinois College of Medicine. Retrieved on [[January 9]], [[2007]].</ref><ref name="Jauch">{{cite web |url=http://www.emedicine.com/neuro/topic9.htm |title=eMedicine - Acute Stroke Management : Article by Edward C Jauch |format= |work= |accessdate=}}</ref> 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. # [[mitochondrion|Mitochondria]] break down, releasing toxins and [[apoptosis|apoptotic]] factors into the cell. # 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 [[neuron]]s, and glutamate can overexcite them. # If and when the brain is reperfused, a number of factors lead to [[reperfusion injury]]. # An [[inflammation|inflammatory]] response is mounted, and [[phagocytosis|phagocytic]] cells engulf damaged but still viable tissue. # Harmful chemicals damage the [[blood brain barrier]]. # [[Cerebral edema]] (swelling of the brain) occurs due to leakage of large [[molecule]]s 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. The fact that the ischemic cascade involves a number of steps has led doctors to suspect that [[neuroprotectants]] such as [[calcium channel blocker]]s or [[glutamate antagonists]] could 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, until recently, human [[clinical trial]]s with neuroprotectants such as [[NMDA receptor antagonist]]s were unsuccessful. == References == {{reflist}} [[Category:Angiology]] [[Category:Pathology]] [[fr:cascade ischémique]]