The
ischemic (ischaemic) cascade is a series of biochemical reactions that take place in the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
and other aerobic tissues after seconds to minutes of
ischemiaIn medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue...
(inadequate blood supply). This is typically secondary to
strokeA stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by thrombosis or embolism or due to a hemorrhage...
, injury, or
cardiac arrestA cardiac arrest, also known as cardiopulmonary arrest or circulatory arrest, is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively during systole....
due to
heart attackMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...
. Most ischemic
neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s that die do so due to the activation of chemicals produced during and after ischemia. The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.
A
cascadeA biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
is a series of events in which one event triggers the next, in a linear fashion.
The
ischemic (ischaemic) cascade is a series of biochemical reactions that take place in the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
and other aerobic tissues after seconds to minutes of
ischemiaIn medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue...
(inadequate blood supply). This is typically secondary to
strokeA stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by thrombosis or embolism or due to a hemorrhage...
, injury, or
cardiac arrestA cardiac arrest, also known as cardiopulmonary arrest or circulatory arrest, is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively during systole....
due to
heart attackMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...
. Most ischemic
neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s that die do so due to the activation of chemicals produced during and after ischemia. The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.
A
cascadeA biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
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 events. 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 ATP
Adenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
for energy to fail.
- The cell switches to anaerobic metabolism
Fermentation is the process of deriving energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. This is in contrast to cellular respiration, where electrons are donated to an exogenous electron acceptor,...
, producing lactic acidLactic acid , also known as milk acid, is a chemical compound that plays a role in several biochemical processes. It was first isolated in 1780 by a Swedish chemist, Carl Wilhelm Scheele, and is a carboxylic acid with a chemical formula of C
3H
6O
3...
.
- ATP-reliant ion transport pumps
In biology, an ion transporter, also called an ion pump, is a transmembrane protein that moves ions across a plasma membrane against their concentration gradient, in contrast to ion channels, where ions go through passive transport-Energy source:...
fail, causing the cell to become depolarizedAn action potential is a transient alteration of the transmembrane voltage across an excitable membrane generated by the activity of voltage-gated ion channels embedded in the membrane. Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and...
, allowing ionAn ion is an atom or molecule where the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge...
s, including calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
(Ca++), to flow into the cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos...
.
- 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
Amino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
glutamate.
- Glutamate stimulates AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog, AMPA...
s and Ca++-permeable NMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, which open to allow more calcium into cells.
- Excess calcium entry overexcites cells and causes the generation of harmful chemicals like free radicals, reactive oxygen species
Reactive oxygen species are free radicals that contain the oxygen atom. They are very small molecules that include oxygen ions and peroxides and can be either inorganic or organic. They are highly reactive due to the presence of unpaired valence shell electrons.ROS form as a natural byproduct of...
and calcium-dependent enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
s such as calpainCalpains are a family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small...
, endonucleaseEndonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain, in contrast to exonucleases, which cleave phosphodiester bonds at the end of a polynucleotide chain. Restriction endonucleases cleave DNA at specific sites, and are divided into three categories, Type I,...
s, ATPaseATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
s, and phospholipaseA phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D distinguished by what type of reaction they catalyze:* Phospholipase A...
s in a process called excitotoxicityExcitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated...
. 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.
- Mitochondria
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5–10 micrometers in diameter...
break down, releasing toxins and apoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
factors into the cell.
- The caspase
Caspases, or cysteine-aspartic proteases, are a family of cysteine proteases, which play essential roles in apoptosis , necrosis and inflammation....
-dependent apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
cascade is initiated, causing cells to "commit suicide."
- If the cell dies through necrosis
Necrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, such as infection, toxins , or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s, and glutamate can overexcite them.
- If and when the brain is reperfused, a number of factors lead to reperfusion injury
Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of...
.
- An inflammatory
Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...
response is mounted, and phagocyticPhagocytosis is the cellular process of phagocytes and protists of engulfing solid particles by the cell membrane to form an internal phagosome...
cells engulf damaged but still viable tissue.
- Harmful chemicals damage the blood brain barrier.
- Cerebral edema
Cerebral edema is an excess accumulation of water in the intracellular and/or extracellular spaces of the brain.- Vasogenic cerebral edema:...
(swelling of the brain) occurs due to leakage of large moleculeA molecule is defined as an electrically neutral group of at least two atoms in a definite arrangement held together by very strong chemical bonds. Molecules are distinguished from polyatomic ions in this strict sense...
s like albumins from blood vessels through the damaged blood brain barrier. These large molecules pull water into the brain tissue after them by osmosisOsmosis is the diffusion of water through a semi-permeable membrane. More specifically, it is the movement of water across a semi-permeable membrane from an area of high water potential to an area of low water potential...
. 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 blockerCalcium channel blockers are a class of drugs and natural substances that disrupt the conduction of calcium channels.It has effects on many excitable cells of the body, such as cardiac muscle, i.e. heart, smooth muscles of blood vessels, or neurons...
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 trialClinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices. These trials can only take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety, and Health Authority/Ethics Committee approval is...
s with neuroprotectants such as
NMDA receptor antagonistNMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...
s were unsuccessful.