The ischemic cascade is a series of biochemical reactions that take place in the brain after seconds to minutes of ischemia (inadequate blood supply) (Arnold, 2003). Most ischemic neurons that 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). In the anatomy of animals, the brain, or encephalon, is the higher, supervisory center of the nervous system. ... In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. ... Neurons (also spelled neurones or called nerve cells) are the primary cells of the nervous system. ...

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 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: A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ...

• Lack of oxygen causes the neuron's normal process for making ATP for energy to fail.
• The cell switches to anaerobic metabolism, producing lactic acid.
• ATP-reliant ion transport pumps fail, 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 acid neurotransmitter glutamate.
• Glutamate stimulates NMDA receptors and Ca⁺⁺-permeable AMPA receptors, which open to allow more calcium into cells.
• Excess calcium overexcites cells and causes the generation of harmful chemicals like free radicals, phospholipases, and calcium-dependent enzymes such 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.
• Mitochondria break down, releasing toxins and 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 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 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 molecules like albumin 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 blockers 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, human clinical trials with neuroprotectants were unsuccesful and had to be cancelled. Adenosine triphosphate (ATP) Adenosine triphosphate (ATP) is the nucleotide known in biochemistry as the molecular currency of intracellular energy transfer; that is, ATP is able to store and transport chemical energy within cells. ... Glycolysis is the initial metabolic pathway of carbohydrate catabolism. ... Lactic acid (α-hydroxypropionic acid) is a chemical compound that plays a role in several biochemical processes. ... Sputter ion pumps are a class of vacuum pump designed to operate in very low pressure (i. ... A. Schematic of an electrophysiological recording of an action potential showing the various phases which occur as the wave passes a point on a cell membrane. ... Jump to: navigation, search An ion is an atom or group of atoms with a net electric charge. ... General Name, Symbol, Number calcium, Ca, 20 Chemical series alkaline earth metals Group, Period, Block 2, 4, s Appearance silvery white Atomic mass 40. ... Jump to: navigation, search A cell is a single unit or compartment, enclosed by a border or wall. ... Jump to: navigation, search In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. ... Glutamate is the anion of glutamic acid. ... The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). ... The AMPA receptor (AMPAR) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system. ... Excitotoxicity is the process by which cell death is produced in neurons by the overactivation of excitatory neurotransmitter receptors such as the NMDA receptor. ... In chemistry free radicals are uncharged atomic or molecular species with unpaired electrons or an otherwise open shell configuration. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... Jump to: navigation, search Ribbon diagram of the catalytically perfect enzyme TIM. Factor D enzyme crystal prevents the immune system from inappropriately running out of control. ... Endonucleases are enzymes that cleave the phosphodiester bond within a nucleotide chain. ... ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and a free phosphate ion. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... Jump to: navigation, search Mitochondria are visible as thread-like structures in the light microscope. ... In biology, apoptosis (from the Greek words apo = from and ptosis = falling, pronounced ap-a-tow-sis[1]) is one of the main types of programmed cell death (PCD). ... Caspases are a group of cysteine proteases, enzymes with a crucial cysteine residue that can cleave other proteins, after an aspartic acid residue, a specificity which is unusual among proteases. ... In biology, apoptosis (from the Greek words apo = from and ptosis = falling, pronounced ap-a-tow-sis[1]) is one of the main types of programmed cell death (PCD). ... Necrosis (in Greek Νεκρός = Dead) is the name given to unprogrammed death of cells/living tissue (compare with apoptosis - programmed cell death). ... Neurons (also spelled neurones or called nerve cells) are the primary cells of the nervous system. ... The absence of oxygen and nutrient in ischemia creates a condition in which the restoration of circulation results in oxidative damage from the oxygen rather than restoration of normal function. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... Phagocytosis (literally, cell eating) is a form of endocytosis where large particles are enveloped by the cell membrane of a (usually larger) cell and internalized to form a phagosome, or food vacuole. ... The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and the central nervous system itself. ... Jump to: navigation, search Cerebral edema is swelling of the brain which can occur as the result of a head injury, cardiac arrest or from the lack of proper altitude acclimatization. ... Jump to: navigation, search A molecule is the smallest particle of a pure chemical substance that still retains its chemical composition and properties. ... Jump to: navigation, search You may be looking for albumen, or egg white. ... The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and the central nervous system itself. ... Osmosis is the diffusion of a solvent through a semipermeable membrane from a region of low solute concentration to a region of high solute concentration. ... Edema (BE: oedema, formerly known as dropsy) is swelling of any organ or tissue due to accumulation of excess fluid. ... Calcium channel blockers are a class of drugs with effects on the muscle of the heart and the muscles of the rest of the body. ... Jump to: navigation, search In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a research study. ...

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 Center of the Washington University School of Medicine.