User:Adewale3/Library Training for BMED

From Wikipedia, the free encyclopedia
Jump to: navigation, search

Anoxic depolarization is a progressive and uncontrollable depolarization of neurons during stroke or brain ischemia in which there is deficient supply of blood to the brain due to rupture or obstruction of the internal carotid artery resulting in a complete insufficiency of oxygen reaching the brain. [1] Anoxic depolarization is induced by the loss of neuronal membrane permeability as a result loss of energy supply to power the Na+/K+-ATPase pump, which mediates membrane ion homeostasis by maintaining transmembrane gradients of K+ and Na+</sup.[2] The hallmarks of anoxic depolarization involve increased concentration of extracellular [[K+]], intracellular [[Na+]] and [[Ca2+]], and extracellular glutamate and aspartate both of which are the main excitotoxins that activate a number of downstream apoptotic and necrotic pathways that contribute to neuronal death and dysfunction.[3]

Neural signaling pathway under normal oxygen uptake[edit]

Neural signaling-human brain

Both electrical and chemical signals are generated by the synapses within the network of neurons.[4] Electrical signal is mediated by the Na+ and K+ channels in which intracellular K+ ion concentration is more than its corresponding extracellular concentration, whereas extracellular concentrations of Na+, Ca2+, and Cl- ions are higher than the corresponding intracellular concentrations. This uneven distribution of ions is maintained by the Na+/K+ ATPase pump which actively pumps Na+ out and K+ into the cell in a ratio of 3:2 per ATP used. Besides, a neuron has a resting membrane potential of -70mV due to the leaky [[K+ channels]].[5] As a neuron depolarizes due to transient permeability of membrane to Na+, the membrane potential becomes more positive. Eventually, a net Na+ influx via the [[Na+ channels]] causes the membrane potential to reach a threshold potential and then fires an all-or-none action potential, which either propagates down the axon or passes on to the other neurons via several gap junctions that link them.[4] The action potential that propagates down the axon of the same neuron triggers Ca2+ influx via the [[Ca2+ channels]] in the presynaptic terminal.[5] Increased intracellular Ca2+ causes presynaptic vesicles to fuse and release neurotransmitters via exocytosis to the synaptic cleft.[6] Chemical signaling occurs when a neurotransmitter binds its specific postsynaptic receptor or activates its specific ligand-gated ion channel to fire an action potential that can be either excitatory or inhibitory depending on the nature of the ligand-gated ion channel. A neurotransmitter is removed from the synaptic cleft by either enzymatic degradation or re-uptake by the same presynaptic neuron via endocytosis or specific transporters.[4]

Brain energy crisis[edit]

Stroke onset[edit]

Within a few seconds of stroke onset, the brain reacts by entering a state of metabolic depression in which energy consumption is reduced to compensate for the reduction in energy production. Metabolic depression occurs as a result of suppressed synaptic transmission and hyperpolarization. The suppression of synaptic transmission occurs because the presynaptic impulse temporarily fails to trigger the release of neurotransmitters, couple with the altered ion conductance and a change in postsynaptic receptors, which make them unresponsive to neurotransmitter binding, thereby inhibiting postsynaptic excitation. [5] Hyperpolarization, on the other hand, is employed to reduce neuronal activity by establishing a high threshold potential for firing an action potential. This energy-conserving response is due to continuous inward current of K+, which helps maintain the membrane ion gradient until the resistance is broken and anoxic depolarization begins.[5]

Imbalance ion-homeostasis[edit]

Maintaining a balance between the intracellular and extracellular ionic concentrations at the postsynaptic terminal is critical to a normal neuronal function. During oxygen depletion to the brain, two events that initiate as well as propagate anoxic depolarization involve excessive cationic influxes and the outflow of ATP in the postsynaptic terminal.[1] The receptors that allow cationic influxes and the outflow of ATP on the postsynaptic terminal are ionotropic receptors, which are ligand-gated ion channels that bind specific neurotransmitters, released from the synaptic vesicles of the presynaptic terminal to trigger the opening of the channels, which serve as conduits for these cations that in turn, initiate action potential in the post synaptic terminal of a normal functioning neuron.[7] The key player in this whole dramatic process of cationic influxes is glutamate, an excitatory neurotransmitter that triggers excitotoxicity during anoxic depolarization.[8] A number of ionotropic receptors have been identified to contribute to anoxic depolarization of nerve cell membrane. They include the NMDA receptor, AMPA receptor, purinergic (P2X7) receptors, pannexin (Panx1) channels, transient receptor potential (TRP) channels, and acid-sensing ion channel (ASICs).[1] During brain ischemia, glutamate is released in excess from the presynaptic terminal leading to uncontrollable opening of the glutamate receptors, including the NMDA receptor and AMPA receptor, which allow an excessive influx of Ca2+ into the intracellular environment. Purinergic and NMDA receptors activate the pannexin-1 channels, which become hyperactive and allow the release of ATP from the intracellular environment. As the extracellular glutamate and ATP increases, several complexes are activated and converge into apoptotic and necrotic cascade pathways, which cause neuronal damage and death. .[1]

Post-anoxic depolarization: neuronal damage[edit]

Low Ca2+ buffering and excitotoxicity under physiological stress and pathophysiological conditions in motor neuron (MNs)

In the aftermath of anoxic depolarization, at the region of infarction, the release of glutamate and aspartate into the extracellular space causes an uncontrollable intracellular mobilization of Ca2+ mainly through the NMDA receptor.[9] This is a critical stage in neuronal damage because it's the Ca2+ overload that gives rise to several downstream cascade of events that lead to necrotic neuronal death and apoptosis, including free radical and nitric oxide productions that cause damage to the membrane.[10] Another cytotoxic events that follow anoxic depolarization are lactate accumulation and acidosis as a result of glycolysis, which causes damage to the mitochondria.[10] Ischemic insult also causes blood-brain barrier disruption.[9] Other secondary damages that occur include lipolysis, proteolysis, cell swelling, microtubule disaggregation, and DNA fragmentation.[5]

Selective vulnerability[edit]

Unlike the muscle cells, which are excitable as well as have the capability to store glucagon, nerve cells generally lacks energy-storing capacity, and this comes at a cost of high vulnerability to energy failure.[11] Neurons are also more susceptible to brain ischemia than the supporting glial cells because neurons have higher energy demand, conduct action potential, and produce glutamate, whereas glial cells lack those properties. Yet neurons differ in their sensitivity to ischemia depending on the specific properties they exhibits relative to their locations in the brain.[12] Selective vulnerability is the term used to describe how some parts of the brain are more sensitive to anoxia than others earlier on in ischemic insult.[10] Anoxia-prone cells in the brain includes the hippocampal pyramidal cells of CA1, cerebellar purkinje cells, pyramidal neocortical neurons in the layers 3, 5, and 6, basal ganglia, reticular neurons of thalamus, and brainstem neurons.[13] While basal ganglia, cerebellar purkinje cells, hippocampal and neocortical cells are more prone to transient ischemic attack (TIA), brainstem and thalamic reticular neurons are more prone to prolonged ischemic attack (stroke proper).[12] Meanwhile, the pyramidal cells of the hippocampus have been identified to be the most vulnerable cells to ischemia.[13] One possible explanation for why selective vulnerability exists attributed the phenomenon to the differential amount of glutamate produced by different neurons since it's glutamate release to the synaptic cleft that triggers Ca2+ influx, which in turn triggers biochemical processes that damage neurons.[12] In another research that looked into the molecular level, variation in the expression of immediate early gene and heat shock protein was identified to cause selective vulnerability.[13]

Anoxic-tolerant brains[edit]

Metabolic depression[edit]

While certain animals have evolved to better cope with brain anoxia, the mammalian brain struggle dealing with even the slightest oxygen deficit. The main component of neuronal physiology that suffers during brain anoxia is the membrane ion permeability, and it turns out that most mammals, including humans have a poorly regulated ion-homeostasis during anoxia.[5] One of the animals known to have evolved to cope with this prolonged cerebral oxygen depletion is freshwater turtle (Chrysemys picta), which is a cold-blooded reptile that utilizes the mechanism of metabolic depression to combat oxygen depletion.[14] Metabolic depression is used in this respect to describe the process in which brain neuronal activity is down-regulated to conserve energy needed to maintain an optimum ionic gradient. Within a few minutes of anoxia onset, there is transient cerebral blood flow that eventually ceases. Meanwhile glycolysis is stimulated to maintain a near optimum ATP production.[3] This compensatory stimulation of glycolysis occurs because the turtle brain cytochrome a and a3 have a low affinity for oxygen.[14] The downside of anaerobic glycolysis is lactate overload, which the turtle buffers by its shell and bone CaCO3 production.[3] Followed by glycolytic activation is the initiation of metabolic depression. Glycolysis is not efficient for ATP production and in order to maintain an optimum ATP concentration, the turtle brain has to reduce its ATP consumption by suppressing its neuronal activity and gradually releasing adenosine, which establishes the ATP consumption/production balance, which in turn, is maintained by reducing ion conductance and releasing GABA. Metabolic depression decreases neuronal activity, which render the turtle comatose for the duration of anoxia.[15]

Pasteur effect[edit]

Another anoxic-resistant animal that’s commonly used as a model to study anoxia in mammalian brain is the crucian carp, which can survive at even extreme anoxic condition than the freshwater turtle. Unlike C. picta that takes such a drastic measure of becoming comatose to maintain an optimum ATP concentration, the crucian carp does not comatose in anoxia. Instead, it stays active by maintaining its normal cardial output as well as increasing its cerebral blood flow, which appears to cease in C. picta.[5] Even though glycolysis is stimulated earlier in anoxia in both crucian carp and C. picta, crucian carp is able to stay active because of its capability to re-route the glycolytic pathway such that lactate is converted into ethanol, which can be released into water via the gills and subsequently preventing lactate overload and acidosis.[3] Since crucian carp has a more efficient strategy to prevent lactate buildup than C. picta, the initial glycolysis continues without ceasing, a process called Pasteur effect.[15] In order to keep up with this fast glucose metabolism via glycolysis as well as maintain the balance between ATP production and consumption, crucian carp moderately suppresses its motor activities and releases GABA, and selectively suppresses some nervous activities, especially unnecessary sensory stimulations.[15] Perhaps, the most important strategy employed by crucian carp to counteract the damage effect of anoxia is by swimming into cooler water, a phenomenon known as voluntary hypothermia.[3]

Mammalian neonate[edit]

Several research groups have studied anoxic-resistance in mammalian brain and several mammalian neonates have been identified to confer resistance to anoxia in a similar fashion as freshwater turtle.[14] This is still a relatively new area of study that have stimulated the interest of a number of neuroscientists because it could have a clinical significance on how to manage, delay, or reduce the damage caused by stroke. A study that looked into anoxic-tolerance in newborn mammals identified two main ways in which newborn mammals cope with acute hypoxia. While most newborns preferentially depress their metabolic rate to conserve energy during anoxia, some mammalian newborns such as the pig, the deer, and other animals in their class, which are capable of a high degree of independent activity from birth, employ hyperpnoea (abnormally rapid or deep breathing.[16] Why metabolic depression or hypometabolism is less effective in adult mammal compared to neonates is unclear at the moment. Due to ethical issues anoxic-tolerance has not been tested in human neonates.

Research: Neuroprotective agents[edit]

NMDA receptor activation and antagonists

Currently, there hasn’t been any effective way to combat stroke. The only treatment that have been approved by FDA to treat stroke is the genetically engineered form of tissue plasminogen activator (t-PA), which is an enzyme that activates plasminogen, which in turn produces plasmin, fibrin-dissolving enzyme. However, the effectiveness of t-PA is time-dependence, and the drug must be administered within 6 hours of onset of symptoms in order to be effective.[17] Many clinical trials have failed in an attempt to develop a neuroprotective drug to combat stroke perhaps because those drugs only deal with one aspect of stroke therefore neglecting the fact that stroke is a multifaceted problem. Some of the potential treatments for stroke that have been tested by a number of researchers using several animal models include sigma-1 receptor ligands to modulate Ca release; NMDA receptor antagonist to prevent Ca2+ overload; and ion channel blockers to prevent excessive ion fluxes. Yet none of these drugs are FDA-approved because either they don't make it to the clinical trial or they fail clinical.

See also[edit]

References[edit]

  1. ^ a b c d Weilinger, N. L. (2012). "Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction". Acta Pharmacologica Sinica. 34. (1): 39–48. doi:10.1038/aps.2011.95.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ Stys, P. (1998). "Anoxic and ischemic injury of myelinated axons in CNS white matter: from Mechanistic Concepts to Therapeutics.". Journal Of Cerebral Blood Flow And Metabolism: Official Journal Of The International Society Of Cerebral Blood Flow And Metabolism. 18. (1): 2–25. doi:10.1097/00004647-199801000-00002. 
  3. ^ a b c d e Nilsson, G. (2004). "Anoxia tolerant brains". Of Cerebral Blood Flow And Metabolism: Official Journal Of The International Society Of Cerebral Blood Flow And Metabolism. 24. (5): 475–486. doi:10.1097/00004647-200405000-00001.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ a b c Purves, Dale (2008). "Neural Signaling". Neuroscience (4th ed.). Sunderland, MA: Sinauer. pp. 23–207.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ a b c d e f g Lutz, P. L (1997). Neuroscience intelligence unit:The Brain Without Oxygen (2nd ed.). Austin, TX: Landes Bioscience and Chapman & Hall. pp. 1–207.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Kochlamazashvili, G (2013). "A dual role of SNAP-25 as carrier and guardian of synaptic transmission". EMBO Reports. 14. (7): 579–580. doi:10.1038/embor.2013.74.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Goyal, R (2013). "Structure activity relationship of synaptic and junctional neurotransmission". Autonomic Neuroscience: Basic & Clinical. 176. (1-2): 11–31. doi:10.1016/j.autneu.2013.02.012.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Madry, C (2010). "The role of pannexin hemichannels in the anoxic depolarization of hippocampal pyramidal cells". Brain: A Journal Of Neurology. 133. (Pt 12): 3755–3763. doi:10.1093/brain/awq284.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ a b Zhao, H (2007). "General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage". Journal Of Cerebral Blood Flow And Metabolism: Official Journal Of The International Society Of Cerebral Blood Flow And Metabolism. 27. (12): 1879–1894. doi:10.1038/sj.jcbfm.9600540.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ a b c Huang, B (2008). "Hypoxic-ischemic brain injury: imaging findings from birth to adulthood". Radiographics: A Review Publication Of The Radiological Society Of North America, Inc. 28. (2): 417–439. doi:10.1148/rg.282075066.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Kitagawa, K. (2012). "Ischemic tolerance in the brain: Endogenous adaptive machinery against ischemic stress". Journal of Neuroscience Research. 90. (5): 1043–1054. doi:10.1002/jnr.23005. 
  12. ^ a b c Agamanolis, D. "Chapter 2: Cerebral Ischemia and Stroke". Neuropathology. Retrieved 4 November 2013. 
  13. ^ a b c Busl, K (2010). "Hypoxic-ischemic brain injury: pathophysiology, neuropathology and mechanisms". Neurorehabilitation. 26. (1): 5–13. doi:10.3233/NRE-2010-0531.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ a b c Lutz, P. L (1992). "Mechanisms for Anoxic Survival in the Vertebrate Brain". Annual Review Of Physiology. 54: 601–618. doi:10.1146/annurev.ph.54.030192.003125. 
  15. ^ a b c John W. Thompson (2013). "2: Anoxia Resistance in Lower and Higher Vertebrates". In Jeffrey M. Gidday, Miguel A. Perez-Pinzon, John H. Zhang. Innate Tolerance in the CNS: Translational Neuroprotection by Pre- and Post-Conditioning. New York: Springer New York. pp. 19–35. ISBN 978-1-4419-9694-7.  Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Mortola, J (1999). "How newborn mammals cope with hypoxia". Respiration Physiology. 116. (2-3): 95–103. 
  17. ^ Behensky, A (2013). "In vitro evaluation of guanidine analogs as sigma receptor ligands for potential anti-stroke therapeutics". The Journal Of Pharmacology And Experimental Therapeutics. 344. (1): 155–166. doi:10.1124/jpet.112.199513.  Unknown parameter |coauthors= ignored (|author= suggested) (help)

External links[edit]


Lai, T (2011). "Stroke intervention pathways: NMDA receptors and beyond". Trends In Molecular Medicine. 17. (5): 266–275. doi:10.1016/j.molmed.2010.12.008.  Unknown parameter |coauthors= ignored (|author= suggested) (help)