Anoxic depolarization in the brain

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Anoxic depolarization is a progressive and uncontrollable

necrotic pathways. This results in neuronal dysfunction and brain death.[3]

Neural signal under normal oxygen uptake

Further information: Action potential
Nerve action potential

Neurons function in the

gap junctions that link them.[4]

Illustration of a synapse

A chemical signal (

neurotransmitter transporters.[4]

Brain energy crisis

Stroke onset

Within a few seconds of stroke onset, the brain responds 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, which, coupled with the altered ion conductance and a change in postsynaptic neuroreceptors, makes synapses 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 across an action potential. This energy-conserving response is due to the continuous inward current of K+ ions, which help maintain the membrane

ion gradient until the resistance is broken and anoxic depolarization begins.[5]

Imbalance in ion-homeostasis

Maintaining a balance between the intracellular and extracellular ionic concentrations at the postsynaptic terminal is critical to normal neuronal function. During oxygen depletion to the

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 cations that, in turn, initiate action potential across the post synaptic terminals of normally functioning neurons.[7]

The key player in the dramatic process of cationic influx is glutamate, an

transient receptor potential (TRP) channels, and acid-sensing ion channels (ASICs).[1]

During brain ischemia, glutamate is released in excess from the presynaptic terminal, leading to the uncontrollable opening of the

glutamate receptors, including the NMDA and AMPA receptors, which allows for 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 increase, several complexes are activated and converge into apoptotic and necrotic cascade pathways, which cause neuronal damage and death.[1]

Post-anoxic depolarization: downstream neuronal damage

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

free radical and nitric oxide productions that cause damage to the membrane.[10]

Another

DNA fragmentation.[5]

Selective vulnerability

Neurons are more susceptible to brain ischemia than the supporting

glial cells, because neurons have higher energy demand, conduct an action potential, and produce glutamate, whereas glial cells lack those properties. Yet neurons differ among themselves in their sensitivity to ischemia, depending on the specific properties they exhibit, relating to their locations in the brain.[11]

Selective vulnerability is how some parts of the brain are more sensitive to

neocortical neurons in some layers, basal ganglia, reticular neurons of the thalamus, and brainstem neurons.[12]

While basal ganglia, cerebellar purkinje cells, hippocampal, and neocortical cells are more vulnerable to transient ischemic attack (TIA), brainstem and thalamic reticular neurons are more vulnerable to prolonged ischemic attack (stroke proper).[11] Meanwhile, the hippocampal pyramidal cells have been identified as the most vulnerable cells to ischemia.[12] One possible explanation for why selective vulnerability exists attributes the phenomenon to the different amounts of glutamate produced by different neurons, since it is glutamate release to the synaptic cleft that triggers Ca2+ influx, which in turn triggers biochemical processes that damage the neurons.[11] In other research, variation in the expression of immediate early gene and heat shock protein was identified as causing selective vulnerability.[12]

Anoxic-tolerance mechanisms

Metabolic depression

The painted turtle (Chrysemys picta) uses the mechanism of metabolic depression to combat oxygen depletion.[13] Within a few minutes of anoxia onset in the turtle's brain there is decreased 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, in the turtle's brain, cytochrome a and a3 have a low affinity for oxygen.[13] Anaerobic glycolysis leads to lactate overload, which the turtle buffers to some extent by increased shell and bone CaCO3 production.[3]

However, glycolysis is not efficient for ATP production, and in order to maintain an optimum ATP concentration, the turtle's brain reduces its ATP consumption by suppressing its neuronal activity and gradually releasing

GABA. The decrease in neuronal activity renders the turtle comatose for the duration of anoxia.[14]

Pasteur effect

Another

gills, thus preventing lactate overload and acidosis.[3]

Since the crucian carp has a more efficient strategy to prevent lactate buildup than C. picta, the initial glycolysis continues without ceasing, a process called the Pasteur effect.[14] In order to keep up with this fast glucose metabolism via glycolysis, as well as maintain the balance between ATP production and consumption, the crucian carp moderately suppresses its motor activities, releases GABA, and selectively suppresses some unnecessary sensory functions.[14] Crucian carp also counteracts the damaging effects of anoxia by swimming into cooler water, a phenomenon known as voluntary hypothermia.[3]

Tolerance in mammalian neonates

The brains of several mammalian neonates have been identified as able to confer resistance to anoxia in a fashion similar to that of the anoxic-tolerant aquatic organisms.

hyperpnoea (abnormally rapid or deep breathing).[15]
Why metabolic depression is less effective in adult mammals, compared to neonates, is unclear at the moment. Due to ethical issues, anoxic-tolerance has not been tested in human neonates.

Research: neuroprotective agents

NMDA receptor activation and antagonists

Currently, there is no effective way to combat stroke. The only FDA-

ischemic stroke.[16]

Many

NMDA receptor antagonists, to prevent Ca2+ overload, and ion channel blockers, to prevent excessive ion fluxes.[citation needed
]

See also

References

  1. ^
    PMID 22864302
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  2. PMID 9428302
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  3. ^
    PMID 15129179
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  4. ^
    ISBN 9780878936977
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  5. ^ a b c d e f Lutz, P. L.; Nilsson, G. E. (1997). Neuroscience intelligence unit: The Brain Without Oxygen (2nd ed.). Austin, TX: Landes Bioscience and Chapman & Hall. pp. 1–207.
  6. PMID 23732543
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  7. PMID 23535140
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  8. PMID 20940167
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  9. ^
    PMID 17684517
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  10. ^
    PMID 18349449
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  11. ^ a b c Agamanolis, D. "Chapter 2: Cerebral Ischemia and Stroke". Neuropathology. Retrieved 4 November 2013.
  12. ^
    PMID 20130351
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  13. ^
    PMID 1348613
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  14. ^
    ISBN 978-1-4419-9694-7
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  15. PMID 10487295
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  16. PMID 23065135
    .

External links
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