Transcript Mechanisms of Ischemic Brain Damage

Mechanisms of Ischemic
Brain Damage
Jenn Mejilla
2 Hypothesis of Brain Ischemia
Calcium Hypothesis
Excitotoxic Hypothesis
Calcium Hypothesis
Massive Ca+2 entry into cells leads to cell
death
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Ca+2 catalyzed the breakdown of structural
components of cells (membrane lipids and
cytoskeletal proteins).
Agonist-receptor interactions at the motor end
plate caused necrosis of the target,
innervated by cholinergic fibers.
When this general hypothesis was applied to the nervous system, it was assumed that
calcium entering dendritic cells, caused necrosis of selectively vulnerable neurons by
ischemia or hypoxia, hypoglycemic coma, and status epilepticus.
Calcium was assumed to enter cells by way of voltage-sensitive calcium channels,
which are abundant at the basal dendrites of cells with a tendency to epileptogenic
firing.
Calcium Metabolism
Presynaptic depolarization causes Ca+2
to enter the cytoplasm of the presynaptic
endings
Followed by release of glutamate. This
activates two types of ionotropic glutamate
receptors- AMPA and NMDA.
(AMPA =amino-3-hydroxy-5-methol-4-isoazole propionic acid)
(NMDA = N-methyl –D- aspartate)
•When glutamate activates the AMPA receptor, a channel is opened that
allows the passage of Na+, K+ and H+. When Na+ enters down its
electrochemical gradient, it depolarizes the membrane. This allows the influx
of Ca+2 by way of any voltage-sensitive calcium channels that may be
localized to the postsynaptic membranes of the dendrites and cell body (eg. L
and T types)
•In addition, it relieves the Mg+2 block of the NMDA gated channel, allowing
Ca+2 to enter this high-conductance, unselective cation channel.
•The excitatory event is terminated by reuptake of glutamate into presynaptic
vesicles and into glial cells.
• Ca+2 entry via NMDA receptors has special pathophysiologic significance
• NMDA receptor-gated channel has a high calcium conductance
• The channels or calcium ions they conduct are in contact with cell
structures that are vulnerable to the increase in intracellular Ca+2.
1. When Ca+2 ions enter cells by way of NMDA receptor-gated
channels, they are more prone to trigger the production of ROS
, reactive oxygen species, such as H2O2, O2-, OH.
2. Postynaptic calcium influx stimulates neuronal NO synthase, allowing
for the simultaneous appearance of O2- and NO in postsynaptic
structures.
Excitotoxic Hypothesis
Described in 1981
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Excitatory amino acid-related toxicity led to
neuronal cell death in tissue slices or primary
neuronal cell cultures.
It was initially argued that glutamate activation
of AMPA receptors leads to an influx of Na+,
Cl- and water- which causes osmolytic cell
damage.
Later, results showed that the osmolytic
damage was reversible, but the influx of
calcium caused a delayed type of damage.
It is now clear that a single Ca+2 exposure
can lead to secondary compromise of
Ca+2, suggesting a delayed failure of
calcium regulation.
Glutamate and Calcium Triggered
Events
Enhanced Lipolysis
Altered Phosphorylation of Proteins
Enhanced production of reactive oxygen
and reactive nitrogen species.
Enhanced Lipolysis
Ischemia leads to lipolysis because ATP and
cytidine triphosphate are no longer present to
catalyze the resynthesis of phospholipids, once
they are broken down, and because calcium
activates enzymes, degrading phospholipids to
biologically active compounds such as FFA’s
and lysophospholipids.
FFA’s and lysophospholipids are mediators of
membrane dysfunction b/c they make act as
ionophores and uncoupling agents.
Once reperfusion is initiated, the oxidative metabolism of arachidonic acid accumulated during the
ischemia leads to the formation of
cyclooxygenase and lipooxygenase productsactive in triggering inflammatory responses.
Altered Phosphorylation of Proteins
Ca+2 is an important modulator of the
phosphorylation state of many proteins. When
proteins are phosphorylated and
dephosphorylated, their functions are altered.
So, when calcium concentration is
transient,particularly when Ca+2 is excessive
and sustained, membrane function and
metabolic activities alteration can cause harmful
effects.
Production of ROS and NOS
Ischemia with reperfusion leads to the
production of ROS . These free radicals give
rise to lipid peroxidation, protein oxidation and
DNA damage.
Oxygen radicals and NO, together, exert toxicity
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NO has important role in brain ischemia.
3 types
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n-NOS and e-NOS (calcium dependent and constitutively
expressed)
i-NOS (expressed by activated macrophages and neutrophils)
Neuronal NOS is involved in synaptic signalling;
however, under ischemic conditions, it mediates cell
death.
The same is true for i-NOS.
Therefore, the production of NO by the calciumDependent n-NOS may be detrimental because it
Allows additional and toxic ROS to be formed.
Dissolution of the Cytoskeleton
Increase in intracellular Ca+2 activates
proteases that break down neurofilaments and
contribute to the disassembly of microtubules.
This breakdown cause serious problems in
intracellular communication, which depends on
the integrity of the cytoskeleton as well as cause
damage to the mitochondria of cells.