mechanism of ischemic brain damage

7/30/2019 mechanism of ischemic brain damage

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Mechanisms of IschemicBrain Damage

Jenn Mejilla


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2 Hypothesis of Brain Ischemia

Calcium Hypothesis

Excitotoxic Hypothesis


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Calcium Hypothesis

Massive Ca+2 entry into cells leads to cell

death

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.


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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.


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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)


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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.


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Ca+2 entry via NMDA receptors has special pathophysiologic significanc

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.


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Excitotoxic Hypothesis

Described in 1981 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 ofcalcium caused a delayed type of damage.


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It is now clear that a single Ca+2 exposure

can lead to secondary compromise of

Ca+2, suggesting a delayed failure ofcalcium regulation.


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Glutamate and Calcium Triggered

Events

Enhanced Lipolysis

Altered Phosphorylation of Proteins

Enhanced production of reactive oxygen

and reactive nitrogen species.


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Enhanced LipolysisIschemia 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 FFAsand lysophospholipids.

FFAs and lysophospholipids are mediators of

membrane dysfunction b/c they make act as

ionophores and uncoupling agents.


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Once reperfusion is initiated, the oxidative meta-

bolism of arachidonic acid accumulated during the

ischemia leads to the formation of

cyclooxygenase and lipooxygenase products-active in triggering inflammatory responses.


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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 harmfuleffects.


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Production of ROS and NOS

Ischemia with reperfusion leads to the

production of ROS . These free radicals giverise to lipid peroxidation, protein oxidation and

DNA damage.

Oxygen radicals and NO, together, exert toxicity

NO has important role in brain ischemia.3 types

n-NOS and e-NOS (calcium dependent and constitutively

expressed)

i-NOS (expressed by activated macrophages and neutrophils)


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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 calcium-

Dependent n-NOS may be detrimental because it

Allows additional and toxic ROS to be formed.


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Dissolution of the Cytoskeleton

Increase in intracellular Ca+2 activates

proteases that break down neurofilaments andcontribute to the disassembly of microtubules.

This breakdown cause serious problems in

intracellular communication, which depends on

the integrity of the cytoskeleton as well as causedamage to the mitochondria of cells.

mechanism of ischemic brain damage

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