Brain edema23

MOLECULAR PATHOBIOLOGY OF
BRAIN EDEMA IN NEUROLOGICAL
INJURY
ADVANCED CRITICAL CARE PHYSIOLOGY CLASSES, TUMS
Reza Nejat, M.D.
Anesthesiologist, FCCM
former-Assistant Professor, SBMU

Pathobiology of Brain Edema
 Cerebral ischemia/reperfusion and
traumatic injuries result in:
 sequences of metabolic impairment,
 energy failure
 mediator interactions such as glutamate
release and glutamate receptor
activation
Advanced Critical Care Physiology Classes

 Mediator interactions such as glutamate
release and glutamate receptor activation:
 excitotoxicity,
 elevated intracellular calcium concentration,
 mitochondrial dysfunction,
 intracellular chaotically enzymatic interactions,
 free radical production,
 chaotic intrinsic nitric oxide production,
 activation of apoptosis cascade,
 inflammatory reactions.

Cerebral edema:
a clinicopathological state
characterised by an increase in brain
water content (> 80%)

 Four Fluid Compartments:
 Brain-blood (cerebral vessels),
 Cerebrospinal fluid (CSF)
(ventricular system),
 Interstitial fluid (brain parenchyma)
 Intracellular fluid (neurons and glial
 cells)

Cerebral Edema:
Vasogenic
Cytotoxic/ionic/cellular
Interstitial/hydrocephalic
Osmotic/hypostatic
Hydrostatic

Cerebral Edema:
Vasogenic: (the most common form)
primarily due to the breakdown of
BBB secondary to
mechanical disruption:
brain trauma, acute malignant hypertension,
radiation
chemical mediators:
tumours, inflammation and infection

Cerebral Edema:
Cytotoxic/ionic/cellular:
BBB intact
Cellular Energy Failure
Disrupted Ionic Pumps
Anaerobic metabolism
GNT

Cerebral Edema:
Interstitial/hydrocephalic:
Intraventricular pressure increases:
breakdown of ventricular ependymal
lining
transependymal migration of CSF into
extracellular space

Cerebral Edema:
Osmotic/hypostatic:
 Imbalance of osmolality between serum
plasma and brain parenchyma
 Salt intoxication
 Water intoxication
 cellular and BBB integrity is maintained
 SIADH, TBI with hypo-osmolal serum

Cerebral Edema:
Hydrostatic:
Arterial pressure exceeds the upper limit
of autoregulation
There is venous congestion (head-down
position, pressure on the jugular veins,
high intrathoracic pressure).

 BBB consists of endothelial cells, TJ,
basement membrane and foot processes
of astrocytes.
 BBB to fulfill its function normally:
 “neurovascular unit” should act in concert:
 cerebral microvasculature endothelial cells,
 neurons,
 extracellular matrix,
 astrocytes and pericytes

 Lipophilic molecules pass through BBB
easily
 Ions and small molecules like glucose and
amino acids are transported through
specific channels and carriers
 Large molecules such as peptides and
proteins are conducted via:
 Endocytosis
 transcytosis
 hiring caveolae and clathrin-coated microvesicles

 Integrity of BBB:
 Depends on the tight junctions (TJ)
located between the endothelial cells of
brain capillaries.

 Astrocytes and pericytes induce
endothelial cells to form the tight
junctions

During BBB injury:
Initially, an increase in caveolae
Later, tight junction breakdown
Finally, endothelial cell injury
 Caveolae:
plasmalemmal vesicles which allow protein
passage through fluid-phase transcytosis or
transendothelial channels

 Brain injuries exacerbate the
leakiness of BBB:
 raising paracellular diffusion through
degraded TJs,
 increasing formation and mobilization
caveolae
 boosting transcytosis

 BBB malfunction follows a biphasic
temporal course:
 an early phase of high permeability
 a more prolonged delayed phase of
leakiness.

 Disintegration of BBB:
 inflammatory mediators,
 reactive oxygen species (ROS),
 VEGF,
 matrix metalloproteinases (MMPs)
 microRNAs

 BBB injury results in:
Activation of glial cells
Production of various mediators:
 bradykinin, serotonin, histamine,
complement, arachidonic acid, NO and
leucotrienes
The movement of protein rich exudates
into extracellular space
 White matter is more affected

 Cerebral blood flow<20ᶜᶜ/min/100g results in:
 Disturbance of Na⁺-K⁺-ATPase pump
 Inward flow of Na⁺↑
 ↑Inward flow of water, H⁺, HCO3⁻, Ca⁺⁺
 Outward flow of K⁺↑

ASTROCYTES

 Astrocytes are highly branched cells:
 Juxtaposed to the soma, dendrites and axons of neurons,
the plasma membrane of microglial cells,
oligodendrocytes, and other astrocytes,
 can potentially influence and be influenced by a large
number of cells, synapses, and vascular structures
 harbor virtually all of the constitutive metabolic enzymes,
especially glutamine synthetase and pyruvate carboxylase
 Involved in the metabolism of glucose, ammonia, and
glutamate

 Astrocytes:
 take up, metabolize neurotransmitters,
 buffer changes in ECF ion concentration,
 serve as intermediates in the cross talk
between neurons and blood vessels
 Express iGluRs and mGluRs
 Express 𝑲𝑲⁺𝑪𝑪𝑪𝑪⁺⁺ channels

 Astrocytes; pivotal role in:
 Axonal Growth
 Energy Metabolism
 Neurotransmitter Homeostasis
 Water/Electrolyte Balance
 Immune Response

 Astrocytes are highly branched cells:
 Rich in receptors of neurotransmitters, growth
factors, cytokines, and chemokines, transporters
for numerous molecules:
 K⁺, water, glutamate, glutamine, glucose, ketone
bodies and lactate,
 can change (transform) their phenotype and
proliferate in response to certain (usually
damaging) conditions.

 𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮 + 𝑵𝑵𝑵𝑵𝟑𝟑 + 𝑨𝑨𝑨𝑨𝑨𝑨 = 𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮𝑮 𝑮𝑮𝑮𝑮 + 𝑨𝑨𝑨𝑨𝑨𝑨 + 𝑷𝑷𝒊𝒊
 rapid metabolism of IC glutamate is a
prerequisite for efficient glutamate clearance
from the extracellular space
 Elevated concentrations of EC glutamate and
glutamate analogues in the brain can lead to
hyperexcitability, seizures and neuronal death

During normal and
abnormal neuronal
activity, there is
cotransport of 3Na+,
1Cl−, 1H+ and
antiport 1K+ ion per
glutamate molecule
along with
water molecule.

 GNT
 During ischaemia/hypoxia, energy dependent
pathways fail and glutamate accumulates to toxic
levels and abnormal surge of neuronal activity
happens through activation of :
 N-methyl-D-aspartate (NMDA) R,
 AMPA R,
 mGlu R
 Kinate R

 GNT
 NMDA (N-methyl D-aspartic acid) Receptor
 Non-NMDA Receptor
 AMPA Receptor
 Kianate Receptor
 mGluR
 Na⁺ and Cl⁻ influx resulting in Ca⁺⁺ influx
 NMDA receptor-mediated K⁺ efflux

 GNT
 Na⁺ and Cl⁻ influx resulting in Ca⁺⁺ influx
 Ca⁺⁺ influx & ROS generation (oxidative stress)
 Ca⁺⁺ dependent conversion of XDH to XOD
 Allowing H₂O₂ and O₂⁻• production
 Ca⁺⁺ activated PLA₂ and NOS
 NMDA receptor-mediated K⁺ efflux resulting in
neuronal apoptosis

 GNT
 ROS production due to NMDA activation
 Uncoupling of MTC
 Leakage of electron from respiratory chain in
MTC
 Arachidonic acid metabolism by oxidases
 Inactivation of PFK, LDH, CPKinas
 Depletion of anti-oxidant capacity of the cell

The time course of ROS production
in GNT:
 Early phase (up to 30 min)
 Later phase (3-24 h)

 Early Phase:
 Glutamate binding to receptor;
 Calcium influx in cytosol;
 XDH→XOD conversion;
 ROS production;
 ROS-induced cyt c release;
 Cyt c as ROS scavenger;
 Cyt c as electron donor;
 Cyt c-dependent energy generation.

 Late Phase:
 Glucose uptake increase;
 Increase in lactate production via
glycolysis;
 Mitochondrial shuttle impairment;
 NADH oxidation via mitochondrial
 NADH-b5-oxidoreductase;
 Massive ROS production by mitochondria;
 Mitochondrial permeability transition.

 Hypoxia/Ischemia:
 Increases transcription of hypoxia-inducible
factor 1 (HIF-1) gene.
 HIF-1, activates hypoxia-responsive element
(HRE) in the genome,
 HRE, a transcription factor regulates the
transcription of:
 multiple genes encoding EPO, vascular
endothelial growth factor (VEGF) and platelet
derived growth factor,
 over 100 other HIF responsive genes including
those involved in cell metabolism encouraging
anaerobic production of ATP, in addition to cell,
survival, proliferation and migration and
vasodilation.

 HIF-1α dependent signaling pathways
might also be a source of
neuroinflammation/apoptosis and
hence BBB dysfunction.
 HIF-1α in hypoxic brain insult
increases expression of VEGF,
VEGFR, MMP-9 and AQP-4
 Astrocytes and pericytes produce
VEGF and MMPs

 MMPs:
 belong to a 25-member family of zinc-
dependent endopeptidases
 secreted in an inactive form in
untraceable or in a very delicately
controlled low concentration in the
adult healthy brain.
 contribute to degrading the extra-
cellular matrix (ECM).

 MMPs:
 several significant physiological
potentials involved in:
 growth,
 development,
 tissue repair and wound healing
 synaptic plasticity
 neurite growth
 myelinogenesis.

 MMPs:
 up-regulated and activated in ischemic
and other brain injuries,
 Its latent form is activated by:
 Endogenous and exogenous plasminogen
activator
 Furin
 free radicals

 AQP-4
 integral membrane proteins
which play important roles in
mediating water homeostasis and
bidirectional passive trans-
cellular water transfer in
response to osmotic gradient.
 the expression of this channel is
modulated by HIF-1 and VEGF

 AQPs in the CNS contribute to:
 Glymphatic (Glial Lymphatic) pathway:
 couples cerebrospinal fluid (CSF) influx
to interstitial spinal fluid (ISF) efflux
 through convective bulk flow from peri-
arterial to peri-venous spaces (Virchow-
Robin spaces) in microvasculature of the
brain

 AQPs are involved in:
 potassium buffering,
 waste material clearance,
 neuroinflammation,
 osmosensation,
 astroglial cell migration,
 Ca signaling,
 neural signal transduction,
 long-term plasticity,
 spatial memory,
 cell adhesion,
 regulating cerebral edema

AQP-4
expression has
an impact on
BBB integrity
*Cytotoxic
edema-induced
vasogenic
edema

 Vascular endothelial cell growth
factors (VEGF), a family of cytokines,
induce angiogenesis through
proliferation, sprouting, migration of
the endothelial cells and new tube
formation by these cells.
 Found in pericytes in the border of
brain lesions
 After binding withVEGFR-2 increases
vascular permeability through
activating cGMP and a NO-dependent
pathway

 VEGFs may be inactivated:
 when they bind with heparan sulfate
proteoglycan (HSPG) moieties of the
ECM or
 are trapped by a secreted isoform of
VEGF receptors (sVEGF-R)
 MMPs may split the bound form of
VEGF
 VEGF may be destructed by proteases
(like MMPs)

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