Aquaporin-4

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Aquaporin-4

• A new insight in interpreting brain tumor edema

Aristotelis S. Filippidis M.D., Christos Tsonidis
M.D. Ph.D. 1Medical school, University of
Thessaly, Larissa, GREECE 2B Neurosurgical
Department, Aristoteleion University of
Thessaloniki, GREECE
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AquaporinS

• Family of more than 13 water channel proteins
• First described in 1991 as aquaporin -1 (AQP1)
• Nobel prize in Chemistry 2003 (Peter Agre)
• Aquaporin-4 (AQP4) is the dominant form in brain

Agre et al. Towards a molecular understanding of
water homeostasis in the brain. Neuroscience
(2004) vol. 129 (4) pp. 849-50
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AqP-4 Localization

• Astrocyte foot processes around capillaries that
  form Blood-Brain-Barrier (BBB)
• Glia limitans
• Ependymal cells
• Supraoptic and suprachiasmatic nuclei of
  hypothalamus
• Cerebellum
• Hippocampal dentate gyrus,
• Hippocampal areas CA1-CA2
• Neocortex
• Nucleus of stria terminalis
• Medial habenular nucleus

Badaut et al. Aquaporins in brain distribution,
physiology, and pathophysiology. J Cereb Blood
Flow Metab (2002) vol. 22 (4) pp. 367-78
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AqP-4 study models

• AQP4 knockout mouse
• Xenopus laevis oocyte-swelling assays
• Neuromyelitis optica
• (autoantibodies against AQP4 formed in human
  patients possibly related to the disease)

Jarius et al. Mechanisms of disease
aquaporin-4 antibodies in neuromyelitis optica.
Nature clinical practice Neurology (2008) vol. 4
(4) pp. 202-14 Saadoun and Papadopoulos.
Aquaporin-4 in brain and spinal cord oedema.
Neuroscience (2009) pp. Tait et al. Water
movements in the brain role of aquaporins.
Trends Neurosci (2008) vol. 31 (1) pp. 37-43
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Brain edema types (revised Klatzo classification)
CYTOTOXIC
HYDROCEPHALIC
VASOGENIC
Klatzo. Evolution of brain edema concepts. Acta
neurochirurgica Supplementum (1994) vol. 60 pp.
3-6
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Elimination routes of Brain edema
Blood-Brain-Barrier
AQP4
Endothelial Cell
H2O
Astrocyte foot process
Tight junction
H2O
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Elimination routes of Brain edema Ependyma
CSF in the 3rd ventricle
GLIA LIMITANS
Ependyma cell
GLIA LIMITANS
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Elimination routes of Brain edemaGlia limitans
subarachnoid space
NOT an established route BUT indirect evidence
exists
Tait et al. Water movements in the brain role
of aquaporins. Trends Neurosci (2008) vol. 31
(1) pp. 37-43
ARACHNOID
Reulen et al. Role of pressure gradients and
bulk flow in dynamics of vasogenic brain edema.
J Neurosurg (1977) vol. 46 (1) pp. 24-35
Subarachnoid space
Rekate et al. The importance of the cortical
subarachnoid space in understanding
hydrocephalus. Journal of Neurosurgery
Pediatrics (2008) vol. 2 (1) pp. 1-11
Filippidis et al. Transmembrane resistance and
histology of isolated sheep leptomeninges.
Neurol Res (2009) pp.
Filippidis et al. Ouabain increases transmembrane
resistance of isolated sheep leptomeninges. Mol.
Biol. Cell 19 (suppl), abstract 1354/B569.(2008)
(CD-ROM)
GLIA LIMITANS
H2O
PIA
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Brain tumor edema characteristics

• Disruption of Blood-Brain-Barrier
• High protein content in the interstitial cellular
  space
• Fluid accumulation in interstitial space
• Expansion of interstitial space
• Post contrast CTs and MRIs enhance at the site of
  edema

Klatzo. Evolution of brain edema concepts. Acta
neurochirurgica Supplementum (1994) vol. 60 pp.
3-6
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Vasogenic Edema brain tumors
Endothelial Cell
Klatzo. Evolution of brain edema concepts. Acta
neurochirurgica Supplementum (1994) vol. 60 pp.
3-6
H2O
Protein
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• So Brain tumors present with VASOGENIC edema

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AQP4 and vasogenic edema

• Loss of AQP4 expression deteriorates vasogenic
  edema in AQP4 knockout mice
• Role in homeostasis is suggested
• Probably VASOGENIC edema is eliminated via an
  AQP4 route

Papadopoulos et al. Aquaporin-4 facilitates
reabsorption of excess fluid in vasogenic brain
edema. FASEB J (2004) vol. 18 (11) pp. 1291-3
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AQP4 and brain tumors

• UPREGULATED in low and high grade astrocytomas
• UPREGULATED in edematous meningiomas
• UPREGULATED in metastatic adenocarcinomas in brain

Papadopoulos et al. Aquaporin-4 facilitates
reabsorption of excess fluid in vasogenic brain
edema. FASEB J (2004) vol. 18 (11) pp. 1291-3
Saadoun et al. Aquaporin-4 expression is
increased in oedematous human brain tumours. J
Neurol Neurosurg Psychiatr (2002) vol. 72 (2) pp.
262-5
Ng et al. Aquaporin-4 expression is increased in
edematous meningiomas. Journal of clinical
neuroscience(2009) pp.
Sawada et al. Expression of aquaporine-4 in
central nervous system tumors. Brain tumor
pathology (2007) vol. 24 (2) pp. 81-4
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AQP4 and brain tumors - Theories

• Role of edema scavanger which is upregulated is
  suggested in order to aid the increased demand of
  brain fluid elimination and maintain homeostasis
• Role of edema inducer that is upregulated and
  aggravates vascular peritumoral brain edema

Papadopoulos et al. Aquaporin-4 facilitates
reabsorption of excess fluid in vasogenic brain
edema. FASEB J (2004) vol. 18 (11) pp. 1291-3
Saadoun et al. Aquaporin-4 expression is
increased in oedematous human brain tumours. J
Neurol Neurosurg Psychiatr (2002) vol. 72 (2) pp.
262-5
Ng et al. Aquaporin-4 expression is increased in
edematous meningiomas. Journal of clinical
neuroscience(2009) pp.
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AQP4 and brain tumors - FUTURE

• For decades neurosurgeons utilize steroids for
  brain tumor edema treatment
• Research on AQP-4 modulators a new era for
  regulating brain tumor edema ???
• Research is quite difficult cause current AQP4
  behavior modulation compounds are highly toxic
  (AgNO3, sulfadiazine)

Niemietz and Tyerman. New potent inhibitors of
aquaporins silver and gold compounds inhibit
aquaporins of plant and human origin. FEBS Lett
(2002) vol. 531 (3) pp. 443-7
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We thank you all for your attention
Merry Christmas and a happy peaceful year from
GREECE