A new insight in interpreting brain tumor edemaA new insight in interpreting brain tumor edema

Aristotelis S. Filippidis M.D., Christos Tsonidis M.D. Ph.D.Aristotelis S. Filippidis M.D., Christos Tsonidis M.D. Ph.D.

1Medical school, University of Thessaly, Larissa, GREECE2B’ Neurosurgical Department, Aristoteleion University of Thessaloniki, GREECE

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.Agre et al. Towards a molecular understanding of water homeostasis in the brain.

Neuroscience (2004) vol. 129 (4) pp. 849-50

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 alBadaut et al. . Aquaporins in brain: distribution, physiology, and pathophysiology. Aquaporins in brain: distribution, physiology, and pathophysiology.

J Cereb Blood Flow Metab (2002) vol. 22 (4) pp. 367-78J Cereb Blood Flow Metab (2002) vol. 22 (4) pp. 367-78

AQP4 knockout mouse Xenopus laevis oocyte-swelling assays Neuromyelitis optica (autoantibodies against AQP4 formed in human patients

possibly related to the disease)

Jarius et alJarius 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. Saadoun and Papadopoulos. Aquaporin-4 in brain and spinal cord oedema. Aquaporin-4 in brain and spinal cord oedema.

Neuroscience (2009) pp. Neuroscience (2009) pp.

Tait et al.Tait et al. Water movements in the brain: role of aquaporins. Water movements in the brain: role of aquaporins.

Trends Neurosci (2008) vol. 31 (1) pp. 37-43Trends Neurosci (2008) vol. 31 (1) pp. 37-43

Brain edema types (revised Klatzo classification)

Klatzo. Klatzo. Evolution of brain edema concepts.Evolution of brain edema concepts.

Acta neurochirurgica Supplementum Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6(1994) vol. 60 pp. 3-6

CYTOTOXIC

VASOGENIC

HYDROCEPHALIC

AQP4AQP4

Elimination routes of Brain edema Blood-Brain-Barrier

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Endothelial CellEndothelial Cell

Tight junction

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Elimination routes of Brain edema Ependyma

CSF in the 3rd ventricle

AQP4AQP4

AQP4AQP4

AQP4AQP4

AQP4AQP4

AQP4AQP4

AQP4AQP4

AQP4AQP4

AQP4AQP4 AQP4AQP4

AQP4AQP4

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Ependyma cell

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Elimination routes of Brain edemaGlia limitans – subarachnoid space

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ARACHNOIDARACHNOID

Subarachnoid space

AQP4AQP4

AQP4AQP4

NOT an established routeBUT indirect evidence exists

Filippidis et al. Transmembrane resistance and histology of isolated sheep leptomeninges. Neurol Res (2009) pp.

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

Filippidis et al.Ouabain increases transmembrane resistance of isolated sheep leptomeninges. Mol. Biol. Cell 19 (suppl), abstract #1354/B569.(2008) (CD-ROM)

Rekate et al. The importance of the cortical subarachnoid space in understanding hydrocephalus. Journal of Neurosurgery: Pediatrics (2008) vol. 2 (1) pp. 1-11

Tait et al. Water movements in the brain: role of aquaporins. Trends Neurosci (2008) vol. 31 (1) pp. 37-43

Brain tumor edema Brain tumor edema characteristicscharacteristics 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 edemaKlatzo.

Evolution of brain edema concepts. Acta neurochirurgica Supplementum

(1994) vol. 60 pp. 3-6

Vasogenic Edema – Vasogenic Edema – brain tumorsbrain tumors

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Endothelial CellEndothelial Cell

Klatzo. Evolution of brain edema concepts.

Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6

So Brain tumors present with

VASOGENIC edema

AQP4 and vasogenic edema

Loss of AQP4 expression deterioratesdeteriorates vasogenic edema in AQP4 knockout mice

Role in homeostasis is suggested

Probably VASOGENIC edema is eliminated via an AQP4 routevia 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

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

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.

AQP4 and brain tumors - FUTUREFUTURE 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

We thank you all for your attention

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