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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Astroc
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AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
Elimination routes of Brain edema Ependyma
CSF in the 3rd ventricle
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4 AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
AQP4AQP4
Ependyma cell
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Elimination routes of Brain edemaGlia limitans – subarachnoid space
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HH22OOPIAPIA GLIAGLIALIMITANSLIMITANS
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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ProteinProtein
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
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